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Anencephaly: An Ongoing Investigation in Washington State One nurse’s recognition of unusually high rates of this birth defect in her hospital revealed a statewide cluster. ABSTRACT In the spring of 2012, a nurse in Washington State detected a cluster of babies born with anencephaly—a fatal condition in which infants are born without parts of the brain or skull. The resulting investigation initially confirmed a rate of anencephaly between January 2010 and January 2013 of 8.4 per 10,000 live births— more than four times the national average. As of November 2015, cases of anencephaly in Washington State have continued to increase, with the current rate estimated at 9.5 per 10,000 live births. While no distinct cause has yet been determined, neural tube defects—including anencephaly—are known to have multiple causes, including folic acid deficit, genetic variants in the folate pathway, and exposure to a variety of environmental and occupational toxins. This article describes many of these risk factors and explores the findings of Washington’s ongoing investigation. Keywords: anencephaly, birth defect, case finding, folic acid, neural tube defect, public health

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n the spring of 2012 two babies without brains were born within weeks of each other at the rural hospital in Washington State where I was working. Both lived only hours, and the devastation felt by the parents as well as the staff in our small facility was palpable. I was stunned when the delivering physician said another patient was expecting the same outcome. After speaking with colleagues at neighboring hospitals, I learned that two other babies with anencephaly had recently been born in the area. In over 30 years of nursing, I had seen only two cases of anencephaly prior to these. I called the Washington State Department of Health and reported a birth defect cluster. In 2013 investigators began studying delivery records for the previous three years in my hospital and in several nearby facilities, and found 23 anencephaly cases across three counties in south central Washington: Yakima, Benton, and Franklin. They calculated a rate of 8.4 per 10,000 live births— more than four times the national average.1

WHAT IS ANENCEPHALY?

Anencephaly is the most severe form of neural tube defect (NTD) in a fetus that can reach term.2 The neural tube—the embryo’s foundation for development 60

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of the central nervous system—is formed early in pregnancy, closing around the 28th day after conception.3-5 When the formation of the spinal cord and brain is incomplete, an NTD occurs. In the case of anencephaly, the baby is typically born without a skull or cerebral hemispheres, but the face and brainstem may be intact. Generally, a baby with anencephaly expires within hours of birth.2 Another manifestation of NTD is spina bifida— an incomplete closure of the spinal cord, which may result in an outcome as serious as paralysis with brain malformations, or as minor as neurogenic bladder control issues.2, 4 The rate of NTDs in the United States is estimated at approximately six per 10,000 live births; anencephaly constitutes roughly one-third of these, or about 2.1 per 10,000 live births.6 However, in the Washington State cluster, anencephaly cases outnumbered spina bifida by more than two to one.7 Detection. NTDs cannot be detected prior to 12 weeks’ gestation. While a blood test for maternal serum alpha-fetoprotein can indicate a problem with the formation of the central nervous system, it cannot determine how serious the problem is.4 In addition, ultrasound may demonstrate an NTD early in ajnonline.com

By Sara Barron, MS, BSN

Image courtesy of the Centers for Disease Control and Prevention and the National Center on Birth Defects and Developmental Disabilities.

the second trimester, but results are considered inconclusive until after 20 weeks’ gestation.4 Many women therefore don’t learn that their baby has brain or spinal malformations until it is too late to decide whether to carry their pregnancy to term.

THE ROLE OF FOLIC ACID

The best-documented cause of NTDs is a diet deficient in folic acid. Although two British doctors postulated a link between NTDs and mothers’ folate levels in the 1960s,8 it wasn’t until the 1980s that results of controlled studies clearly demonstrated that folic acid supplementation could substantially decrease the number of NTD cases.9-11 In 1991, the British Medical Research Council (MRC) published a large, double-blind, randomized controlled study that found that folic acid 4 mg daily was associated with a 72% decrease in the risk of NTDs in infants born to women with a prior history of these abnormalities.12 In 1992, the U.S. Public Health Service accepted the findings of the MRC study; but because high doses of folic acid can mask signs of vitamin B12 deficiency, it decreased its recommended daily dose to 0.4 mg.13, 14 Soon thereafter, in 1998, in recognition of the fact that many pregnancies are unplanned and that neural tube formation is likely to be complete before a woman confirms her pregnancy, the U.S Food and Drug Administration (FDA) began mandating the addition of folic acid to grain products.14 This additional source of folic acid for all women of childbearing age helped drop the U.S. anencephaly rate from 4.2 per 10,000 live births in 1995–1996, prior to fortification, to 3.5 in 1999–2000, the year following fortification.15 By 2006, the anencephaly rate was estimated to have dropped to 2.1 per 10,000 live births.6 Washington State’s initial review of the delivery data in Yakima, Benton, and Franklin counties showed that among women who reported never taking folic acid supplements in early pregnancy, 78% had given birth to a baby with anencephaly but 91% had had healthy pregnancies.7

