Public Health Prenatal Health
M. Anne George, Mary H. George
  • LAST REVIEWED: 02 February 2016
  • LAST MODIFIED: 26 May 2016
  • DOI: 10.1093/obo/9780199756797-0096


Maternal and fetal health covers a spectrum of topics, including maternal and fetal mortality and morbidity and their causes such as adequate health care, risks associated with environmental and lifestyle exposures, maternal stress, maternal diseases, and many other health issues. Both maternal and fetal deaths are an enormous burden. In many developing countries, a strong emphasis is placed on policy and practice initiatives to reduce maternal, fetal, and newborn mortality because complications of pregnancy and childbirth remain a leading cause of death. The World Health Organization (WHO) estimates that 1,500 women die daily due to complications in pregnancy or childbirth and that 10,000 babies are born stillborn or die in the first month of life. In these countries, malnutrition is a major contributor to women’s preventable morbidity and mortality and has considerable adverse outcomes for the developing fetus. Elsewhere in the world where maternal and fetal mortality rates are lower, long-term consequences of maternal and fetal stressors, poor nutrition, environmental or behavioral teratogens, and maternal disease are the major concern. This has led to considerable research, and development of best practice guidelines, that focus on maternal behaviors and diseases, prenatal environmental exposures, including prenatal alcohol and tobacco exposure, and treatment of preexisting conditions such as depression. Some issues, such as HIV/AIDS and nutrition, affect maternal and prenatal health throughout the world but to differing degrees.

General Overviews

Maternal health has been defined by the WHO across three periods: “Maternal health refers to the health of women during pregnancy, childbirth and the postpartum period. While motherhood is often a positive and fulfilling experience, for too many women it is associated with suffering, ill-health and even death. The major direct causes of maternal morbidity and mortality include haemorrhage, infection, high blood pressure, unsafe abortion, and obstructed labour” (WHO, Maternal Health). There are a limited number of general introductory works on the topics of maternal health and fetal development and the risks to fetal health. Sigelman and Rider 2010 describes health and risks across the life span, including fetal development and risks from maternal behaviors and environmental exposures. Gilbert and Epel 2009 similarly describes the human in relation to its environment, with fetal development being a more predominant topic than maternal health.

  • Gilbert, S. F., and D. Epel. 2009. Ecological developmental biology: Integrating epigenics, medicine and evolution. Sunderland, MA: Sinauer.

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    Ecological development biology is the study of the interaction of the organism and its environment and includes the impact on the organism of pathological environments, including nutrition and teratogens. This book has chapters relevant to fetal health on teratogenic agents, endocrine disruptors, and fetal development of adult diseases.

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    • Sigelman, C. K., and E. A. Rider. 2010. Life-span human development. 7th ed. Belmont, CA: Wadsworth.

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      Taking a life-span approach to health, this book explores development theories and has a well-documented section on prenatal development and birth. It includes summaries on human development theories, stages of fetal development, known teratogens, and perinatal environments.

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      Maternal Mortality

      Maternal mortality continues to be a major cause of death in many countries throughout the world. International organizations, such as WHO and UNICEF, have been concerned with the high rates and uneven distribution of maternal and fetal death worldwide and report annually statistics through the WHO’s World Health Statistics (World Health Organization 2015a, World Health Organization 2015b). Persistence of global health inequities leading to maternal deaths has become such a concern that the WHO’s Millennium Declaration (World Health Organization 2010) included health services to women during and after pregnancy as one of its goals. Improved antenatal health care across African countries has been found to increase the chances of birthing in health-care facilities and reduce maternal mortality (Berhan and Berhan 2014). Even within countries with low rates of maternal mortality, such as found in the United States, causes for concern are that rates are not declining and are unevenly distributed across populations, with exceptionally high rates within the African American population compared to other American women (Berg, et al. 2010).

      • Berg, C. J., W. M. Callaghan, C. Syverson, and Z. Henderson. 2010. Pregnancy-related mortality in the United States, 1998–2005. Obstetrics and Gynecology 116.6: 1302–1309.

        DOI: 10.1097/AOG.0b013e3181fdfb11Save Citation »Export Citation »E-mail Citation »

        Although pregnancy-related maternal death is low in the United States compared to developing countries, rates were found to be higher in the period 1998 to 2005 than at any time in the previous twenty-year period. Reasons for the increased death rate were not clear. The main causes of death (each contributing over 10 percent of the deaths) were hemorrhage, thrombotic pulmonary embolism, infection, hypertensive disorders of pregnancy, cardiomyopathy, cardiovascular conditions, and noncardiovascular medical conditions. Maternal deaths caused by hemorrhage and hypertensive disorders declined but those due to cardiovascular conditions increased. Maternal death rates were found to not be evenly distributed across populations, with African American women continuing to have a three- to four-fold higher risk of pregnancy-related death.

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        • Berhan, Y., and A. Berhan. 2014. Antenatal care as a means of increasing birth in the health facility and reducing maternal mortality: A systematic review. Ethiopian Journal of Health Sciences 24 (Suppl.): 93–104.

          DOI: 10.4314/ejhs.v24i0.9SSave Citation »Export Citation »E-mail Citation »

          Antenatal care and health-care delivery were shown to be negatively correlated with maternal mortality across African countries in this systematic review and meta-analysis of seventeen small-scale studies conducted over a decade (2003–2013).

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          • Say, L., D. Chou, A. Gemmill, et al. 2014. Global causes of maternal death: A WHO systematic analysis. Lancet Global Health 2.6: e323–e333.

            DOI: 10.1016/S2214-109X(14)70227-XSave Citation »Export Citation »E-mail Citation »

            The authors developed and analyzed global, regional, and subregional estimates of the causes of maternal death during 2003 to 2009, updating the previous WHO systematic review. They identified twenty-three eligible studies published from 2003 to 2012 and included 417 datasets from 115 countries. They found 73 percent of all maternal deaths worldwide were due to direct obstetric causes: hemorrhage (27.1 percent), hypertensive disorders (14.0 percent), and sepsis (10.7 percent). The remaining 27 percent were due to indirect causes: abortion, embolism, and all other causes. Regional estimates varied substantially.

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            • World Health Organization. 2010. 20 ways the World Health Organization helps countries reach the Millennium Development Goals. Geneva, Switzerland: World Health Organization.

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              The UN Millennium Declaration, adopted by 189 countries, endorses a framework to reduce poverty and hunger and to improve education, gender equality, clean water access, and environmental sustainability. One goal is to increase access to sexual and reproductive health services and “skilled care before, during and after pregnancy and childbirth.”

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              • World Health Organization. 2015a. Trends in maternal mortality: 1990 to 2015. Estimates by WHO, UNICEF, UNFPA, The World Bank and the United Nations Population Division. Geneva, Switzerland: World Health Organization.

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                Globally, the risk for maternal death declined by nearly 44 percent from 1990 to 2015, yet there were an estimated 303,000 maternal deaths in 2015. Risk remains much higher in developing regions, than in developed regions of the world, where over 99 percent of maternal deaths occur. Highest risk remains in sub-Saharan Africa, which accounted for two-thirds (201,000) and southern Asia with 22 percent (66,000) of global deaths. Women in two countries, Nigeria and India, are at particularly high risk for maternal death. This report shows trends in rates, categorized according to geography and progress being made over time, and it notes common elements for those that have been successful in meeting targets.

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                • World Health Organization. 2015b. World Health Organization statistics 2015. Geneva, Switzerland: World Health Organization.

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                  The World Health Statistics is the most comprehensive source of health statistics. Published annually since 2005, it contains comparative health data from 194 countries. It notes that nearly 800 women die every day due to complications in pregnancy and childbirth.

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                  Fetal Mortality

                  Annually, approximately 3 million babies are born stillborn or die within the first twenty-eight days of life, even after global rates fell by nearly one-third during the past two decades. The United Nations Inter-agency Group (Child Mortality Estimates) provides statistical comparisons across countries, showing that risk is higher in low- and middle-income countries. Lawn, et al. 2009 describes epidemiological evidence for this tremendous loss of life. Yakoob, et al. 2009 and Blencowe and Cousens 2013 provide overviews of challenges and inadequate interventions implemented to prevent such loss. Obstetrical causes leading to perinatal death are described in Ngoc, et al. 2006.

                  Antenatal Health Care

                  Access to prenatal care varies considerably throughout the world. According to the WHO’s Reproductive Health website, for many, inadequate access to prenatal health care is a major concern. In South American countries, where adequacy of care is population-dependent, the risk of inadequate care is associated with birth-weight outcomes (Woodhouse, et al. 2014). In contrast, women in Western countries may have opportunities for more prenatal health care than is required, according to Villar, et al. 2007, and prenatal care may have no subsequent effect on child health outcomes (Noonan, et al. 2013). In addition, it is not entirely clear if complications increase with more health care, as shown in the international study of providing looser control over hypertension during pregnancy (Magee, et al. 2015). Yet, in Western countries, women disadvantaged by having an unplanned pregnancy (Dibaba, et al. 2013), or at a young age (Allen, et al. 2012), have a greater risk of delayed or nonattendance at antenatal care.

                  • Allen, J., J. Gamble, H. Stapleton, and S. Kildea. 2012. Does the way maternity care is provided affect maternal and neonatal outcomes for young women? A review of the research literature. Women and Birth 25:54–63.

                    DOI: 10.1016/j.wombi.2011.03.002Save Citation »Export Citation »E-mail Citation »

                    Having a background of socioeconomic deprivation may be a greater risk factor than age for young pregnant women. A review of the literature found that some models of care increase antenatal visit attendance and decrease the risk of preterm birth.

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                    • Dibaba, Y., M. Fantahun, and M. J. Hindin. 2013. The effects of pregnancy intention on the use of antenatal care services: Systematic review and meta-analysis. Reproductive Health 10:50.

                      DOI: 10.1186/1742-4755-10-50Save Citation »Export Citation »E-mail Citation »

                      Delayed and inadequate antenatal care is a risk for women with untended pregnancies compared to women with intended pregnancies. Risk is evident for women in both developed and developing countries.

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                      • Magee, L. A., P. von Dadelszen, E. Rey, et al. 2015. Less-tight versus tight control of hypertension in pregnancy. New England Journal of Medicine 372.5: 407–417.

                        DOI: 10.1056/NEJMoa1404595Save Citation »Export Citation »E-mail Citation »

                        This international multicenter trial found no significant difference between pregnancy loss, high-level neonatal care, or overall maternal complications between women whose blood pressure was tightly controlled through medication and those whose blood pressure was less tightly controlled. The women whose blood pressure was less tightly controlled did have more complications within six weeks, mostly due to higher frequency of severe hypertension. The importance of this study is that maternal medication for hypertension may lead to pregnancy complications.

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                        • Noonan, K., H. Corman, O. Schwartz-Soicher, and N. E. Reichman. 2013. Effects of prenatal care on child health at age 5. Maternal and Child Health Journal 17.2: 189–199.

                          DOI: 10.1007/s10995-012-0966-2Save Citation »Export Citation »E-mail Citation »

                          Previous evidence indicates that antenatal care can improve the health of the pregnant woman, including reduced smoking. This US population-based study found that antenatal care has no effect on four markers of child health (overall health status, asthma, overweight, and height).

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                          • Reproductive health. Geneva, Switzerland: World Health Organization.

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                            The WHO states that within its definition of health is implicit “the right of access to appropriate health care services that will enable women to go safely through pregnancy and childbirth and provide couples with the best chance of having a healthy infant.” This WHO website provides fact sheets, reports on reproductive health from global regions of the world, policy documents, and publications as well as a library of current relevant literature.

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                            • Villar, J., G. Carroli, D. Khan-Neelofur, G. Piaggio, and M. Gülmezoglu. 2007. Patterns of routine antenatal care for low-risk pregnancy. Cochrane Database of Systematic Reviews 4:1–30.

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                              Women with low-risk pregnancies may require less health care, based on this review of ten randomized controlled trials (RCTs) comparing timing and frequency of prenatal visits and type of practitioner. Reducing frequency of visits had no impact on maternal or fetal health outcomes, nor did type of attending practitioners.

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                              • Woodhouse, C., J. Lopez Camelo, and G. L. Wehby. 2014. A comparative analysis of prenatal care and fetal growth in eight South American countries. PLoS One 9.3: e91292.

                                DOI: 10.1371/journal.pone.0091292Save Citation »Export Citation »E-mail Citation »

                                Antenatal care was found to be significantly positively associated with birthweight and negatively associated with low birthweight in all eight South American countries studied. Variation between countries indicates that estimates are population based and not generalizable to other populations. Trends show a decreased association in recent years. Antenatal care is highly variable across these countries.

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                                Adequate nutrition is required for maternal and fetal health. Research has focused on the specific nutrients required for good health and the consequences of nutrient deficiencies for either mother or fetus. Much research has focused on the benefits of vitamin D, iron, and folic acid, all of which appear to result in increased birthweight. Black, et al. 2008; Hollis and Wagner 2004; and Ramakrishnan, et al. 1999 each describes the importance of maternal nutritional status before and during pregnancy for both general maternal well-being but also for healthy pregnancy outcomes, and each paper describes the risks associated with specific nutrient deficiencies. Vitamins and minerals important to maternal and fetal well-being are iron (Allen 2000), vitamin D (Thorne-Lyman and Fawzi 2012 and Salle, et al. 2000), and folate (Fekete, et al. 2012). New areas of research include supplementation of multiple micronutrients (Ramakrishnan, et al. 2012) and fatty acid intake (Imhoff-Kunsch, et al. 2012). Nutritional status of specific populations, such as pregnant adolescents, can be a health risk, as noted in Lenders, et al. 2000. Merialdi, et al. 2003 reviews nutritional interventions to prevent fetal growth retardation. Christian and Stewart 2010 takes a different approach by reviewing the specific implications of nutrients and the long-term consequences of nutritional interventions with respect to preventing chronic illnesses. A relatively new area of study is fetal programming, with the fetal origins hypothesis positing that the fetus develops according to what he or she “learns” during fetal development, as described in Rasmussen 2001; Gicquel, et al. 2008; and Guilloteau, et al. 2009. Many authors emphasize the need for further research, particularly because so many studies included in systematic reviews and meta-analyses are decades old.

