Bookmark and Share

September 2008 | Back to Table of Contents

Clinical and Health Affairs

Prenatal Environmental Exposures and Child Health

Minnesota’s Role in the National Children’s Study

By Wendy L. Hellerstedt, M.P.H., Ph.D., Patricia M. McGovern, Ph.D., M.P.H., R.N., Patricia Fontaine, M.D., M.S., Charles N. Oberg, M.D., M.P.H., and Jill E. Cordes, R.N., B.S.N.

Abstract
Five medical conditions are responsible for approximately $250 billion in annual health care costs in the United States: obesity, asthma, diabetes, schizophrenia, and autism. For some individuals, these conditions may begin with in utero exposures. However, firm evidence about the links between these conditions and such exposures has yet to be established. The National Children’s Study (NCS) is designed to examine how maternal health and the fetal environment are associated with these and other conditions, including birth defects. The NCS will assess how hundreds of social, physical, and environmental exposures affect the health of 100,000 children. The results will provide a data resource from which to develop effective preventive strategies, establish health and safety guidelines, find cures and interventions, influence legislation, and shape public health programs for families and children. The purpose of this article is to describe some of what is known about teratogenesis, how child and adult health can be affected by in utero exposures, and Minnesota’s role in the NCS.


A growing body of evidence suggests that the foundation of adult health begins in utero.1-8 Increasingly, prenatal environmental exposures are thought to lead to fetal loss, congenital anomalies, and other health conditions that affect the survival, growth, health, and development of offspring. This is based on growing understanding of fetal development and the mechanisms of teratogenesis, the process by which birth defects occur.

Fetal susceptibility to environmental teratogens is based on the genotype of the conceptus and how and when it interacts with the teratogen. There are critical periods when the fetal organ systems and tissues are most sensitive to specific teratogens. These usually correspond to the time when they are undergoing rapid growth and morphological changes. For example, the heart is most sensitive during the 3rd and 5th weeks of gestation; thus, a teratogen that could be responsible for structural heart defects may have a minimal impact if the fetus is not exposed to it until the 3rd trimester of pregnancy.

In addition to timing and genetic susceptibility, other factors can affect the outcome of fetal exposure to a potential teratogen. These include the nature of the exposure, the route and degree of maternal exposure, and the rate of placental transfer and systemic absorption.9 Teratogens are most frequently studied relative to birth defects, which occur in 3% of all live births.10 Birth defects account for more than 20% of infant deaths in the United States and often co-occur with other poor outcomes in infants.11 An analysis of more than 7 million births in the United States showed that preterm infants are more than twice as likely to be born with birth defects.12 Another recent study suggests that preterm births, and not birth defects, may be the leading cause of infant mortality in the United States, accounting for about a third of all infant deaths.13 Both birth defects and poor fetal growth are also associated with significant long-term morbidity.14,15 Although birth defects that are associated with known teratogens may be preventable, about 65% of birth defects have no known or identifiable cause.10 And although many potential or likely causes of preterm birth and low birth weight have been identified, interventions to prevent them are often unsuccessful because their exact etiology remains poorly understood.16

The fetal origins hypothesis—that the origins of later disease can occur in utero—is strongly related to teratogenesis in that it suggests that fetal programming occurs in response to a stimulus during a critical period of development. A disordered fetal environment thus increases the risk for adult disease. Although a classic teratogenic event results from a single exposure to an environmental teratogen, in the fetal origins model, there may be ongoing changes in the endocrine or metabolic systems of the fetus in response to an exposure. Studies have shown, for example, that infants who are born with intrauterine growth retardation and/or whose mothers experienced nutritional deprivation at specific times during gestation are at increased risk of developing insulin resistance or hypertension as adults.1,8 In addition to risk factors for coronary artery disease, maternal deprivation, low birth weight, and/or intrauterine growth retardation may also be associated with obesity, kidney disease, breast and other cancers, and schizophrenia.2,4,5,8 The fetal origins model emphasizes the importance of maternal health and behaviors not only for the health of the fetus but also for the health of the offspring with respect to chronic disease.

Identifying Teratogens
Because most teratogens are not known, the etiology of most birth defects is unknown. For example, autism spectrum disorders (ASDs) likely have a strong genetic component that may interact with environmental exposures to increase risk; but specific genes—and environmental exposures—have not been conclusively identified.3 Among the many potential teratogens under investigation for ASD are maternal exposure to neurotoxins and endocrine disruptors from air pollution.6 The identification of teratogens depends, in part, on how common the outcome and/or the exposure are. If a teratogen causes an outcome that is rare (eg, a drug exposure that is responsible for 1 in 10,000 miscarriages), it is not likely to be identified. It is also difficult to detect a teratogen that causes an outcome that is also common to those not exposed to it (eg, cocaine exposure and preterm birth). Some teratogens cause an outcome that is rare among those not exposed (eg, maternal diethylstilbestrol exposure and clear-cell adenocarcinoma of the vagina and cervix among offspring) and can be detected through well-designed studies.17 The easiest teratogens to identify are those for which the outcome is singularly associated with a teratogen (eg, alcohol consumption during pregnancy and fetal alcohol syndrome).

To identify teratogens, it is necessary to have precise documentation of the timing and dose of exposure. Some teratogens do not exert harm below a certain threshold of exposure, as evidenced in the studies of exposure to radiation following the atomic bombing of Hiroshima and infant microcephaly: risk increased proportionate to the distance the mother lived from the hypocenter of the blast at the time of the bombing.7 Because there are critical periods of embryonic and fetal growth, teratogens may have a limited time when they can exert damage. The major limb defects associated with fetal thalidomide exposure from 1957 to 1962 illustrate that the critical periods for development (and teratogenesis) can be short. The most important period for limb development is 24 to 26 days after fertilization. Exposure to thalidomide, or another relevant teratogen, before day 33 may cause severe limb defects, such as amelia, the absence of limbs. Exposure in the 3rd trimester—well after limb development is complete—may have no effect.18

Further Information

For a list of known teratogens: msds.chem.ox.ac.uk/
teratogens.html
 

For information about adjunct studies: nationalchildrensstudy.gov/research/adjunctstudies/Pages/default.aspsor contact the University of Minnesota research team at
ncs-info@ncs.umn.edu

For NCS hypotheses and related literature reviews: nationalchildrensstudy.
gov/research/

For information and consultation on pediatric environmental health issues, contact the Great Lakes Center for Children’s Environmental Health:
uic.edu/sph/glakes/kids/

To identify teratogens, women must also know they have been exposed, thus teratogens associated with maternal drug or radiation treatment may be identifiable because timing and dose is often documented and not dependent on recall. Because tobacco exposure is so common and because its dose and timing can be reported, it has been possible to study the effect of exposure to tobacco smoke on intrauterine growth.19 It is much more difficult to identify inadvertent exposures to teratogens in the workplace or in air, food, or water.

Fetal exposure can occur as compounds pass from the maternal circulation through the placenta, or it can be independent of placental circulation. Examples of placenta-dependent exposures are polychlorinated biphenols (PCBs), polycyclic hydrocarbons such as benzo[a]pyrene found in environmental tobacco smoke, ethanol, and carbon monoxide. Lead is actively transported across the placenta via calcium transport mechanisms. Placenta-independent exposures include ionizing radiation, heat exposure during the 1st trimester, and noise.9,18,20

The National Children’s Study
The National Children’s Study (NCS) will examine how environmental, biologic, behavioral, and genetic factors are associated with the health of infants, children, adolescents, and young adults. Congress enacted the Children’s Health Act of 2000, which authorized the Eunice Kennedy Shriver National Institute for Child Health and Human Development to conduct the NCS. The study is a collaborative effort led by the U.S. Department of Health and Human Services—through the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC)—and the U.S. Environmental Protection Agency (EPA). More than 40 other federal agencies and departments have assisted with the study design.