                                • Allen, L. H. 2000. Anemia and iron deficiency: Effects on pregnancy outcome. American Journal of Clinical Nutrition 71.5: 1280S–1284S.

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                                  This article reviews current knowledge of the effects of maternal anemia and iron deficiency on pregnancy outcomes, showing the link between iron deficiency anemia and preterm delivery and low birthweight, and possibly inferior neonatal health. Data are inadequate to determine the contribution of maternal anemia to maternal mortality. Iron deficiency leads to anemia, which is particularly problematic because of the high rate of iron deficiency worldwide that develops before or during pregnancy.

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                                  • Black, R. E., L. H. Allen, Z. A. Bhutta, et al. 2008. Maternal and child undernutrition: Global and regional exposures and health consequences. Lancet 371.9608: 243–260.

                                    DOI: 10.1016/S0140-6736(07)61690-0Save Citation »Export Citation »E-mail Citation »

                                    Short maternal stature and iron deficiency anemia increase the risk of maternal death at delivery, accounting for approximately 20 percent of maternal mortality. This article describes the importance of nutrition for maternal outcomes and for young children. Available online with free registration.

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                                    • Christian, P., and C. P. Stewart. 2010. Maternal micronutrient deficiency, fetal development, and the risk of chronic disease. Journal of Nutrition 140.3: 437–445.

                                      DOI: 10.3945/jn.109.116327Save Citation »Export Citation »E-mail Citation »

                                      While micronutrient deficiency has well-documented implications for fetal growth, this review examines micronutrient implications for metabolism, vasculature, and organ growth and function, leading to increased risk of chronic diseases such as type 2 diabetes and cardiovascular diseases. The review includes animal and human studies, limited intervention studies, and plausible mechanisms. Where data are lacking, the review suggests pathways derived from existing animal and human models.

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                                      • Fekete, K., C. Berti, M. Trovato, et al. 2012. Effect of folate intake on health outcomes in pregnancy: A systematic review and meta-analysis on birth weight, placental weight and length of gestation. Nutrition Journal 11.1: 75–83.

                                        DOI: 10.1186/1475-2891-11-75Save Citation »Export Citation »E-mail Citation »

                                        In this systematic review and meta-analysis, the authors include RCTs measuring the relationship between doses of folate supplementation and birthweight, placental weight, and gestational length. Findings confirm that, after the first trimester, there is a dose-related relationship between greater folate intake and higher birthweight. There is no confirmed relationship, however, between folate supplementation and placental weight or gestational length. The authors outline limitations in the analysis because the included studies are over thirty years old and have a high risk of bias related to the research standards of the time.

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                                        • Gicquel, C., A. El-Osta, and Y. Le Bouc. 2008. Epigenetic regulation and fetal programming. Best Practice & Research Clinical Endocrinology & Metabolism 22.1: 1–16.

                                          DOI: 10.1016/j.beem.2007.07.009Save Citation »Export Citation »E-mail Citation »

                                          Fetal programming examines the potentially adverse consequences of developmental plasticity in response to fetal environmental and nutritional signals, leading to adverse effects independent of effects on fetal growth, which is contrary to early studies. Adverse consequences reflect a mismatch between fetal and neonatal environments and subsequent challenges, with the mechanism still unclear.

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                                          • Guilloteau, P., R. Zabielski, H. M. Hammon, and C. C. Metges. 2009. Adverse effects of nutritional programming during prenatal and early postnatal life, some aspects of regulation and potential prevention and treatments. Journal of Physiology and Pharmacology 60 (Suppl. 3): 17–35.

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                                            This review focuses on nutritional imprinting regulation on hormonal and epigenetic mechanisms. Human models may be questioned for their validity. The hypothalamic–pituitary–adrenal (HPA) axis and GH–IGF axis may have a crucial role in the regulation induced by nutritional programming and be a consequence of elevated insulin levels during critical developmental periods.

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                                            • Hollis, B. W., and C. L. Wagner. 2004. Assessment of dietary vitamin D requirements during pregnancy and lactation. American Journal of Clinical Nutrition 79:717–726.

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                                              Concerns about vitamin D have resurfaced in the medical and scientific literature because the prevalence of vitamin D deficiency in the United States. This review discusses past and current literature, assessing dietary needs in adults, with particular focus on women during pregnancy and lactation.

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                                              • Imhoff-Kunsch, B., V. Briggs, T. Goldenberg, and U. Ramakrishnan. 2012. Effect of n-3 long-chain polyunsaturated fatty acid intake during pregnancy on maternal, infant, and child health outcomes: A systematic review. Paediatric and Perinatal Epidemiology 26 (Suppl. 1): 91–107.

                                                DOI: 10.1111/j.1365-3016.2012.01292.xSave Citation »Export Citation »E-mail Citation »

                                                The goal of this systematic review and meta-analysis was to confirm findings of previous observational studies that identify a relationship between marine foods and positive pregnancy and birth outcomes. Marine-food consumption is positively related to increased birthweight and negatively related to risk of preterm delivery. Reported disruptions to the relationship may include the type to seafood consumed, duration of consumption, and period during the pregnancy. The authors do not identify a relationship between marine-food consumption and maternal blood pressure, preeclampsia, gestation duration, birth length, infant head circumference, small-for-gestational age, still birth, and/or infant death.

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                                                • Lenders, C. M., T. F. McElrath, and T. O. Scholl. 2000. Nutrition in adolescent pregnancy. Current Opinion in Pediatrics 12.3: 291–296.

                                                  DOI: 10.1097/00008480-200006000-00021Save Citation »Export Citation »E-mail Citation »

                                                  The importance of adequate nutrition during pregnancy is reviewed from a pediatric perspective. Pregnancy, particularly during adolescence, is a time of extreme nutritional risk. The adolescents most likely to become pregnant are often those with inadequate nutritional status and unfavorable socioeconomic background. Available online for purchase or by subscription.

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                                                  • Merialdi, M., G. Carroli, J. Villar, et al. 2003. Nutritional interventions during pregnancy for the prevention of treatment of impaired fetal growth: An overview of randomized controlled trials. Journal of Nutrition 133.5: 1626S–1631S.

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                                                    This paper reviews the efficacy of nutrition interventions to prevent or treat fetal growth retardation. Protein energy supplementation reduces the risk of being small for gestational age, although one trial reported a negative effect. Calcium protects against low birthweight. Micronutrient supplements, except for magnesium, do not affect birthweight.

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                                                    • Ramakrishnan, U., F. K. Grant, T. Goldenberg, V. Bui, A. Imdad, and Z. A. Bhutta. 2012. Effect of multiple micronutrient supplementation on pregnancy and infant outcomes: A systematic review. Paediatric and Perinatal Epidemiology 26 (Suppl. 1): 153–167.

                                                      DOI: 10.1111/j.1365-3016.2012.01276.xSave Citation »Export Citation »E-mail Citation »

                                                      This meta-analysis systematically reviews sixteen RCTs to assess whether supplementation with multiple micronutrients contributes to improved pregnancy and fetal outcomes. In comparison to supplementation with iron and folic acid, multiple micronutrients contribute to higher infant birthweight and increased gestational age. Supplementation with multiple micronutrients has no effect on risk of preterm birth, stillbirth, or neonatal death.

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                                                      • Ramakrishnan, U., R. Manjrekar, J. Rivera, T. Gonzáles-Cossío, and R. Martorell. 1999. Micronutrients and pregnancy outcome: A review of the literature. Nutrition Research 19.1: 103–159.

                                                        DOI: 10.1016/S0271-5317(98)00178-XSave Citation »Export Citation »E-mail Citation »

                                                        This review draws conclusions regarding birth outcomes and maternal mortality resulting from deficiencies of various nutrients: copper, selenium zinc, calcium and magnesium, folic acid, iodine, Vitamin A, Vitamin C, and B-complex vitamins. Evidence is insufficient regarding interactions among micronutrients at the metabolic level and regarding pregnancy outcomes. Available online for purchase or by subscription.

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                                                        • Rasmussen, K. M. 2001. The “fetal origins” hypothesis: Challenges and opportunities for maternal and child nutrition. Annual Review of Nutrition 21:73–95.

                                                          DOI: 10.1146/annurev.nutr.21.1.73Save Citation »Export Citation »E-mail Citation »

                                                          The fetal origins hypothesis postulates that conditions, most likely nutritional, “program” the fetus for the development of chronic diseases in adulthood. Associations between birthweight and various determinants or consequences of chronic diseases have been identified in many, but not all, of the available studies. Available online for purchase or by subscription.

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                                                          • Salle, B. L., E. E. Delvin, A. Lapillonne, N. J. Bishop, and F. H. Glorieux. 2000. Perinatal metabolism of vitamin D. American Journal of Clinical Nutrition 71.5: 1317S–1324S.

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                                                            Vitamin D has been well described as an important mineral for fetal well-being. This article reviews the literature on metabolism of vitamin D, the source of vitamin D for the fetus, and dependence on maternal sources for the fetus. The authors conclude that in countries where vitamin D sources are low, because of little sunshine exposure or lack of supplemental sources in dairy products, vitamin D should be administered at the end of pregnancies.

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                                                            • Thorne-Lyman, A., and W. W. Fawzi. 2012. Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: A systematic review and meta-analysis. Paediatric and Perinatal Epidemiology 26 (Suppl. 1): 75–90.

                                                              DOI: 10.1111/j.1365-3016.2012.01283.xSave Citation »Export Citation »E-mail Citation »

                                                              This systematic review and meta-analysis includes intervention and observational studies assessing the effects of vitamin D supplementation during pregnancy. The authors’ analysis of the five randomized trials indicate vitamin D protects against low birthweight and possibly small-for-gestational age, although the latter was nonsignificant. No effects are identified for preterm delivery.

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                                                              Improved understanding of the human genome has led to the field of epigenetics and a description of fetal reprogramming. Although some evidence has developed over decades, recent identification of epigenic marks and subsequent monitoring has led to improved understanding. Each individual’s human cells have the same DNA, but different patterns of active (or expressed) and inactive genes are found in each cell type. Programming during early development establishes those patterns, with epigenetic changes occurring because of diet, exposures to various toxins, or other lifestyle factors. The Development of Origins of Health and Disease hypothesizes that in utero or postnatally, adaptations to environmental exposures cause changes that have health implications later in life. The epigenome refers to heritable, environmentally responsive elements that regulate gene expression without altering DNA. Epigenetic mechanisms mediate gene expression in later life, leading to health consequences, including metabolic diseases (Rinaudo and Wang 2010) or cardiovascular disease (Santos and Joles 2012, Kelishadi and Poursafa 2014). Well known human epidemiological studies used data from natural population-based experiments, such as acute exposure to famine, illnesses, or chemicals (Boekelheide, et al. 2012; Lumey, et al. 2011), to examine outcomes later in adulthood. Insights come from birth studies with researchers viewing life stages and integrating animal models and epidemiological studies. This area of research has also revealed positive outcomes of fetal reprogramming (Santos and Joles 2012). Hogg, et al. 2012 characterizes nutritional, glucocorticoid, and chemical exposures and their potential association with epigenetic changes in the fetus and placenta.

                                                              • Boekelheide, K., B. Blumberg, R. E. Chapin, et al. 2012. Predicting later-life outcomes of early-life exposures. Environmental Health Perspectives 120.10: 1353–1361.

                                                                DOI: 10.1289/ehp.1204934Save Citation »Export Citation »E-mail Citation »

                                                                In utero exposure to stressors can lead to adult diseases. This review article presents a good overview of the literature on well-studied stressors (illnesses, famine, chemicals) and provides suggestions on the development of public health protective practices.

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                                                                • Hogg, K., E. M. Price, C. W. Hanna, and P. Robinson. 2012. Prenatal and perinatal environmental influences on the human fetal and placental epigenome. Clinical Pharmacology & Therapeutics 92.6: 716–726.

                                                                  DOI: 10.1038/clpt.2012.141Save Citation »Export Citation »E-mail Citation »

                                                                  This review examines three types of exposures (nutritional, glucocorticoid, and endocrine-disrupting chemicals) and their potential association with epigenetic changes in the fetus and the placenta, a key mediator of the in utero environment. Characterizing epigenetic alterations may provide insight into mechanisms affecting health, since there are few human studies that directly link exposures and reprogramming to subsequent health status. Drug, hormonal, and nutritional exposures in pregnancy can cause birth defects through epigenetic developmental programming.

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                                                                  • Kelishadi, R., and P. Poursafa. 2014. A review on the genetic, environmental and lifestyle aspects of early origins of cardiovascular disease. Current Problems in Pediatrics and Adolescent Health Care 44:54–72.

                                                                    DOI: 10.1016/j.cppeds.2013.12.005Save Citation »Export Citation »E-mail Citation »

                                                                    This comprehensive review of the developmental origins of health and disease presents the literature on the associations between cardiovascular disease and prenatal risks, including fetal programming and maternal weight status and gain during pregnancy.

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                                                                    • Lumey, L. H., A. D. Stein, and E. Susser. 2011. Prenatal famine and adult health. Annual Review of Public Health 32:237–262.

                                                                      DOI: 10.1146/annurev-publhealth-031210-101230Save Citation »Export Citation »E-mail Citation »

                                                                      Human studies literature on the association between acute prenatal famine and adult physical and mental health is included in this comprehensive study of documented famines throughout the world, starting with such exposure in Sweden and Finland throughout the 1800s to recent exposure up to 2000 in Bangladesh. The studies consistently show prenatal famine is associated with adult body size, diabetes, and schizophrenia.

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                                                                      • Rinaudo, P., and E. Wang. 2010. Fetal programming and metabolic syndrome. Annual Review of Physiology 74:107–130.

                                                                        DOI: 10.1146/annurev-physiol-020911-153245Save Citation »Export Citation »E-mail Citation »

                                                                        This article reviews the animal model studies on fetal reprogramming due to prenatal stress. It notes the possible contribution of cellular responses to stress that have outcomes in metabolic syndromes, such as diabetes.

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                                                                        • Rozek, L. S., D. C. Dolinoy, M. A. Sartor, and G. S. Omenn. 2014. Epigenetics: Relevance and implications for public health. Annual Review of Public Health 35:105–122.

                                                                          DOI: 10.1146/annurev-publhealth-032013-182513Save Citation »Export Citation »E-mail Citation »

                                                                          This article reviews key findings in human studies and animal models and provides a good overview of measures needed to gain the most for public health implications.

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                                                                          • Santos, M. S., and J. A. Joles. 2012. Early determination of cardiovascular disease. Clinical Endocrinology & Mechanism 26:581–597.

                                                                            DOI: 10.1016/j.beem.2012.03.003Save Citation »Export Citation »E-mail Citation »

                                                                            An overview of the models and possible mechanisms that associate prenatal stressors and cardiovascular disease is presented in this comprehensive review of animal model research. Importantly, the review also includes the advantages of fetal programming through the use of antioxidants, micronutrients, secondhand tobacco smoke, climate change, vitamin D deficiency, and other insults during fetal development.

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                                                                            Teratogens are environmental agents, drugs, or diseases that cause birth defects. Two well-studied broad areas of teratogenicity are exposures to environmental toxins (such as chemicals, infections, air pollution, lead, and tobacco smoke) and exposures to substances consumed by the mother such as medical and nonmedical drugs. Teratogens can cause a spectrum of harm over the life span from fetus to adulthood. Dose and timing of exposure can be important elements with respect to the extent of harm. Some researchers focus on one or a few related teratogens, while others emphasize causes of a condition and search for teratogenic links. An example of the latter is Froehlich, et al. 2011, which summarizes one health condition (attention deficit hyperactivity disorder [ADHD]) and its association to a variety of teratogens, both environmental and behavioral, indicating the extensive literature published in a single year, 2010.

                                                                            • Froehlich, T. E., J. S. Anixt, I. M. Loe, V. Chirdkiatgumchai, L. Kuan, and R. C. Gilman. 2011. Update on environmental risk factors for attention-deficit/hyperactivity disorder. Current Psychiatry Reports 13.5: 333–344.

                                                                              DOI: 10.1007/s11920-011-0221-3Save Citation »Export Citation »E-mail Citation »

                                                                              This paper reviews the literature published in the single year, 2010, to understand the scientific literature examining the association between environmental risk factors and ADHD. Proposed mechanisms by which each exposure is linked to the neurological condition are also discussed.

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                                                                              Prenatal Exposure to Environmental Toxins

                                                                              Most research on adverse effects of environmental toxins examines postnatal and childhood exposure. Few longitudinal studies with large population sizes exist that describe the links between prenatal exposure and subsequent health outcomes (see Wigle, et al. 2008). Results from large-scale population-based biomonitoring studies that have more recently begun in countries such as Canada and Sweden should better inform the topic of prenatal exposure to environmental toxins. Toxins, such as heavy metals, pesticides, and benzene, can enter through the placenta during fetal development. The placenta also acts as a barrier for some harmful substances, thus mediating the association between exposures and adverse outcomes, although this is not the case for all heavy metals, including lead, which crosses the placenta (Caserta, et al. 2013). Environmental exposure to various chemicals and heavy metals can cause reproductive problems in women (Caserta, et al. 2011). During the fetal stage, neurodevelopment in the nervous system includes cortical functional differentiation, synaptogenesis, myelination, and programmed apoptosis, which are all important to later cognitive functioning. Exposure to lead, tobacco, methylmercury, polychlorinated biphenyl (PCBs), and other toxins have been linked to impaired intellectual development, behavioral problems, and executive functioning. Adverse physical consequences on the fetus of exposure to toxins may include preterm fetal loss, reduced growth, preterm birth, various childhood and adult respiratory diseases, and neurodevelopmental consequences. Wigle, et al. 2008 describes epidemiological evidence that exist for adverse outcomes due to prenatal contaminant exposure to lead, mercury, arsenic, cadmium, PCBs, various fungicides and pesticides, environmental smoke, and others. Bellinger 2013 reviews the current literature on prenatal exposure to various environmental agents, while Stillerman, et al. 2008 takes the opposite approach by examining the pregnancy outcome and linking these to the evidence on environment agents. Dorman, et al. 2001 describes the evidence on pharmacokinetic processes and physical features that mediate neurotoxicity.

                                                                              • Bellinger, D. 2013. Prenatal exposures to environmental chemicals and children’s neurodevelopment: An update. Safety and Health at Work 4:1–11.

                                                                                DOI: 10.5491/SHAW.2013.4.1.1Save Citation »Export Citation »E-mail Citation »

                                                                                This review describes current literature on the neurodevelopmental impacts of chemical exposures during pregnancy. The review focuses primarily on chemicals of recent concern, including phthalates, bisphenol-A, polybrominated diphenyl ethers, and perfluorinated compounds, but also addresses chemicals, as well as those that have been better documented, such as air pollutants, lead, methylmercury, manganese, arsenic, and organophosphate pesticides.

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                                                                                • Caserta, D., A. Graziano, G. Lo Monte, G. Bordi, and M. Moscarini. 2013. Heavy metals and placental fetal-maternal barrier: A mini-review on the major concerns. European Review for Medical and Pharmacological Sciences 17:2198–2206.

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                                                                                  Although the placenta is a filter for harmful substances, including heavy metals, it is not completely impermeable. Heavy metals have been detected in placental tissues, amniotic fluid, and umbilical cord blood. This review summarizes the current state of knowledge about the interaction between heavy metals and placental barrier and considers implications on fetal health.

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                                                                                  • Caserta, D., A. Mantovani, R. Marci, et al. 2011. Environment and women’s reproductive health. Human Reproduction Update 17.3: 418–433.

                                                                                    DOI: 10.1093/humupd/dmq061Save Citation »Export Citation »E-mail Citation »

                                                                                    This review provides details of environmental compounds, including lead, that are associated with adverse reproductive outcomes and subsequent effects on the fetus.

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                                                                                    • Dorman, D. C., S. L. Allen, J. Z. Byczkowski, et al. 2001. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: Pharmacokinetic and pharmacodynamic considerations. Environmental Health Perspective 9 (Suppl. 1): 101–111.

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                                                                                      This article describes the pharmacokinetic processes (absorption, distribution, metabolism, and excretion) and physical features (e.g., absence of a placental barrier and the gradual development of the blood-brain barrier) that modulate developmental neurotoxicity.

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                                                                                      • Stillerman, K. P., D. R. Mattison, L. C. Giudice, and T. J. Woodruff. 2008. Environmental exposures and adverse pregnancy outcomes: A review of the science. Reproductive Sciences 15.7: 631–650.

                                                                                        DOI: 10.1177/1933719108322436Save Citation »Export Citation »E-mail Citation »

                                                                                        This review examines the epidemiological literature linking environmental contaminants and adverse pregnancy outcomes. The authors summarize the evidence linking specific adverse outcomes, such as preterm delivery, decreased fetal growth and lower-term birthweight, pregnancy loss, developmental delays, and adult chronic illnesses to specific environmental exposures, including air pollution, pesticides, organic solvents, herbicides, and others. Available online for purchase or by subscription.

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                                                                                        • Wigle, D. T., T. E. Arbuckle, M. C. Turner, et al. 2008. Epidemiologic evidence of relationships between reproductive and child outcomes and environmental chemical contaminants. Journal of Toxicology and Environmental Health, Part B 11:373–517.

                                                                                          DOI: 10.1080/10937400801921320Save Citation »Export Citation »E-mail Citation »

                                                                                          A comprehensive review and examination of the strength of epidemiological evidence of prenatal and maternal exposure to numerous contaminants, indicating conclusive evidence for maternal exposure to methylmercury, PCBs, environmental tobacco smoke (ETS), and other toxicants. Limited evidence exists for other associations, such as maternal lead exposure and spontaneous abortion and preterm birth.

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                                                                                          Lead exposure has a long history in the research literature (Goyer 1996), with a well-documented association between maternal exposure and subsequent adverse outcomes for children, in particular in the central nervous system, and for women. Lanphear, et al. 2005 finds a nonlinear dose-response relationship between exposure and children’s intellectual functioning. Kennedy, et al. 2012 finds lead exposure may be associated with hypertension in pregnant women. Long-term effects are evident in studies such as examination of the link between prenatal lead exposure and subsequent criminal behavior (Wright, et al. 2008). US Centers for Disease Control and Prevention 2010 comprise guidelines for identifying and managing elevated blood lead levels for pregnant women.

                                                                                          • Goyer, R. A. 1996. Results of lead research: Prenatal exposure and neurological consequences. Environmental Health Perspectives 104.10: 1050–1054.

                                                                                            DOI: 10.1289/ehp.961041050Save Citation »Export Citation »E-mail Citation »

                                                                                            This article describes advances in lead toxicity research over the past thirty years and achievements in reducing lead levels. It also describes prenatal exposure through exogenous and endogenous contributions from maternal blood lead levels with lead readily crossing the placenta, with adverse consequences to the central nervous system and possible mechanisms.

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                                                                                            • Kennedy, D. A., C. Woodland, and G. Koren. 2012. Lead exposure, gestational hypertension and pre-eclampsia: A systematic review of cause and effect. Journal of Obstetrics and Gynaecology 32:512–517.

                                                                                              DOI: 10.3109/01443615.2012.693987Save Citation »Export Citation »E-mail Citation »

                                                                                              This review examines the literature on the harmful effects of lead exposure for pregnant women. Positive associations between lead exposure and gestational hypertension or preeclampsia were found in six of the nine papers examined.

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                                                                                              • Lanphear, B. P., R. Hornung, J. Khoury, et al. 2005. Low-level environmental lead exposure and children’s intellectual function: An international pooled analysis. Environmental Health Perspectives 113:894–899.

                                                                                                DOI: 10.1289/ehp.7688Save Citation »Export Citation »E-mail Citation »

                                                                                                Important results from this study, based on pooled analysis from seven international studies, found that the slope of the dose-effect relationship relating blood lead level and neurodevelopment is nonlinear. An increase from 2.4 to 10 μg/dL in childhood blood lead level was associated with a decline of 3.9 points in IQ, while increases from 10 to 20 and from 20 to 30 were associated with declines of 1.9 and 1.1 points, respectively, thereby resulting in the rate of decline in children’s scores being greater at blood lead levels below 10 μg/dL than it is at levels above zero.

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                                                                                                • US Centers for Disease Control and Prevention. 2010. Guidelines for the identification and management of lead exposure in pregnant and lactating women. Atlanta, GA: US Centers for Disease Control and Prevention.

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                                                                                                  As well as presenting guidelines on the prevention and treatment of lead exposure, this document summarizes the evidence on risks for pregnant and lactating women. It concludes that a blood lead level of 5 μg/dL places a woman’s fetus at increased risk of adverse effects.

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                                                                                                  • Wright, J. P., K. N. Dietrich, M. D. Ris, et al. 2008. Association of prenatal and childhood blood lead concentrations with criminal arrests in early adulthood. PLoS Medicine 5.5: e101.

                                                                                                    DOI: 10.1371/journal.pmed.0050101Save Citation »Export Citation »E-mail Citation »

                                                                                                    In the first study that links prenatal lead exposure and subsequent criminal behavior, it was observed that pregnant women’s blood lead concentrations during the first and early second trimester of pregnancy are associated with higher rates of total arrests and arrests for offenses involving violence among the offspring.

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                                                                                                    Environmental Tobacco Exposure

                                                                                                    Exposure of nonsmoking women to tobacco smoke (i.e., ETS or secondhand smoke) has been shown to be linked to reduced birthweight, sudden infant death syndrome (SIDS), decreased lung development, and other longer term health consequences. ETS is a common pollutant, and it has been described by many researchers as one of the most harmful and ubiquitous prenatal hazards. It is also one of the most studied, with over fifty years of evidence documenting the hazardous risk of prenatal tobacco exposure. Because of its concern over the harm caused by ETS, the WHO (World Health Organization 1999) convened a group of worldwide experts to examine the evidence about the harms of prenatal exposure to tobacco and to make recommendations on its elimination. Literature reviews have been conducted on specific outcomes, such as SIDS (Adgent 2006), decreased lung function and asthma (Wang and Pinkerton 2008), birthweight or increased risk for low birthweight (Leonardi-Bee, et al. 2008), and a variety of physical, neurocognitive, or behavioral effects (DiFranza, et al. 2004). Jaakkola, et al. 2001 finds a link between ETS during the third trimester and length of gestation; however, Leonardi-Bee, et al. 2008 finds that the evidence shows no clear link between gestational age and ETS. The literature is inconclusive with respect to ETS and behavioral problems, with Liu, et al. 2013 observing an increased risk of externalizing behavioral problems for children prenatally exposed to ETS, and Yang, et al. 2013 finding no adverse cognitive, behavioral, or developmental outcomes associated with exposure to maternal prenatal smoking. Simons, et al. 2014 reports an increased risk for asthma for children prenatally exposed to ETS after controlling for ETS during postnatally.

                                                                                                    • Adgent, M. A. 2006. Environmental tobacco smoke and sudden infant death syndrome: A review. Birth Defects Research, Part B 77:69–85.

                                                                                                      DOI: 10.1002/bdrb.20068Save Citation »Export Citation »E-mail Citation »

                                                                                                      This article reviews the evidence on the association between ETS exposure and SIDS by examining the epidemiological literature, animal model research, biological plausibility of metabolic and placental transfer of nicotine, and mechanisms following exposure.

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                                                                                                      • DiFranza, J. R., C. A. Aligne, and M. Weitzman. 2004. Prenatal and postnatal environmental tobacco smoke exposure and children’s health. Pediatrics 113:1007–1015.

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                                                                                                        This review examines the extensive literature linking prenatal ETS with adverse consequences, including SIDS, dose-response to intrauterine growth, behavioral problems, neurocognitive decrements, and increased rates of adolescent smoking. Studies of prenatal and postnatal ETS exposure suggest independent effects of each, with considerable respiratory risks during fetal development.

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                                                                                                        • Jaakkola, J. J., N. Jaakkola, and K. Zahlsen. 2001. Fetal growth and length of gestation in relation to prenatal exposure to ETS assessed by hair nicotine concentration. Environmental Health Perspective 109.6: 557–561.