The NCS is the largest and most comprehensive study of child health and development ever conducted in the United States: 100,000 pregnant women will be enrolled and followed during and after pregnancy. Their children will be followed until 21 years of age. It will provide an unprecedented amount of data about important childhood conditions such as asthma, birth defects, injuries, diabetes, obesity, physical development, autism, and other behavioral and mental health conditions. That data will be used to develop effective prevention strategies, establish health and safety guidelines, inform treatment options, influence health legislation, and shape public health programs for families and children.

The NCS will be conducted in 105 locations nationwide including several Minnesota counties. The University of Minnesota received funding in September 2007 to conduct NCS research in Ramsey County. South Dakota State University (SDSU) in Brookings was funded in November 2005 to conduct the study in Pipestone, Yellow Medicine, and Lincoln counties in Minnesota, and in Brookings County in South Dakota.

The SDSU center will enroll a total of 1,250 infants over 5 years. Women and children in Pipestone, Yellow Medicine, and Lincoln counties will be enrolled in the study starting in the spring of 2009. The University of Minnesota will begin enrolling Ramsey County women and children in 2010, with the goal of collecting data from 1,000 Ramsey County children and their parents (250 births a year for 4 years). The research teams in Minnesota have been working with a number of partners, including major health plans and hospital systems and the Minnesota Department of Health. The SDSU team has also been working with the Countryside, Lincoln, Lyon, Murray, and Pipestone public health agencies, and the University of Minnesota team has been working with the St. Paul-Ramsey County Health Department.

The NCS and Suspected Teratogens
Among the emerging environmental concerns the NCS will examine are the effects of suspected eco-estrogens such as perfluorochemicals (PFCs) and bisphenol A (BPA) and phthalates. “Plastics” is the general term for a wide array of synthetic or semisynthetic products that are produced by polymerization. Phthalates, a group of chemicals that make plastic products soft and increase flexibility, are found in many products used by women and children including perfume, hairspray, soap, skin moisturizers, food packaging, pacifiers, bottle nipples, rattles, and teething rings. BPA is used to make polycarbonate plastic products that are clear and shatter-proof. Plastics that contain BPA are frequently found in baby bottles and food containers, in dental sealants, and in the protective lining of food cans. Phthalates and BPA are classified as endocrine disruptors.

Because plastic products are ubiquitous in our environment, everyone in the population is exposed to them. The CDC examined the urine of a general population sample and found phthalate metabolites in 75% and BPA in 93% of the subjects.21,22 In the most recent report on the NHANES 2001-2002 subsample, the concentrations for the monoester phthalate metabolites are reported to be similar to concentrations to those reported in the earlier survey.21,23

Perfluoronated chemicals (PFCs) are compounds used in products such as nonstick cookware and fabrics that are more resistant to heat, oil, grease, and water. The evidence that PFCs are associated with fetal growth is inconclusive. No effect of perfluorooctanesulfate (PFOS) exposure on fetal growth in humans was reported in a study using self-reported birth weight and occupational histories or in a study that examined maternal and infant cord blood samples from 15 mother-infant dyads.24,25 However, Apelberg et al. reported that levels of both PFOS and perfluorooctanoate (PFOA) were inversely related to birth weight, newborn head circumference, crown-heel length, and ponderal index, although their study used cord blood samples taken post-delivery to measure these metabolites.26 Another recent study suggested an inverse association between maternal plasma PFOS and PFOA levels during pregnancy and birth weight, but no effects were seen for preterm birth, small size for gestation, or low birth weight.27 The health risk limits—or threshold for a specific hazardous agent at which adverse health effects may be observed—for PFOS and PFOA are under discussion at the state and federal levels.