                                                                                                          DOI: 10.1289/ehp.01109557Save Citation »Export Citation »E-mail Citation »

                                                                                                          ETS during the third trimester was found to be associated with length of gestation. Measuring concentration in hair samples, the risk of preterm delivery (less than thirty-seven weeks) was higher in those exposed to high and medium exposure levels than those with low level exposure, suggesting a dose-related effect.

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                                                                                                          • Leonardi-Bee, J., A. Smyth, J. Britton, and T. Coleman. 2008. Environmental tobacco smoke and fetal health: Systematic review and meta-analysis. Archives of Disease in Childhood: Fetal and Neonatal Edition 93.5: F351–F361.

                                                                                                            DOI: 10.1136/adc.2007.133553Save Citation »Export Citation »E-mail Citation »

                                                                                                            This article reviews the literature and reports on a meta-analysis of fifty-eight studies, observing reduced mean birthweight (by 33 grams or more) in both retrospective and prospective studies and an increased risk of low-birthweight births. Exposure to ETS has not been shown to have a clear effect on gestational age.

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                                                                                                            • Liu, J., W. L. Patrick, P. W. L. Leung, L. McCauley, Y. Ai, and J. Pinto-Martin. 2013. Mother’s environmental tobacco smoke exposure during pregnancy and externalizing behavior problems in children. Neurotoxicology 34:167–174.

                                                                                                              DOI: 10.1016/j.neuro.2012.11.005Save Citation »Export Citation »E-mail Citation »

                                                                                                              This study found that ETS during pregnancy more than doubled the risk of externalizing behavior problems in offspring of exposed mothers, although no dose-response relationship was found. No association was found between ETS and internalizing or total behavior problems.

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                                                                                                              • Simons, E., T. To, R. Moineddin, D. Stieb, and S. D. Dell. 2014. Maternal second-hand smoke exposure in pregnancy is associated with childhood asthma development. Journal of Allergy and Clinical Immunology in Practice 2.2: 201–207.

                                                                                                                DOI: 10.1016/j.jaip.2013.11.014Save Citation »Export Citation »E-mail Citation »

                                                                                                                Children prenatally exposed to smoking either directly through their mothers’ smoking or indirectly through secondhand smoke during pregnancy were at higher risk for asthma. The association persisted for children of nonsmoking mothers with home secondhand smoke exposure during pregnancy, after adjusting for home secondhand smoke exposure from birth to age seven years.

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                                                                                                                • Wang, L., and K. E. Pinkerton. 2008. Detrimental effects of tobacco smoke exposure during development on postnatal lung function and asthma. Birth Defects Research, Part C 84:54–60.

                                                                                                                  DOI: 10.1002/bdrc.20114Save Citation »Export Citation »E-mail Citation »

                                                                                                                  This article reviews the epidemiological literature and animal model literature that link ETS and maternal smoking with decreased lung growth in offspring and an increased risk of developing asthma. Lung development during in utero and early postnatal stages appears to determine airway function in later life.

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                                                                                                                  • World Health Organization. Tobacco free initiative: International consultation on environmental tobacco (ETS) and child health. Consultation Report. Geneva, Switzerland: World Health Organization, 1999.

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                                                                                                                    This report from worldwide experts examines ETS and makes recommendations about eliminating exposure. The consultation concluded that maternal smoking during pregnancy is a major cause of SIDS, reduced birthweight, and decreased lung function and that ETS exposure among nonsmoking pregnant women can cause a decrease in birthweight.

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                                                                                                                    • Yang, S., A. Decker, and M. S. Kramer. 2013. Exposure to parental smoking and child growth and development: A cohort study. BMC Pediatrics 13:104.

                                                                                                                      DOI: 10.1186/1471-2431-13-104Save Citation »Export Citation »E-mail Citation »

                                                                                                                      No adverse cognitive, behavioral, or developmental outcomes were associated with exposure to maternal prenatal smoking. Associations were observed with postnatal smoking of both parents, which may indicate confounding by genetic and family environmental factors.

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                                                                                                                      Tobacco and Lead Combined

                                                                                                                      Smoking during pregnancy may increase lead concentrations (Chelchowska, et al. 2013). While tobacco exposure and lead exposure, or other pollutants, can cause independent risks to the fetus, the literature is not conclusive about whether together they produce higher elevations of blood level concentrations of lead. Prenatal tobacco exposure may increase risk caused by other exposures, according to Froehlich, et al. 2009, which found greater adverse outcome from the risk of childhood lead and tobacco exposure. This contrasts to findings in Desrosiers, et al. 2013 which found increased behavioral problems in children prenatally exposed to tobacco but did not find that exposure to lead exacerbated tobacco effects, suggesting that these substances act independently.

                                                                                                                      • Chelchowska, M., J. Ambroszkiewicz, K. Jablonka-Salach, et al. 2013. Tobacco smoke exposure during pregnancy increases maternal blood lead levels affecting neonate birth weight. Biological Trace Element Research 155.2: 169–175.

                                                                                                                        DOI: 10.1007/s12011-013-9775-8Save Citation »Export Citation »E-mail Citation »

                                                                                                                        This paper reports a study in which lead exposure from cigarette smoke was measured using inductively coupled plasma mass spectrometry in 150 healthy pregnant women. Mean lead concentrations were significantly higher in the smoking group in each of the trimesters. Birthweight of the smoking mothers’ infants was significantly lower and negatively correlated with lead levels in plasma and in whole blood, leading to the conclusion that smoking during pregnancy increases lead concentrations in maternal blood.

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                                                                                                                        • Desrosiers, C., O. Boucher, N. Forget-Dubois, E. Dewailly, P. Ayotte, S. W. Jacobson, J. L. Jacobson, and G. Muckle. 2013. Associations between prenatal cigarette smoke exposure and externalized behaviors at school age among Inuit children exposed to environmental contaminants. Neurotoxicology Teratology 39:84–90.

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                                                                                                                          This study, conducted among Inuit women from the Canadian Arctic where prenatal tobacco exposure is prevalent, explored its effects with co-exposure with neurotoxic environmental contaminants Prenatal tobacco exposure was associated with increased externalizing behaviors and higher prevalence of ADHD on school-aged children. Interactions with lead, and mercury, two contaminants associated with behavioral problems, were also explored, but were found not to exacerbate tobacco effects, suggesting that these substances act independently.

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                                                                                                                          • Froehlich, T. E., B. P. Lanphear, P. Auinger, R. Hornung, J. N. Epstein, J. Braun, and R. S. Kahn. 2009. Associations of tobacco and lead exposure with attention deficits and hyperactivity disorder. Pediatrics 124:e1054–e1063.

                                                                                                                            DOI: 10.1542/peds.2009-0738Save Citation »Export Citation »E-mail Citation »

                                                                                                                            Prenatal tobacco exposure, along with childhood lead exposures, was found to be associated with ADHD. Compared with children with neither exposure, those with both exposures had considerably greater risk of ADHD (odds ratio: 8.1 [95 percent confidence interval: 3.5–18.7]) than would be expected if the independent risks were multiplied (tobacco–lead exposure interaction).

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                                                                                                                            Air Pollution

                                                                                                                            Air pollution is ubiquitous in the world’s urban centers and harmful to humans. Most research has focused on the association between air pollution on adult mortality and respiratory morbidity, although a growing body of literature now examines the birth outcomes of prenatal exposure to air pollution. In the past decade, more studies have examined the relationship between adverse reproductive or birth outcomes and ambient air pollution. Reviews (Veras, et al. 2010; Ghosh, et al. 2007; Stillerman, et al. 2008 [cited under Teratogens: Prenatal Exposure to Environmental Toxins) summarize the epidemiological or scientific literature. Stillerman, et al. 2008 also summarizes the state of the science on many environmental exposures including air pollution. There has been some inconsistency in the scientific literature regarding prenatal exposure. Using more specific measurements for both fetus and air quality, recent studies have shown air pollution to be associated with birthweight (Darrow, et al. 2011) and smaller head size (Ritz, et al. 2014). Other studies attempted to study exposure from specific source, such as traffic (Aguilera, et al. 2010) or incinerators (Candela, et al. 2013). Large datasets were used to increase sample size in studies such as those conducted in Trasande, et al. 2013 and Agarwal, et al. 2010. Taking another approach, Herr, et al. 2011 attempted to study the mechanisms for prenatal outcomes from air pollution and from tobacco smoking. Most studies have been conducted in the United States, and there is some suggestion that other sites would contribute to the evidence. Candela, et al. 2013 studies a large population exposed to air pollution in Italy.

                                                                                                                            • Agarwal, N., C. Banternghansa, and L. T. M. Bui. 2010. Toxic exposure in America: Estimating fetal and infant health outcomes from 14 years of TRI reporting. Journal of Health Economics 29:557–574.

                                                                                                                              DOI: 10.1016/j.jhealeco.2010.04.002Save Citation »Export Citation »E-mail Citation »

                                                                                                                              Tracking exposure from the Toxic Release Inventory in the United States, significant adverse effects of toxic air pollution are found for fetal and infant mortality rates. Data show reducing rates, varying by quartile and by types of toxic concentrations.

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                                                                                                                              • Aguilera, I., R. Garcia-Esteban, C. Iñiguez, et al. 2010. Prenatal exposure to traffic-related air pollution and ultrasound measures of fetal growth in the INMA Sabadell cohort. Environmental Health Perspectives 118.5: 705–711.

                                                                                                                                DOI: 10.1289/ehp.0901228Save Citation »Export Citation »E-mail Citation »

                                                                                                                                This study used longitudinal ultrasound measurements to assess the effect of traffic-related air pollution on fetal growth. The results show some support to an effect of exposure to traffic-related air pollutants from early pregnancy on fetal growth during mid-pregnancy.

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                                                                                                                                • Candela, S., A. Ranzi, L. Bonvicini, et al. 2013. Air pollution from incinerators and reproductive outcomes: A multisite study. Epidemiology 24.6: 863–870.

                                                                                                                                  DOI: 10.1097/EDE.0b013e3182a712f1Save Citation »Export Citation »E-mail Citation »

                                                                                                                                  Previous studies on the association between incinerator emissions and pregnancy outcomes have been inconsistent. This Italian study examined all births (N = 21,517) to women living within 4 km of a municipal incinerator at the time of delivery. Results found that incinerator pollution was not associated with small for gestational age, but it was associated with preterm delivery. Even at the lowest level of exposure, risk for preterm delivery increased.

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                                                                                                                                  • Darrow, L. A., M. Klein, M. J. Strickland, J. A. Mulholland, and P. E. Tolbert. 2011. Ambient air pollution and birth weight in full-term Infants in Atlanta, 1994–2004. Environmental Health Perspectives 119:731–737.

                                                                                                                                    DOI: 10.1289/ehp.1002785Save Citation »Export Citation »E-mail Citation »

                                                                                                                                    Results show an association between exposure to ambient air pollution in late pregnancy and birthweight in full-term infants.

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                                                                                                                                    • Ghosh, R., J. Rankin, T. Pless-Mulloli, and S. Glinianaia. 2007. Does the effect of air pollution on pregnancy outcomes differ by gender? A systematic review. Environmental Research 105.3: 400–408.

                                                                                                                                      DOI: 10.1016/j.envres.2007.03.009Save Citation »Export Citation »E-mail Citation »

                                                                                                                                      This review contributed to refining the literature linking air pollution and adverse pregnancy outcomes by examining gender differences, finding that males were at higher risk for preterm births. Less strong evidence (only four studies) suggested that gender differences exist with respect to lower birthweight.

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                                                                                                                                      • Herr, C. E. W., R. Ghosh, M. Dostal, et al. 2011 Exposure to air pollution in critical prenatal time windows and IgE levels in newborns. Pediatric Allergy Immunology 22:75–84.

                                                                                                                                        DOI: 10.1111/j.1399-3038.2010.01074.xSave Citation »Export Citation »E-mail Citation »

                                                                                                                                        This study analyzed the mechanisms by which exposure to ambient air pollutants influences respiratory health. These may include altered prenatal immune development. In analyses stratified by maternal atopy, both air pollutants and cigarette smoke were associated with altered cord serum Immunoglobulin among neonates with nonatopic mothers. Concentrations of polycyclic aromatic hydrocarbons and particulate matter, constituents of both ambient air pollution and cigarette smoke, appear to influence fetal immune.

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                                                                                                                                        • Ritz, B., J. Qiu, P. C. Lee, et al. 2014. Prenatal air pollution exposure and ultrasound measures of fetal growth in Los Angeles, California. Environmental Research 130:7–13.

                                                                                                                                          DOI: 10.1016/j.envres.2014.01.006Save Citation »Export Citation »E-mail Citation »

                                                                                                                                          Exposure to traffic-derived air pollution during late pregnancy was associated with smaller head size at birth.

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                                                                                                                                          • Trasande, L., K. Wong, A. Roy, D. A. Savitz, and G. Thurston. 2013. Exploring prenatal outdoor air pollution, birth outcomes and neonatal health care utilization in a nationally representative sample. Journal of Exposure Science and Environmental Epidemiology 23:315–321.

                                                                                                                                            DOI: 10.1038/jes.2012.124Save Citation »Export Citation »E-mail Citation »

                                                                                                                                            This national, mostly urban US study examined the health-care utilization in the months following delivery. Air pollutants were not individually associated with mean birthweight. When exposure to three or four pollutants was found, and after controlling for hospital characteristics, demographics, and birth month, increased risks of low birthweight and very low birthweight and preterm delivery were found. Considerable increased costs of hospitalization were associated with exposure to air pollutants.

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                                                                                                                                            • Veras, M. M., E. G. Caldini, M. Dolhnikoff, and P. H. N. Saldiva. 2010. Air pollution and effects on reproductive-system functions globally with particular emphasis on the Brazilian population. Journal of Toxicology and Environmental Health, Part B: Critical Reviews 13.1: 1–15.

                                                                                                                                              DOI: 10.1080/10937401003673800Save Citation »Export Citation »E-mail Citation »

                                                                                                                                              This review of epidemiological studies from different geographical regions shows that the current levels of airborne pollutants adversely affect pregnancy outcomes, including low birthweight, and show higher frequency of preterm birth and neonatal mortality.

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                                                                                                                                              Maternal Substance Use

                                                                                                                                              A number of substances used during pregnancy can affect maternal and fetal health. Extensive research has been conducted over the past half century on the outcomes of prenatal exposure to alcohol, tobacco, and other drugs, including marijuana and cocaine. Both animal model and epidemiological research have contributed to the scientific literature, and more recently the use of magnetic resonance imaging (MRI) and other testing has led to further refinement of outcomes. Challenges of alcohol, tobacco, and other drug epidemiological studies include controlling for dosage and timing during pregnancy and controlling for poly drug use (e.g., concurrent use of alcohol and tobacco). Adverse outcomes are not only affected by dosage, frequency, and timing of each substance but also by the overall health status of the mother or fetus. Still, the cumulative body of knowledge provides a good understanding of the teratogenic effects of exposure to nonmedicinal drugs. Kuczkowski 2007 provides an overview of the literature on many substances.

                                                                                                                                              • Kuczkowski, K. M. 2007. The effects of drug abuse on pregnancy. Current Opinion in Obstetrics and Gynecology 19.6: 578–585.

                                                                                                                                                DOI: 10.1097/GCO.0b013e3282f1bf17Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                This article reviews maternal risks of substances most commonly used during pregnancy—cocaine, amphetamines, opioids, marijuana, alcohol, tobacco, and others. Besides specific drug-related risks, other risks of using nonmedical drugs include lack of prenatal care, premature labor, and cigarette smoking. Many drugs readily cross the placenta.

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                                                                                                                                                Alcohol is the most widely used substance by pregnant women throughout the world, although in some parts of the world, alcohol use is taboo for women. Alcohol is a well-documented teratogen, and prenatal alcohol exposure is the most widely known preventable cause of mental retardation. The first English-language description of fetal alcohol syndrome (FAS) is found in Jones, et al. 1973, and since then extensive literature has linked prenatal alcohol exposure to lifelong adverse health, cognitive, and behavioral outcomes. Jones, et al. 1973 and other works, including Streissguth and O’Malley 2000 (by researchers at the University of Washington) have included longitudinal cohort studies. Other teams at various sites have focused on other areas, such as those in California who study brain and neurobehavioral outcomes of prenatal alcohol exposure (Riley and McGee 2005). For nearly a half-century, thousands of studies around the world have examined various outcomes, with human participants or animal models and using longitudinal studies and now brain imaging, and have resulted in a detailed understanding of the consequences of prenatal alcohol exposure. Consequences of heavy prenatal alcohol exposure are well documented, although dosage, frequency, pattern of alcohol use, and individual differences affect outcomes. Terminology has changed since 1973, and many more terms are used to specify consequences of fetal alcohol exposure and diagnostic categories, including FAS, partial FAS, fetal alcohol effects, alcohol-related neurodevelopment disorders, and others. Portraying the spectrum of health, cognitive, and behavioral outcomes of prenatal alcohol exposure, the most umbrella terms are fetal alcohol spectrum disorder (FASD, used in Canada, Australia, and elsewhere) or fetal alcohol spectrum disorders (used in the United States and elsewhere under which diagnostic categories are designated. Many researchers interested in FASD report findings on animal, clinical epidemiological, and public health research in a journal titled Alcoholism: Clinical and Experimental Research. A searchable database on alcohol, including the term “fetal alcohol syndrome” is Project Cork. Recent advances in the field are compilations, including systematic reviews or meta-analyses, of the existing research in general (Pruett, et al. 2013) or on specific topics such as dose (Flak, et al. 2014; Gray 2013; Valenzuela, et al. 2012); specific consequences, such as motor functions (Bay and Kesmodel 2011; Lucas, et al. 2014); or social skills (Kully-Martens, et al. 2012). Another advance in the understanding of outcomes related to prenatal alcohol exposure comes from new forms of measure, that is, various neuroimaging techniques (O’Leary-Moore, et al. 2011; Roussotte, et al. 2010; Coles and Li 2011). The emerging field of epigenetics is also contributing to the evidence on outcomes related to prenatal alcohol exposure (Ungerer, et al. 2013; Hellemans, et al. 2010).

                                                                                                                                                • Alcoholism: Clinical and Experimental Research.

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                                                                                                                                                  A monthly journal founded by the US National Council on Alcoholism and Drug Dependence. This highly respected journal reports results of scientific studies in alcohol epidemiology and clinical and health-care research and routinely reports research on prenatal alcohol exposure.

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                                                                                                                                                  • Bay, B., and U. S. Kesmodel. 2011. Prenatal alcohol exposure: A systematic review of the effects on child motor function. Acta Obstetricia et Gynecologica Scandinavica 90.3: 210–226.

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                                                                                                                                                    This systematic review on the effects of prenatal alcohol exposure on motor function in humans found thirty-nine articles. The findings are consistent in observing that high daily alcohol intake (binge drinking) is associated with deficits in gross and fine motor function and low weekly intake is not associated with such deficits.

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                                                                                                                                                    • Coles, C. D., and Z. Li. 2011. Functional neuroimaging in the examination of effects of prenatal alcohol exposure. Neuropsychological Review 21:119–132.

                                                                                                                                                      DOI: 10.1007/s11065-011-9165-ySave Citation »Export Citation »E-mail Citation »

                                                                                                                                                      The results of functional neuroimaging techniques (EEG, PEG, SPECT, fMRI) used in very recent years to understand the brain prenatally exposed to alcohol are reviewed. Results suggest that prenatal exposure may lead to a general decrease in neural efficiency or a global decrement in processing resources. Future research using these techniques are suggested.

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                                                                                                                                                      • Flak, A. L., S. Su, J. Bertrand, C. H. Denny, U. S. Kesmodel, and M. E. Cogswell. 2014. The association of mild, moderate, and binge prenatal alcohol exposure and child neuropsychological outcomes: A meta-analysis. Alcoholism, Clinical and Experimental Research 38.1: 214–226.

                                                                                                                                                        DOI: 10.1111/acer.12214Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                        Thirty-four cohort studies are included in this meta-analysis. Any binge prenatal alcohol exposure was associated with child cognition in their analysis based on eight studies of 10,000 children age six months to fourteen years. A statistically significant detrimental association between moderate prenatal alcohol exposure and child behavior was found, based on three high-quality studies of 11,900 children age nine months to five years. A small, positive association was found between mild to moderate prenatal alcohol exposure and child cognition, although this association was not significant after post hoc exclusion of one large study that assessed mild consumption, nor was it significant when including only studies that assessed moderate alcohol consumption. None of the other completed meta-analyses resulted in statistically significant associations between mild, moderate, or binge prenatal alcohol exposure and child neuropsychological outcomes.

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                                                                                                                                                        • Gray, R. 2013. Low-to-moderate alcohol consumption during pregnancy and child development—Moving beyond observational studies. British Journal of Obstetrics and Gynaecology 120:1039–1041.

                                                                                                                                                          DOI: 10.1111/1471-0528.12211Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                          With the long-standing question of how much alcohol is needed to cause harm to the fetus, this paper examines why there is inconsistency in the literature on evidence on adverse effects of prenatal exposure at low to moderate levels of exposure. The author concludes that there is strong evidence that moderate prenatal exposure is associated with child IQ. Research methods and genetic variation in both mother and fetus are causes of inconsistency in the reported literature.

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                                                                                                                                                          • Hellemans, K. G. C., J. H. Wliwowska, P. Verma, and J. Weinberg. 2010. Prenatal alcohol exposure: Fetal programming and late life vulnerability to stress, depression and anxiety disorders. Neuroscience and Biobehavioral Reviews 34:791–807.

                                                                                                                                                            DOI: 10.1016/j.neubiorev.2009.06.004Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                            This article reviews evidence demonstrating altered HPA function and increased depression/anxiety in FASD and discusses the hypothesis that fetal programming of the HPA axis by prenatal alcohol exposures alters neuroadaptive mechanisms that mediate the stress response. The organism is sensitized to stressors encountered later in life, mediating the increased vulnerability to depression and anxiety disorders. The authors provide evidence for sex differences. They suggest that the data and hypothesis could increase an understanding of the mechanisms underlying the increased vulnerability to mental illness among individuals with FASD.

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                                                                                                                                                            • Jones, K. L., D. W. Smith, C. N. Ulleland, and P. Streissguth. 1973. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1.7815: 1267–1271.

                                                                                                                                                              DOI: 10.1016/S0140-6736(73)91291-9Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                              Also see “Recognition of the Fetal Alcohol Syndrome in Early Infancy,” Lancet 2.7836 (1973), pp. 999–1001. These articles and others by the same authors were the first English-language reports describing the case histories of eight unrelated children born to mothers who were chronic alcoholics, with the children showing similar patterns of craniofacial, limb, and cardiovascular defects associated with prenatal-onset growth deficiency and developmental delay.

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                                                                                                                                                              • Kully-Martens, K., K. Denys, S. Treit, S. Tamana, and C. Rasmussen. 2012. A review of social skills deficits in individuals with fetal alcohol spectrum disorders and prenatal alcohol exposure: Profiles, mechanisms, and interventions. Alcohol Clinical & Experimental Research 36.4: 568–576.

                                                                                                                                                                DOI: 10.1111/j.1530-0277.2011.01661.xSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                This review article examines the literature on prenatal exposure to alcohol and social skills deficits that are prevalent across the lifespan in exposed individuals and are independent of facial dysmorphology and IQ associated with FASD.

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                                                                                                                                                                • Lucas, B. R., J. Latimer, R. Z. Pinto, et al. 2014. Gross motor deficits in children prenatally exposed to alcohol: A meta-analysis. Pediatrics 134:e192–e209.

                                                                                                                                                                  DOI: 10.1542/peds.2013-3733Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                  This meta-analysis of fourteen studies, with participants age three days to thirteen years, found a significant association between diagnosis of FASD, or moderate to heavy prenatal alcohol exposure, and gross motor impairment, specifically balance, coordination, and ball skills.

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                                                                                                                                                                  • O’Leary-Moore, S. K., S. E. Parnell, R. J. Pipinski, and K. K. Sulik. 2011. Magnetic resonance-based imaging in animal models of fetal alcohol spectrum disorder. Neuropsychological Review 21:167–185.

                                                                                                                                                                    DOI: 10.1007/s11065-011-9164-zSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                    The results of animal model studies using various imaging techniques (MRI, DTI, MRS) are reviewed. Region-specific alterations are found regarding the presence of neurochemicals, especially in the cerebellum as well as in regions of the cerebellar following prenatal alcohol exposure. Sex differences are found.

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                                                                                                                                                                    • Project Cork.

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                                                                                                                                                                      Produced at Dartmouth Medical School, this website provides a bibliography of current authoritative information on substance abuse with nearly 890,000 searchable entries indexed by over 400 terms, including the term “fetal alcohol syndrome” and “fetal alcohol effects.” Each entry provides bibliographic information and an abstract.

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                                                                                                                                                                      • Pruett, D., E. H. Waterman, and A. B. Caughey. 2013. Fetal alcohol exposure: Consequences, diagnosis, and treatment. Obstetrical and Gynecological Survey 68.1: 62–69.

                                                                                                                                                                        DOI: 10.1097/OGX.0b013e31827f238fSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                        This review article provides an overview for physicians of the evidence on outcomes related to maternal alcohol use during pregnancy: craniofacial dysmorphologies, organ systems abnormalities, behavioral and intellectual deficits, and fetal death. It also discusses the possible mechanisms of how alcohol affects the fetus, including individual differences, and implications of dose and timing of exposure. In addition, criteria for diagnosis, early detection of maternal alcohol use, and fetal alcohol exposure, such as the use of fatty acid ethyl esters, and current treatment strategies, are discussed.

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                                                                                                                                                                        • Riley, E. P., and C. L. McGee. 2005. Fetal alcohol spectrum disorders: An overview with emphasis on changes in brain and behavior. Experimental Biology and Medicine 230.6: 357–365.

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                                                                                                                                                                          This overview of important issues about prenatal alcohol exposure emphasizes the structural and neurobehavioral consequences. Also reviewed are diagnostic criteria, possible moderating factors, prevalence estimates, estimates of the financial impact, and summary of the wide range of neuropsychological deficits found in children prenatally exposed to alcohol.

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                                                                                                                                                                          • Roussotte, F., L. Soderberg, and E. Sowell. 2010. Structural, metabolic, and functional brain abnormalities as a result of prenatal exposure to drugs of abuse: Evidence from neuroimaging. Neuropsychology Review 20:376–397.

                                                                                                                                                                            DOI: 10.1007/s11065-010-9150-xSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                            This is a review of the literature using neuroimaging on children prenatally exposed to alcohol and to cocaine and methamphetamines. Neuroimaging studies have found that prenatal alcohol exposure is associated with structure and metabolism of many brain systems, including in frontal, parietal, and temporal regions, in the cerebellum and basal ganglia, and in the white-matter tracts that connect these brain regions.

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                                                                                                                                                                            • Streissguth, A. P., and K. O’Malley. 2000. Neuropsychiatric complications and long-term consequences of fetal alcohol spectrum disorders. Seminars in Clinical Neuropsychiatry 5.3: 177–190.

                                                                                                                                                                              DOI: 10.1053/scnp.2000.6729Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                              Prenatal alcohol exposure can cause wide-ranging central nervous system sequelae that persist throughout life and manifest in a spectrum of effects from clinically indistinguishable to severely impairing. The interaction brain damage and complex psychosocial circumstances can compound development and result in costly and devastating social consequences.

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                                                                                                                                                                              • Ungerer, M., J. Knezovich, and M. Ramsay. 2013. In utero alcohol exposure, epigenetic changes, and their consequences. Alcohol Research: Current Reviews 35.1: 37–46.

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                                                                                                                                                                                Accumulating evidence supports the contribution of epigenetic mechanisms to the development of FASD. Rodent model studies contribute to the evidence, which is otherwise difficult to study because of the cell-type specific. This article reviews the current evidence exploring the roles of different epigenetic mechanisms in neurogenesis and how this process is affected by exposure to alcohol, leading to FASD.