The NCS has the potential to conclusively identify teratogens and to assess whether maternal metabolism and endocrine function can “program” fetal development. Among the many issues it will examine are whether:

  • impaired maternal glucose metabolism is associated with birth defects, offspring obesity, and insulin resistance;
  • maternal mediators of inflammation are associated with preterm birth;
  • prenatal infections and mediators of inflammation are associated with schizophrenia;
  • maternal subclinical hypothyroidism is associated with neurodevelopmental disabilities;
  • prenatal maternal stress, genetic, and environmental factors are associated with childhood asthma; and
  • prenatal exposure to hormonally active environmental agents is associated with abnormal development of the offspring reproductive system.28

The Role of Health Care Providers
The support of obstetricians, family physicians, pediatricians, and nurses will be critical for meeting the NCS’s ambitious goals—particularly recruiting and retaining 1,000 to 1,250 families per study center. Physicians are uniquely positioned to help the research team build relationships with families and to encourage their participation, as they are among the most trusted sources of information about occupational and environmental health risks.29 Parents residing in the selected counties are likely to question their physicians about the value of participating in the NCS and, if enrolled, about the meaning of any findings.

Representatives from both the University of Minnesota and SDSU research teams have started conducting outreach with physicians in order to learn how best to integrate the NCS protocols in clinics and hospitals while minimizing provider and patient burden. As the NCS researchers begin enrolling and following participants, they will maintain communication with physicians to keep them abreast of their clients’ involvement in the study. In addition to yielding its own findings, the NCS will serve as a platform upon which additional scientific studies can be built.

Conclusion
The NCS is an ambitious study, and its duration and scope pose many challenges that will require a significant mobilization of people, funding, and leadership at all levels. It also requires attention to issues of privacy, confidentiality, timing for reporting findings, and the ethical considerations that arise in research involving pregnant women and children. The success of the NCS will depend on the collaboration of academics, health care providers, community representatives, and families who will contribute to the aim of this research project: to improve the health and welfare of infants, children, and youth for generations to come. MM

Wendy Hellerstedt is an associate professor in the School of Public Health and the co-principal investigator for the NCS: Ramsey County. Patricia McGovern is a professor in the School of Public Health and the principal investigator of the NCS: Ramsey County. Patricia Fontaine is an associate professor in the Medical School, a family physician, and a co-investigator for the NCS: Ramsey County. Charles Oberg is an associate professor in the School of Public Health, a pediatrician, and a co-investigator for the NCS: Ramsey County. Jill Cordes is a research coordinator in the School of Public Health and the hospital liaison for the NCS: Ramsey County. All are at the University of Minnesota-Twin Cities.

We would like to thank the following people for their thoughtful review of this manuscript: William Toscano, Ph.D., professor and division head, and Timothy Church, Ph.D., professor and NCS co-investigator, both from the Division of Environmental Health Sciences, School of Public Health, University of Minnesota; and Bonny Specker, Ph.D., M.S., principal investigator, NCS, South Dakota State University Study Center, Brookings, South Dakota.

This project has been funded, in part, with funds from the Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under contract No. HHSN267200700022C.