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                                                                                                                                                                                • Valenzuela, C. F., R. A. Morton, M. R. Diaz, and L. Topper. 2012. Does moderate drinking harm the fetal brain? Insights from animal models. Trends in Neuroscience 35.5: 284–292.

                                                                                                                                                                                  DOI: 10.1016/j.tins.2012.01.006Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                  This review examines animal model studies of moderate alcohol exposure, concluding that there are long-lasting neurobehavioral deficits in the offspring of laboratory animals. In particular, alterations in learning, memory, motor coordination, social behavior, and stress responses were found, as well as an increased vulnerability to substance abuse. These alterations have been associated with impairments in neurotransmitter systems, neuromodulators, and/or synaptic plasticity in several brain regions.

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                                                                                                                                                                                  Tobacco is a widely used substance. The links between maternal tobacco use and long- and short-term morbidity and mortality for mother and child is well established from both animal and human studies. The specific mechanisms have yet to be confirmed (Suter, et al. 2012). The considerable risks to the fetus and child include placental and fetal biological and anatomical changes (Jauniaux and Burton 2007), respiratory dysfunction (Burke, et al. 2012; Maritz and Harding 2011), metabolic disorders (Somm, et al. 2009), ADHD or related disorders (Tiesler and Heinrich 2014), and other behavioral or antisocial behaviors (Tiesler and Heinrich 2014; Ginzel, et al. 2007). The long list of illnesses associated with prenatal tobacco exposure are described in Tiesler and Heinrich 2014; Mund, et al. 2013; Maritz and Harding 2011; and Ginzel, et al. 2007. Still, both Maritz and Harding 2011 and Ginzel, et al. 2007 conclude by cautioning against the use of nicotine replacement therapy for pregnant women.

                                                                                                                                                                                  • Burke, H., J. Leonardi-Bee, A. Hashim, et al. 2012. Prenatal and passive smoke exposure and incidence of asthma and wheeze: Systematic review and meta-analysis. Pediatrics 129.4: 735–744.

                                                                                                                                                                                    DOI: 10.1542/peds.2011-2196Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                    Exposure to pre- or postnatal passive smoke exposure was associated with a 30 percent to 70 percent increased risk of incident wheezing, with postnatal exposure greater than prenatal exposure. It also caused a 21 percent to 85 percent increase in incident asthma, with the strongest effect from prenatal maternal smoking.

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                                                                                                                                                                                    • Ginzel, K. H., G. S. Maritz, D. F. Marks, et al. 2007. Critical review: Nicotine for the fetus, the infant and the adolescent? Journal of Health Psychology 12:215–224.

                                                                                                                                                                                      DOI: 10.1177/1359105307074240Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                      Summarizing the literature on the fetotoxicity and neuroteratogencity of nicotine, this review cautions against the use of nicotine replacement therapy during pregnancy.

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                                                                                                                                                                                      • Jauniaux, E., and G. J. Burton. 2007. Morphological and biological effects of maternal exposure to tobacco smoke on the fetoplacental unit. Early Human Development 83.11: 699–706.

                                                                                                                                                                                        DOI: 10.1016/j.earlhumdev.2007.07.016Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                        This article describes literature on the effects of maternal smoking on placental anatomy and biology and on fetal anatomy and biology.

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                                                                                                                                                                                        • Maritz, G. S., and R. Harding. 2011. Life-long programming implications of exposure to tobacco smoking and nicotine before and soon after birth: Evidence for altered lung development. International Journal of Environmental Research and Public Health 8:875–898.

                                                                                                                                                                                          DOI: 10.3390/ijerph8030875Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                          Maternal smoking can have lifelong programming consequences before birth through altered lung development. Lungs become more susceptible to obstructive lung disease and accelerate lung aging. The authors conclude that nicotine replacement therapy should not be used.

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                                                                                                                                                                                          • Mund, M., F. Louwen, D. Klingelhoefer, and A. Gerber. 2013. Smoking and pregnancy—A review on the first major environmental risk factor of the unborn. International Journal of Environmental Research and Public Health 10:6485–6499.

                                                                                                                                                                                            DOI: 10.3390/ijerph10126485Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                            This review summarizes the numerous adverse pregnancy outcomes linked with cigarette consumption before and during pregnancy. Maternal prenatal cigarette smoke disturbs the equilibrium among the oxidant and antioxidant system, resulting in a negative impact on the genetic and cellular level of both mother and fetus.

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                                                                                                                                                                                            • Somm, E., V. M. Schwitzgebel, D. M. Vauthay, M. L. Aubert, and P. S. Hüpppi. 2009. Prenatal nicotine exposure and the programming of metabolic and cardiovascular disorders. Molecular and Cellular Endocrinology 304:69–77.

                                                                                                                                                                                              DOI: 10.1016/j.mce.2009.02.026Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                              Reviews the evidence from epidemiological literature and animal model research that prenatal nicotine exposure could lead to the cluster of metabolic disorders linking obesity, hypertension, dyslipidemia, and type 2 diabetes. Prenatal nicotine exposure appears to alter pancreatic islet development, and control of fat storage and energy expenditure homeostasis.

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                                                                                                                                                                                              • Suter, M. A., A. M. Anders, and K. M. Aagaard. 2012. Maternal smoking as a model for environmental epigenetic changes affecting birthweight and fetal programming. Molecular Human Reproduction 19.1: 1–6.

                                                                                                                                                                                                DOI: 10.1093/molehr/gas050Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                The mechanisms leading to reduced fetal growth are not well understood in spite of the well-established association between maternal smoking and low birthweight. Not all fetuses parentally exposed to tobacco smoke are born growth restricted or small for gestational age. This review explores the evidence on whether maternal tobacco smoke in utero alters the fetal epigenome and whether such alterations are associated with reduced fetal weight.

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                                                                                                                                                                                                • Tiesler, C. M., and J. Heinrich. 2014. Prenatal nicotine exposure and child behavioural problems. European Child & Adolescent Psychiatry 23:913–929.

                                                                                                                                                                                                  DOI: 10.1007/s00787-014-0615-ySave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                  This review summarizes the literature on the association between prenatal tobacco exposure and subsequent behavioral problems, attempting to find causality in various areas. The majority of studies, and especially several recent epidemiological studies, observed a higher likelihood for ADHD or ADHD symptoms in exposed subjects, although causality has not been established. The literature on studies exploring the association between prenatal tobacco exposure and conduct or externalizing problems in the offspring suggests a causal effect. Insufficient literature exists to draw conclusions regarding prenatal tobacco exposure and internalizing problems. Prenatal tobacco exposure has been associated with altered brain structure and function in human offspring, and a proposed biological mechanism is related to nicotine’s adverse influence on neurotransmitter systems during brain development.

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                                                                                                                                                                                                  Marijuana is a commonly used illegal, and in some jurisdictions legal, drug. Medicinal marijuana is becoming increasing used. The teratogenic effects of marijuana have been studied. The only two longitudinal epidemiological studies, one in Canada (Fried 2002) and one in the United States (Goldschmidt, et al. 2012) found differing results regarding academic abilities. New animal model and human studies indicate potential health hazards of prenatal exposure, although the evidence remains incomplete. Reviews have been conducted on prenatal exposure to cannabis and behavioral outcomes using animal models (Schneider 2009), on molecular mechanisms (Morris, et al. 2011), and on infant outcomes (Huizink 2014). Two recent reviews summarize the literature on both maternal and fetal or infant outcomes of prenatal marijuana exposure (Huizink 2014; Warner, et al. 2014).

                                                                                                                                                                                                  • Fried, P. A. 2002. Conceptual issues in behavioral teratology and their application in determining long-term sequelae of prenatal marijuana exposure. Journal of Child Psychology and Psychiatry 43:81–102.

                                                                                                                                                                                                    DOI: 10.1111/1469-7610.00005Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                    This article reports the review of the only two longitudinal studies on the teratogenic effects of marijuana. Cannabis exposure does not impact standardized IQ scores, but it is negatively associated with attentional behavior and visual analysis/hypothesis testing. The results are reviewed with respect to presence or absence of behavioral effects during various developmental stages.

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                                                                                                                                                                                                    • Goldschmidt, L., G. A. Richardson, J. A. Willford, S. G. Severtson, and N. L. Day. 2012. School achievement in 14-year old youths prenatally exposed to marijuana. Neurotoxicology and Teratology 26.4: 521–532.

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                                                                                                                                                                                                      A significant negative relation was found between prenatal marijuana exposure and composite academic scores and reading scores at age fourteen years. The results were mediated by earlier negative effects of prenatal marijuana exposure, including intelligence test performance at age six, attention problems and depression symptoms at age ten, and early initiation of marijuana use.

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                                                                                                                                                                                                      • Huizink, A. C. 2014. Prenatal cannabis exposure and infant outcomes: Overview of studies. Progress in Neuro-Psychopharmacology & Biological Psychiatry 52:45–52.

                                                                                                                                                                                                        DOI: 10.1016/j.pnpbp.2013.09.014Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                        Accumulating evidence from both human and preclinical studies indicates that fetal development is affected by prenatal marijuana exposure. Findings on infant behavior or cognition are inconsistent. Beyond infancy, subtle differences have been found in specific cognitive or behavioral outcomes.

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                                                                                                                                                                                                        • Morris, C. V., J. A. DiNieri, H. Szutorisa, and Y. L. Hurd. 2011. Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment. European Journal of Neuroscience 34:1574–1583.

                                                                                                                                                                                                          DOI: 10.1111/j.1460-9568.2011.07884.xSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                          This review of the molecular mechanisms of both prenatal cannabis and prenatal tobacco exposure indicates that such exposures may be associated with epigenetic alterations leading to long-term disturbances in gene regulations and increasing the vulnerability to addiction.

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                                                                                                                                                                                                          • Schneider, M. 2009. Cannabis use in pregnancy and early life and its consequences: Animal models. European Archives of Psychiatry and Clinical Neuroscience 259:383–393.

                                                                                                                                                                                                            DOI: 10.1007/s00406-009-0026-0Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                            This article summarizes the behavioral outcomes of prenatal and early postnatal exposure to cannabis. In animal models, prenatal cannabinoid exposure is associated with deficits in learning and memory, as well as altered sensitivity to drug abuse, with some studies showing gender specificity. Authors concluded that evidence is incomplete. Available online for purchase or by subscription.

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                                                                                                                                                                                                            • Warner, T. D., D. Roussos-Ross, and M. Behnke. 2014. It’s not your mother’s marijuana. Effects on maternal–fetal health and the developing child. Clinical Perinatology 41:877–894.

                                                                                                                                                                                                              DOI: 10.1016/j.clp.2014.08.009Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                              This review provides a comprehensive review of marijuana’s effects on infertility, pregnancy-related complications, fetal growth, and birth outcomes. The authors note that the three longitudinal studies on birth outcomes have inconsistent findings. Studies on infertility, while limited in number, indicate decreased fertility for both males and females. In addition, studies on pregnancy complications are limited in number but suggestive of placental resistance, providing a partial explanation for intrauterine growth resistance.

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                                                                                                                                                                                                              Cocaine is a commonly used illegal substance. Cocaine readily crosses the placenta, so there is the potential for it to directly affect fetal development or disrupt nervous system development. Twenty years and more ago, prenatal cocaine exposure received considerable attention in the media, which associated using mothers with “crack babies”; however, current evidence from well-designed prospective investigations shows less severe sequelae in the majority of infants prenatally exposed to cocaine. At birth, prenatally exposed infants are at higher risk of preterm birth, low birthweight, and small for gestational age (Gouin, et al. 2011). Recent reviews have been conducted to examine the association between prenatal exposure to cocaine and birthing issues (Gouin, et al. 2011); the development and behavior consequences (Lambert and Bauer 2012); results from studies using neuroimaging, alcohol, or methamphetamines (Roussotte, et al. 2010 [cited under Maternal Substance Use: Alcohol]; Grewen, et al. 2014); and on the general impact on infants and toddler for both prenatal exposure to cocaine and to opioids (Bandstra, et al. 2010). Most reviews conclude that prenatal cocaine exposure is associated with subtle deficits. Some studies include other maternal drug use in their reviews; for example Bandstra, et al. 2010 reviews the evidence for prenatal exposure both to cocaine and to opioids, and Roussotte, et al. 2010 (cited under Maternal Substance Use: Alcohol) includes both alcohol and cocaine exposure. Longer term outcomes are also studied; for example Bandstra, et al. 2011 examines prenatal cocaine exposure and subsequent language development, while Ackerman, et al. 2010 reviews the literature on consequences of prenatal cocaine exposure at later ages because no effects had been noted to age six years of age. Lucca and Baldisserotto 2013 studies the outcomes of prenatal exposure to crack cocaine.

                                                                                                                                                                                                              • Ackerman, J. P., T. Riggins, and M. M. Black. 2010. A review of the effects of prenatal cocaine exposure among school-aged children. Pediatrics 125:554–565.

                                                                                                                                                                                                                DOI: 10.1542/peds.2009-0637Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                Noting that previous studies to age six had shown no long-term effects on children from prenatal cocaine exposure on physical growth, developmental test scores, or language outcomes, this review focused on outcomes for school-age children. The authors found that environmental variables moderated or explained the effects of prenatal cocaine exposure for school-age children’s functioning. After controlling for these effects, associations were found between exposure and sustained attention and behavioral self-regulation among school-age children.

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                                                                                                                                                                                                                • Bandstra, E. S., C. E. Morrow, V. H. Accornero, E. Mansoor, L. Xue, and J. C. Anthony. 2011. Estimated effects of in utero cocaine exposure on language development through early adolescence. Neurotoxicology and Teratology 33:23–35.

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                                                                                                                                                                                                                  The researchers examined the longitudinal effects of prenatal cocaine exposure on language development, finding an enduring stable effect on children’s language abilities, with no growth in effects over time.

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                                                                                                                                                                                                                  • Bandstra, E. S., C. E. Morrow, E. Mansoor, and V. H. Accornero. 2010. Prenatal drug exposure: Infant and toddler outcomes. Journal of Addictive Diseases 29.2: 245–258.

                                                                                                                                                                                                                    DOI: 10.1080/10550881003684871Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                    This paper describes an overview of current literature on the impact of prenatal exposure to drugs, including opioids and cocaine. Prenatal cocaine exposure appears to be associated with subtle decrements in neurobehavioral, cognitive, and language function, although the caregiving environment may mediate or moderate the effects. Infants prenatally exposed to heroin are at increased risk for lower birthweight, length, and head circumference compared to those nonexposed. Infants whose mothers were on methadone maintenance during pregnancy had higher birthweights than those born to heroin-dependent mothers not maintained on methadone. This review also includes the evidence on the use of methadone maintenance, which appears to improve fetal growth, compared to heroin-exposed infants. Some policymakers recommend lower-dose methadone to reduce or eliminate neonatal abstinence syndrome; others suggest that the evidence does not support the association between methadone maintenance and reduced neonatal abstinence syndrome.

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                                                                                                                                                                                                                    • Gouin, K., K. Murphy, P. S. Shah, and Knowledge Synthesis Group on Determinants of Low Birth Weight and Preterm Births. 2011. Effects of cocaine use during pregnancy on low birthweight and preterm birth: Systematic review and meta-analyses. American Journal of Obstetrics and Gynecology 204.340: e1–e12.

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                                                                                                                                                                                                                      The conclusion from this review found that cocaine use during pregnancy is associated with significantly higher risks of preterm birth, low birthweight, and small for gestational age infants as well as shorter gestational age at delivery and reduced birthweight.

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                                                                                                                                                                                                                      • Grewen, K., M. Burchinal, C. Vachet, et al. 2014. Prenatal cocaine effects on brain structure in early infancy. NeuroImage 101:114–123.

                                                                                                                                                                                                                        DOI: 10.1016/j.neuroimage.2014.06.070Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                        MRI scans were conducted on newborns to observe brain structural differences to explain the documented subtle deficits in cognitive and behavioral functions of children prenatally exposed to cocaine, compared with two control groups (no exposure and exposed to multiple drugs). Results suggest that prenatal cocaine exposure is associated with structural deficits in neonatal cortical gray matter, specifically in prefrontal and frontal regions involved in executive function and inhibitory control. It is unclear whether the smaller gray-matter volumes in prefrontal and frontal cortical regions are merely delayed or permanently altered.

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                                                                                                                                                                                                                        • Lambert, B. L., and C. R. Bauer. 2012. Developmental and behavioral consequences of prenatal cocaine exposure: A review. Journal of Perinatology 32:819–828.

                                                                                                                                                                                                                          DOI: 10.1038/jp.2012.90Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                          This review examines the literature on the association between in utero cocaine exposure and developmental and behavioral effects, including growth, neurobiology, intelligence, academic achievement, language, executive functioning, behavioral regulation, and psychopathology. The authors found, for example, consistent evidence of poorer cognitive performance of exposed children, yet found a consensus that prenatal exposure to cocaine alone does not independently lower global intelligence. Studies using neuroimaging techniques suggest an association between PCE and abnormalities in both brain structure and function. In other areas, the research is inconsistent. They note the lack of consistency in methodological approaches may contribute to the inconsistency.

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                                                                                                                                                                                                                          • Lucca, J., and M. Baldisserotto. 2013. Cerebral ultrasound findings in infants exposed to crack cocaine during gestation. Pediatric Radiology 43:212–218.

                                                                                                                                                                                                                            DOI: 10.1007/s00247-012-2528-6Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                            This study examined the outcomes of prenatal exposure to crack, a smokeable and addictive form of cocaine. Babies born to women who used crack during patients were subjected to transfontanellar US imaging. Abnormalities were found in 35 percent of babies. The abnormalities were discrete, and the authors concluded they were unlikely to be clinically significant.

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                                                                                                                                                                                                                            Maternal Stress

                                                                                                                                                                                                                            New research indicates the longer-term effects of prenatal exposure to stress. The fetal programming hypothesis is the basis of maternal stress research, theorizing that what is learned during fetal stages has long-term implications for adult diseases. Epigenetic modifications are well described in Ellison 2010. Glynn and Sandman 2006 describes the link between prenatal exposure to stress and adult diseases. Austin, et al. 2005 describes the current evidence on prenatal exposure to stress. A controlled animal model study, Davis, et al. 2005 discusses results of the administration of corticotrophin-releasing hormone (CRH) into the fetal and maternal circulation system, observing that stress responses may be affected by critical timing. Likely because of the considerable evidence on prenatal alcohol exposure and the hypothesis that some pregnant drinkers are also stressed, Schneider, et al. 2001 and Schneider, et al. 2004 are studies examining the outcomes of the combined risks of prenatal exposure to both stress and alcohol. Huizink 2011 concludes that study design flaws may be problematic in drawing conclusions when researchers have tried to disentangle the influences of prenatal substance use from prenatal stress. Graignic-Philippe, et al. 2014 summarizes the importance of applying context to maternal stress in order to understand fetal and child outcomes. Angelidou, et al. 2012 reviews the literature that suggests premature birth and susceptibility genes may increase vulnerability to allergic, environmental, infectious, or stress-related triggers and in turn the risk of autism spectrum disorders (ASD).

                                                                                                                                                                                                                            • Angelidou, A., S. Asad, K. -D. Alysandratos, A. Anna Karagkouni, S. Kourembanas, and T. C. Theoharides. 2012. Perinatal stress, brain inflammation and risk of autism: Review and proposal. BMC Pediatrics 12:89.

                                                                                                                                                                                                                              DOI: 10.1186/1471-2431-12-89Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                              There is little understanding of the pathogenesis of ASD. Increasing evidence suggests various ASD phenotypes. Many genes have been identified that increase susceptibility to ASD, but environmental factors may also contribute. This article reviews literature that suggests in utero inflammation can lead to preterm labor, with insufficient development of gut-blood–brain barriers permitting exposure to potential neurotoxins. The risk may be increased with gestational allergic or autoimmune conditions, or if mothers are exposed to stressors. Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers.

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                                                                                                                                                                                                                              • Austin, M. P., L. R. Leader, and N. Reilly. 2005. Prenatal stress, the hypothalamic-pituitary-adrenal axis, and fetal and infant neurobehaviour. Early Human Development 81.11: 917–926.

                                                                                                                                                                                                                                DOI: 10.1016/j.earlhumdev.2005.07.005Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                These authors examine the small but growing evidence for the theory that prenatal stress impacts offspring neural function and behavior in animal populations.

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                                                                                                                                                                                                                                • Davis, E. P., L. M. Glynn, C. Dunkel Schetter, C. Hobel, A. Chicz-Demet, and C. A. Sandman. 2005. Corticotropin-releasing hormone during pregnancy is associated with infant temperament. Developmental Neuroscience 27.5: 299–305.

                                                                                                                                                                                                                                  DOI: 10.1159/000086709Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                  Researchers administered CRH into maternal and fetal circulation from the placenta in an animal model study. Previous research shows that elevated levels of placental CRH are associated with spontaneous preterm birth. Results showed possible sensitive periods for the effects of stress on infant temperament.

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                                                                                                                                                                                                                                  • Ellison, P. T. 2010. Fetal programming and fetal psychology. Infant and Child Development 19:6–20.

                                                                                                                                                                                                                                    DOI: 10.1002/icd.649Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                    Summarizes epidemiological evidence that prenatal conditions determine outcomes in adult health and support the fetal programming hypothesis. Epigenetic modification of gene expression appears to affect the HPA axis. Epigenetics has contributed to understanding patterns of gene expression, including the sensitivity of the HPA axis from prenatal alteration of gene expression. Available online for purchase or by subscription.

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                                                                                                                                                                                                                                    • Glynn, L. M., and C. A. Sandman. 2006. The influence of prenatal stress and adverse birth outcome on human cognitive and neurological development. International Review of Research in Mental Retardation 32:109–129.

                                                                                                                                                                                                                                      DOI: 10.1016/S0074-7750(06)32004-6Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                      Review of the evidence on the link between prenatal exposure to stress and subsequent health outcomes, including hypertension, coronary heart disease, and diabetes, as well as psychiatric illnesses and cognitive and neurological functions. Available online for purchase or by subscription.

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                                                                                                                                                                                                                                      • Graignic-Philippe, R., J. Dayan, S. Chokron, A. Y. Jacquet, and S. Tordjman. 2014. Effects of prenatal stress on fetal and child development: A critical literature review. Neuroscience & Biobehavioral Reviews 43:137–162.

                                                                                                                                                                                                                                        DOI: 10.1016/j.neubiorev.2014.03.022Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                        In this critical literature review, the authors conclude that the most conclusive adverse outcome of maternal stress is preterm delivery or low birthweight. The authors emphasize the importance individual response, presence of protective factors like social support, the gestational stage during which a stressor is introduced, its duration, and whether there is chronic exposure.

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                                                                                                                                                                                                                                        • Huizink, A. 2011. Prenatal substance use, prenatal stress and offspring behavioural outcomes; considerations for future studies. Nordic Journal of Psychiatry 66.2: 115–122.

                                                                                                                                                                                                                                          DOI: 10.3109/08039488.2011.641586Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                          This review found that studies that disentangled prenatal influences consistently show an effect of prenatal substances use exposure on birthweight but little evidence for causal effects on behavior. The opposite was found for studies on the effects of prenatal stress, which may have an effect on behavior. Few studies differentiate these two prenatal exposures.

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                                                                                                                                                                                                                                          • Schneider, M. L., C. F. Moore, and G. W. Kraemer. 2001. Moderate alcohol during pregnancy: Learning and behavior in adolescent rhesus monkeys. Alcoholism: Clinical and Experimental Research 25.9: 1383–1392.

                                                                                                                                                                                                                                            DOI: 10.1111/j.1530-0277.2001.tb02362.xSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                            Less research has been conducted on low-level exposure to alcohol, although heavy exposure has been well documented for its cognitive and behavioral outcomes. This animal model trial observed that the most adverse behavioral outcomes were associated with moderate prenatal alcohol exposure plus prenatal stress, indicating that maternal stress might heighten the adverse effects fetal alcohol exposure.

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                                                                                                                                                                                                                                            • Schneider, M. L., C. F. Moore, and G. W. Kraemer. 2004. Moderate level alcohol during pregnancy, prenatal stress, or both and limbic-hypothalamic-pituitary-adrenocortical axis response to stress in rhesus monkeys. Child Development 75.1: 96–109.

                                                                                                                                                                                                                                              DOI: 10.1111/j.1467-8624.2004.00656.xSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                              This study adds to evidence using animal model research regarding the impact of a combination of moderate prenatal alcohol exposure and prenatal maternal stress on the fetal or early childhood stages. Offspring show reduced behavioral adaptation to stress compared with controls.

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                                                                                                                                                                                                                                              Depression during pregnancy appears to have health consequences for the fetus. In a review of prenatal exposure to maternal depression, Field, et al. 2006 finds adverse health consequences for the fetus. Alder, et al. 2007 finds that maternal depression is associated with obstetric complications. Research focuses on depression treatments during pregnancy and fetal outcomes or postpartum depression. Davalos, et al. 2012 reports a number of outcomes that affect a developing fetus and could impact into adulthood. Suri, et al. 2014 notes the paucity of research in this area along with short untreated depression.

                                                                                                                                                                                                                                              • Alder, J., N. Fink, J. Bitzer, I. Hösli, and W. Holzgreve. 2007. Depression and anxiety during pregnancy: A risk factor for obstetric, fetal and neonatal outcome? A critical review of the literature. Journal of Maternal-Fetal & Neonatal Medicine 20.3: 189–209.

                                                                                                                                                                                                                                                DOI: 10.1080/14767050701209560Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                Elevated levels of maternal depression and anxiety are associated with obstetric complications and preterm labor and have implications for fetal and neonatal well-being and behavior. Potentially confounding and protective factors and plausible biological mechanisms have received little attention.

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                                                                                                                                                                                                                                                • Davalos, D. B., C. A. Yadon, and H. C. Tregellas. 2012. Untreated prenatal maternal depression and the potential risks to offspring: A review. Archives of Women’s Mental Health 15.1: 1–14.

                                                                                                                                                                                                                                                  DOI: 10.1007/s00737-011-0251-1Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                  A review of unmedicated prenatal depression identified numerous associated fetal health issues, including irregularities in fetal habituation patterns, frontal EEG asymmetry, and reduced vagal tone. These irregularities are thought to contribute to challenges in infant development, including general central nervous system development, abnormal brain processing, emotional dysregulation, and stress vulnerability. The authors outline multiple challenges in their analysis, including the lack of research comparing medicated and unmedicated pregnant mothers as well as lack of research overall.

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                                                                                                                                                                                                                                                  • Field, T., M. Diego, M. Hernandez-Reif. 2006. Prenatal depression effects on the fetus and newborn: A review. Infant Behavior and Development 29.3: 445–455.

                                                                                                                                                                                                                                                    DOI: 10.1016/j.infbeh.2006.03.003Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                    A review on prenatal effects of maternal depression shows elevated fetal activity, delayed growth, and increased rates of prematurity and low birthweight. Newborns show profiles mimicking maternal prenatal biochemical/physiological profiles, including elevated cortisol, lower dopamine and serotonin levels, greater right frontal EEG activation, and lower vagal tone.

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                                                                                                                                                                                                                                                    • Suri, R., A. S. Lin, L. S. Cohen, and L. L. Altshuler. 2014. Acute and long-term behavioral outcome of infants and children exposed in utero to either maternal depression or antidepressants: A review of the literature. Journal of Clinical Psychiatry 75.10: e1142.

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                                                                                                                                                                                                                                                      Compares neonatal outcomes of infants exposed to untreated depression or antidepressants in utero. Notes short-term effects of neonatal exposure to untreated depression included disturbed sleep as well as lower scores in habituation, orientation, and motor clusters of the Brazelton Neonatal Behavioral Assessment score. Long-term effects of untreated depression were less conclusive but may include increased behavioral difficulties, adolescent depression, and/or a delay in sensitivity to nonnative language discrimination. The authors noted a need for further research focusing on the effects of untreated depression on neonatal outcomes in humans.