References
1. Godfrey KM, Barker DJ. Fetal programming and adult health. Public Health Nutr. 2001;4(2B):611-24.
2. Hilakivi-Clarke L, de Assis S. Fetal origins of breast cancer. Trends Endocrinol Metab. 2006;17(9):340-8.
3. Newschaffer CJ, Croen LA, Daniels J, et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health. 2007;28:235-58.
4. Nilsson E, Stålberg G, Lichtenstein P, Cnattingius S, Olausson PO, Hultman CM. Fetal growth restriction and schizophrenia: a Swedish twin study. Twin Res Hum Genet. 2005;8(4):402-8.
5. Ozanne SE, Fernandez-Twinn D, Hales CN. Fetal growth and adult diseases. Semin Perinatol. 2004;28(1):81-7.
6. Windham GC, Zhang L, Gunier R, Croen LA, Grether JK. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay area. Environ Health Perspect. 2006;114(9):
1438-44.
7. Wood JW, Johnson KG, Omori Y. In utero exposure to the Hiroshima atomic bomb. An evaluation of head size and mental retardation: 20 years later. Pediatrics. 1967;39(3):385-92.
8. Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney disease: the role of fetal programming. Hypertension. 2006;47:502-8.
9. Dicke JM. Teratology: principles and practice. Med Clin North Am. 1989;73(3):567–82.
10. Centers for Disease Control and Prevention. Hospital stays, hospital charges, and in-hospital deaths among infants with selected birth defects—United States, 2003. MMWR. 2007;56(2):25-9.
11. Matthews TJ, MacDorman MF. Infant mortality statistics from the 2004 period linked birth/infant death data set. Natl Vital Stat Rep. 2007;55(14):1-32.
12. Honein MA, Kirby RS, Meyer RE, et al. The association between major birth defects and preterm birth. Matern Child Health J. 2008;Epub. Available at: http://www.springerlink.com/content/ b7m216122j2jp84t/?p=7b572af020ca4b13932e6f9eb3fa85b8&pi=2. Accessed July 14, 2008.
13. Callaghan WM, MacDorman MF, Rasmussen SA, Qin C, Lackritz EM. The contribution of preterm birth to infant mortality rates in the United States. Pediatrics. 2006;118(4):1566-73.
14. Boyle CA, Cordero JF. Birth defects and disabilities: a public health issue for the 21st century. Am J Public Health. 2005;95(11):1884-6.
15. Hack M, Youngstrom EA, Cartar L, et al. Behavioral outcomes and evidence of psychopathology among very-low-birth-weight infants at age 20 years. Pediatrics. 2004;114(4):932-40.
16. Goldenberg RL, Culhane JF. Low birth weight in the United States. Am J Clin Nutr. 2007;85(2):584S-590S.
17. Melnick S, Cole P, Anderson D, Herbst AL. Rates and risks of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix: an update. N Engl J Med. 1987;316(9):514-6.
18. De Santis M, Di Gianantonio E, Straface G, et al. Ionizing radiations in pregnancy and teratogenesis: a review of literature. Reprod Toxicol. 2005;20(3):323-9.
19. Windham GC, Hopkins B, Fenster L, Swan SH. Prenatal active or passive tobacco smoke exposure and the risk of preterm delivery or low birth weight. Epidemiology. 2000;11(4):427-33.
20. Brent RL. Environmental causes of human congenital malformations: the pediatrician’s role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. Pediatrics. 2004;113(4 Suppl):957-68.
21. Blount BC, Silva MJ, Caudill SP, et al. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect. 2000;108(10):979-82.
22. Centers for Disease Control and Prevention. National report on human exposure to environmental chemicals: spotlight on bisphenol A and 4-tertiary-octyphenol, October 2007. Available at: http://www.cdc.gov/exposurereport/pdf/factsheet_bisphenol.pdf. Accessed July 12, 2008.
23. Centers for Disease Control and Prevention. Third National Report on Human Exposure to Environmental Chemicals. National Center for Environmental Health (NCEH Pub. No. 05-0570), July 2005. Available at: http://www.cdc.gov/exposurereport/report.htm. Pdf. Accessed July 18, 2008.
24. Grice M, Alexander B, Hoffbeck R, Kampa D. Self-reported medical conditions in perfluorooctanesufonyl fluoride manufacturing workers. J Occup Environ Med. 2007;49(7):722-9.
25. Inoue K, Okada F, Ito R, et al. Perflurooctane sulfonate (PFOS) and related perfluorinated compounds in human maternal and cord blood samples: assessment of PFOS exposure in a susceptible population during pregnancy. Environ Health Perspect. 2004;112(11):1204-7.
26. Apelberg BJ, Goldman LR, Calafat AM, Herbstman JB, Zsuzsanna K, Heidler J, et al. Determinants of fetal exposure to polyfluoroalkyl compounds in Baltimore, Maryland. Environ Science Technol. 2007;41(11):
3891-7.
27. Fei C, McLaughlin J, Tarone R, Olsen J. Perflouorinated chemicals and fetal growth: a study within the Danish National Birth Cohort. Environ Health Perspect, 2007; 115(11):1677-82.
28. Eunice Kennedy Shriver National Institute of Child Health and Human Development. The National Children’s Study Research Plan, Version 1.3, Rockville, NICHD, 2007. Available at: http://www.nationalchildrensstudy.gov/research/research_plan/upload/ Chapter_4_032008.pdf. Accessed July 18, 2008.
29. Covello VT. Risk communication and occupational medicine. J Occup Med. 1993;35(1):18-9.

. .