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                                                                                                                                                                                                                                                      Antidepressant Medications

                                                                                                                                                                                                                                                      Prenatal exposure to antidepressants remains a priority for clinicians. The prevalence of depression during pregnancy is 10 percent to 16 percent with potential risks both to continuation of treatment if selective serotonin reuptake inhibitors (SSRIs) are found to be teratogenic and risks to discontinuation of treatment for maternal depression. After fifteen years of research, evidence on risks associated with prenatal exposure to antidepressants, including SSRIs, remains inconclusive. Hayes, et al. 2012 and Nordeng, et al. 2012 are large cohort studies but identify contradicting results. Reviews include Moses-Kolko, et al. 2005; Hallberg and Sjöblom 2005; and Gentile 2007. Oberlander, et al. 2010 examines the behavioral effects on three-year-olds to prenatal exposure to SSRIs. Huybrechts, et al. 2014 is a systematic review and meta-analysis in which the authors posit that it may be possible that the observed increase in risk to fetuses currently associated with prenatal exposure to antidepressants may in fact be due to multiple weak, confounding effects of maternal depression.

                                                                                                                                                                                                                                                      • Gentile, S. 2007. Serotonin reuptake inhibitor-induced perinatal complications. Paediatric Drugs 9.2: 97–106.

                                                                                                                                                                                                                                                        DOI: 10.2165/00148581-200709020-00003Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                        This review summarizes fifty studies evaluating maternal Serotonin reuptake inhibitor (SRI) use in late pregnancy for fetal and birth complications. SRI exposure in late pregnancy is clearly associated with an increased central nervous system and respiratory effects. Some evidence suggests that SRIs may interfere with neonatal physiology of the respiratory system and parasympathetic activity.

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                                                                                                                                                                                                                                                        • Hallberg, P., and V. Sjöblom. 2005. The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding: A review and clinical aspects. Journal of Clinical Psychopharmacology 25.1: 59–73.

                                                                                                                                                                                                                                                          DOI: 10.1097/ Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                          This review examines SRIs’ use during pregnancy and lactation, which is discouraged for safety reasons. SRIs are often preferred over tricyclic antidepressants to reduce adverse effects and risk of overdose.

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                                                                                                                                                                                                                                                          • Hayes, R. M., P. Wu, R. C. Shelton, et al. 2012. Maternal antidepressant use and adverse outcomes: A cohort study of 228,876 pregnancies. American Journal of Obstetrics & Gynecology 49:e1–e9.

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                                                                                                                                                                                                                                                            This retrospective cohort study evaluated the effect of SSRI and other antidepressant exposure on pregnancy outcomes by trimester. In the first trimester, 75 percent of women discontinued use of antidepressant medication. Second-trimester antidepressant use is associated with preterm birth, and third-trimester use of SSRIs is associated with neonatal convulsions.

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                                                                                                                                                                                                                                                            • Huybrechts, K. F., R. S. Sanghani, J. Avorn, and A. C. Urato. 2014. Preterm birth and antidepressant medication use during pregnancy: A systematic review and meta-analysis. PLoS One 9.3: e92778.

                                                                                                                                                                                                                                                              DOI: 10.1371/journal.pone.0092778Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                              In this meta-analysis, the authors review forty-one studies evaluating the relationship between maternal use of antidepressants and preterm birth as contributors to neonatal morbidity and mortality. Findings indicate maternal use of antidepressants is associated with increased risk of preterm birth and that the risk is enhanced in later-stage gestational use. Secondary analyses controlling for confounding effects of maternal depression indicate that several weak confounders could contribute to the effect but that a single confounder is not likely to cause the observed relationship.

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                                                                                                                                                                                                                                                              • Moses-Kolko, E. L., D. Bogen, J. Perel, et al. 2005. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: Literature review and implications for clinical applications. JAMA: The Journal of the American Medical Association 293.19: 2372–2383.

                                                                                                                                                                                                                                                                DOI: 10.1001/jama.293.19.2372Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                Authors reviewed the evidence (thirteen case reports describing a total of eighteen cases) regarding SRI-related neonatal behavioral syndrome, which is associated with in utero SRI exposure during the last trimester of pregnancy. This identification poses clear risks and benefits of discontinuing an SRI during pregnancy. Available online for purchase or by subscription.

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                                                                                                                                                                                                                                                                • Nordeng, H., M. M. H. J. van Gelder, O. Spigset, G. Koren, A. Einarson, and M. Eberhard-Gran. 2012. Pregnancy outcomes after exposure to antidepressants and the role of maternal depression. Journal of Clinical Psychopharmacology 32.2: 186–194.

                                                                                                                                                                                                                                                                  DOI: 10.1097/JCP.0b013e3182490eafSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                  This subproject of the Norwegian Mother and Child Cohort Study did not confirm a relationship between prenatal exposure to SSRIs and congenital malformations, birthweight, and gestational age. A subanalysis does identify a relationship between the underlying illness, maternal depression, and preterm birth.

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                                                                                                                                                                                                                                                                  • Oberlander, T. F., M. Papsdorf, U. M. Braine, S. Misri, C. Ross, and R. Grunau. 2010. Prenatal effects of selective serotonin reuptake inhibitor antidepressants, serotonin transporter promoter genotype (SLC6A4), and maternal mood on child behavior at 3 years of age. Archives of Pediatrics & Adolescent Medicine 164.5: 444–451.

                                                                                                                                                                                                                                                                    DOI: 10.1001/archpediatrics.2010.51Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                    Prenatal exposure to SSRIs and maternal mood are found to effect child behavior at age three years, specifically with increased internalizing behaviors.

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                                                                                                                                                                                                                                                                    In 2010 the WHO recommended antiretroviral therapy (ART) to HIV-infected women during pregnancy to prevent mother-to-child transmission. Research has focused on adherence to ART and transmission rates, particularly in countries where HIV is concentrated. Mofenson 2010 examines the literature on the prevention of mother-to-child transmission. Both Sturt, et al. 2010 and Suksomboon, et al. 2007 are systematic reviews examining optimal therapies to reduce transmission. Suthar, et al. 2013 finds that integrating ART into antenatal care is feasible. Giuliano, et al. 2013 examines determinants of HIV transmission with ART, which still occurs in small proportions of infants. Nachega, et al. 2012 examines ART adherence rates during pregnancy in different countries.

                                                                                                                                                                                                                                                                    • Giuliano, M., M. Andreotti, G. Liotta, et al. 2013. Maternal antiretroviral therapy for the prevention of mother-to-child transmission of HIV in Malawi: Maternal and infant outcomes two years after delivery. PloS One 8.7: e68950.

                                                                                                                                                                                                                                                                      DOI: 10.1371/journal.pone.0068950Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                      Despite increased availability of ART during pregnancy, some infants still contract the virus. This observational study examined 311 pregnant HIV-infected women in Malawi receiving ART. HIV transmission from mother to child occurred among women with high CD4+ counts. HIV-exposed infants also experienced other adverse events, including anemia and associated lower infant weight as well as gastroenteritis. Despite these risks, the authors still conclude maternal ART is significantly beneficial for both maternal and infant health.

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                                                                                                                                                                                                                                                                      • Mofenson, L. M. 2010. Prevention in neglected subpopulations: Prevention of mother-to-child transmission of HIV infection. Clinical Infectious Diseases 50:S130–S148.

                                                                                                                                                                                                                                                                        DOI: 10.1086/651484Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                        This review article examines the prevention of HIV mother-to-child transmission. In Western countries, testing routines, antiretroviral therapy, elective cesarean delivery, and avoidance of breastfeeding have reduced newborn infection to 1 to 2 percent. The perinatal epidemic continues in sub-Saharan Africa, where implementation of identified simple, inexpensive, effective antiretroviral prophylaxis regimens is slow.

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                                                                                                                                                                                                                                                                        • Nachega, J. B., A. U. Olalekan, J. Anderson, et al. 2012. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: A systematic review and meta-analysis. AIDS 26.16: 2039–2052.

                                                                                                                                                                                                                                                                          DOI: 10.1097/QAD.0b013e328359590fSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                          This systematic and meta-analysis examined adequate ART adherence during and after pregnancy, which was only 72 percent of all pregnant women. The authors concluded that optimal adherence is a challenge among pregnant and postpartum women. Pregnancy-related deterrents included morning sickness and heartburn. Additional deterrents included HIV- and AIDS-related symptoms such as nausea and fatigue. Finally, individual barriers to optimal adherence included stress (physical, economic, and emotional), depression, alcohol and drug use, and the ART regimen itself. High adherence was related to disclosure of HIV status and social support.

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                                                                                                                                                                                                                                                                          • Sturt, A. S., E. K. Dokubo, and T. T. Sint. 2010. Antiretroviral therapy (ART) for treating HIV infection in ART-eligible pregnant women. Cochrane Database of Systematic Reviews 17.3: CD008440.

                                                                                                                                                                                                                                                                            DOI: 10.1002/14651858.CD008440Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                            This review, part of a WHO series of systematic reviews, focuses on mother-to-child transmission in utero, intrapartum, and during breastfeeding. Three RCTs and six observational studies were selected, none addressing maternal mortality, optimal regimens during pregnancy, or when therapy should start according to laboratory parameters and gestational age.

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                                                                                                                                                                                                                                                                            • Suksomboon, N., N. Poolsup, and S. Ket-Aim. 2007. Systematic review of the efficacy of antiretroviral therapies for reducing the risk of mother-to-child transmission of HIV infection. Journal of Clinical Pharmacy and Therapeutics 32.3: 293–311.

                                                                                                                                                                                                                                                                              DOI: 10.1111/j.1365-2710.2007.00825.xSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                              This systematic review examines the efficacy of antiretroviral therapies in reducing the risk of mother-to-child transmission of HIV infection, low birthweight, and fetal/child mortality rates. Fifteen trials were included examining therapeutic regimens using zidovudine, nevirapine monotherapy, lamivudine, nevirapine, or a combination, comparing dosage and timing for efficacy.

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                                                                                                                                                                                                                                                                              • Suthar, A. B., A. Beqiri, K. Lorenz-Denhe, C. McClure, and C. Duncombe. 2013. Integrating antiretroviral therapy into antenatal care and maternal and child health settings: A systematic review and meta-analysis. Bulletin of the World Health Organization 91:46–56.

                                                                                                                                                                                                                                                                                DOI: 10.2471/BLT.12.107003Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                Because of the extensive number of pregnant women who are not tested or who do not attend antenatal care facilities, mother-to-infant transmission of HIV, and subsequent mortality by age two years, is extensive. This review found that ART in antenatal clinics leads to higher ART coverage. ART integration is feasible, in spite of various barriers for caregivers and for women.

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                                                                                                                                                                                                                                                                                Gestational diabetes is common, and medical treatment has been problematic because of adverse health risks. Similar to many maternal diseases, such as depression or HIV/AIDS, research focuses on harm to the fetus of the therapy and risks of nontreatment. Both Melamed and Yogev 2009 and Giuffrida, et al. 2003 examine the small body of literature on the most effective methods of treating diabetes during pregnancy. Hartling, et al. 2013 examines the benefits and harms associated with treating gestational diabetes. Oteng-Ntim, et al. 2012 examines the effects of lifestyle interventions. Both studies identified a paucity of robust research upon which their systematic review and meta-analyses could be based.

                                                                                                                                                                                                                                                                                • Giuffrida, F. M. A., A. A. Castro, A. N. Atallah, and S. A. Dib. 2003. Diet plus insulin compared to diet alone in the treatment of gestational diabetes mellitus: A systematic review. Brazilian Journal of Medical and Biological Research 36.10: 1297–1300.

                                                                                                                                                                                                                                                                                  DOI: 10.1590/S0100-879X2003001000004Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                  This systematic review of six RCTs compares the efficacy of two therapeutic modalities, diet alone and diet plus insulin, in preventing macrosomia in fetuses. A meta-analysis of the data leads to the conclusion about the potential benefit of insulin, although results are not significant enough to set treatment guidelines.

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                                                                                                                                                                                                                                                                                  • Hartling, L., D. M. Dryden, A. Guthrie, M. Muise, B. Vandermeer, and L. Donovan. 2013. Benefits and harms of treating gestational diabetes mellitus: A systematic review and meta-analysis for the US Preventive Services Task Force and the National Institutes of Health Office of Medical Applications of Research. Annals of Internal Medicine 159.2: 123–129.

                                                                                                                                                                                                                                                                                    DOI: 10.7326/0003-4819-159-2-201307160-00661Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                    This systematic review and meta-analysis summarizes evidence of the benefits and harms of treating gestational diabetes with diet modification, glucose monitoring, and insulin in comparison to no treatment. Evidence suggests treating gestational diabetes reduces preeclampsia, shoulder dystocia, and very low birthweight. The authors found no support for the hypothesized harms associated with treatment of gestational diabetes, but the lack of findings could be the result of study heterogeneity or lack of power across studies.

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                                                                                                                                                                                                                                                                                    • Melamed, N., and Y. Yogev. 2009. Can pregnant diabetics be treated with glyburide? Women’s Health 5.6: 649–658.

                                                                                                                                                                                                                                                                                      DOI: 10.2217/whe.09.55Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                      Evidence is weak, based on only one case study, to support the recommendation that oral hypoglycemic agents should not be used during pregnancy because of potential adverse fetal outcomes. Studies have shown that glyburide minimally crosses the placenta. Large RCTs are required.

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                                                                                                                                                                                                                                                                                      • Oteng-Ntim, E., R. Varma, H. Croker, L. Poston, and P. Doyle. 2012. Lifestyle interventions for overweight and obese pregnant women to improve pregnancy outcome: Systematic review and meta-analysis. BMC Medicine 10.1: 47.

                                                                                                                                                                                                                                                                                        DOI: 10.1186/1741-7015-10-47Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                        This systematic review and meta-analysis includes thirteen RCTs and six non-RCTs with wide variations in the interventions between the studies. Lifestyle, dietary, and activity advice lowers the risk of gestational diabetes among overweight and obese pregnant women. Lifestyle interventions have no reported relationship with caesarean delivery, large for gestational age, birthweight, or macrosomia. The authors report that the quality of studies included is poor but confirm results are consistent with existing evidence.

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