HISPANICS: A POPULATION AT GREATER RISK

Hispanics have NTD pregnancies nearly twice as often as non-Hispanic whites.16, 17 While no specific cause for this discrepancy has been established, several possible factors have been proposed, including diet, lower folic acid intake, genetic influences, environmental factors, and exposure to toxins.18, 19 Hispanics tend to consume less folic acid than people of other ethnicities because they often favor corn products over wheat or rice; and although cornmeal and corn grits are fortified in the United States, corn masa flour and all products made from it (tortillas, for [email protected]



example) are not.14, 18 The fortification of corn products has thus far been banned in this country because of FDA concerns, among them the possible instability of folic acid during the processing of corn into corn masa flour.18, 20 However, efforts are currently under way to change this policy.20 In Washington State, interviews with mothers ­regarding their diet—and specifically their corn intake—were only begun in early 2015,21 so there is insufficient data to determine the effects of corn intake, if any. However, as south central Washington is the leading producer of sweet corn in the United States,22 intake of corn among all ethnicities is likely to be higher. Commercial corn supplies can be contaminated with fumonisins, a type of toxin produced by mold, which may also be responsible for causing NTDs.19, 23 This is illustrated by an anence­phaly cluster that occurred in 1991 in Brownsville, Texas—a small town near the Mexican border—where a physician reported delivering three babies with anencephaly within 36 hours.19 An investigation revealed that, in a county that expected only 6,000 births a year, there had actually been six anencephalic births in six weeks. Cornmeal samples taken at the time of the cluster tested positive for mycotoxin, and tests for fumonisin exposure in the mothers’ blood demonstrated AJN ▼ March 2016



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OTHER RISK FACTORS

Maria Rosario Perez was one of the babies in the Washington State anencephaly cluster. Born May 25, 2012, she lived only 55 minutes. Photo by Erika Schultz / The Seattle Times.

that the higher the exposure, the greater the risk of NTDs.19, 23 Studies from Mexico and Guatemala have likewise documented the associations between corn intake, fumonisin exposure, and higher rates of anencephaly.23, 24 Administration of folate has been shown to help decrease the risk of NTDs after exposure to fumonisin mycotoxins.19 Two years prior to the Brownsville cluster, an outbreak of equine leukoencephalomalacia—a disease that causes liquefaction of the brain in horses—was traced to feed made from corn containing fumonisins.19 The contaminated animal feed was immediately removed from the market, but contaminated corn remained in the human food chain. While investigation of the Brownsville cluster demonstrated the association between fumonisin and NTDs in humans,23, 25 it wasn’t until 2001 that the FDA issued recommendations concerning this mycotoxin in the human food supply.23 To this date, these recommendations remain nonbinding. 62

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Defects in folic acid metabolism. In response to the 1991 Brownsville cluster, the Texas legislature funded the Texas Neural Tube Defect Project—a six-year case–control study of NTDs in infants born to mothers living along the Texas–Mexico border. Among the findings was that mothers with lower serum levels of B12 and/or methionine and higher homocysteine levels had a higher risk of anencephalic pregnancies.19 Findings from other studies suggest that a maternal variant in a gene involved in folate metabolism, 5,10-methylenetetrahydrofolate reductase (MTHFR), might explain the association between low folate levels and NTDs.3, 19, 26-28 This MTHFR variant diminishes the mother’s ability to convert folic acid to the active form of folate needed by the fetus for proper neural tube development.3 Folic acid supplementation may help offset this effect. A 2003 study of the MTHFR genotypes of over 7,000 infants worldwide showed that Mexico had the highest prevalence of the homozygous (inherited from both parents) genotype—32%.29 According to the World Health Organization, Mexico also had one of the highest rates of anencephaly in the world: 15.32 per 10,000 live births.30 The study further showed that 18% of Hispanics in the Atlanta area of the United States tested positive for the MTHFR variant, as compared with 11% of non-Hispanic whites and 3% of blacks. The Texas Birth Defect Registry report of birth defects between 1999 and 2011 supports these results, finding the rate of anencephaly to be highest among Hispanics: 3.19 per 10,000 live births, as compared with 2.17 among non-Hispanic whites, and 1.90 among non-Hispanic blacks.31 The Washington State investigation, on the other hand, has not as yet demonstrated a significant difference between rates of anencephaly in Hispanics and non-Hispanic whites. (There have been no reported cases among blacks.) Obesity and diabetes. Maternal obesity (defined as a body mass index of 30 kg/m2 or higher) and diabetes are known risk factors for NTDs, both independently and together.19, 32 In the six-year Brownsville case– control study, obesity increased the odds of giving birth to a baby with an NTD by 1.6 times, while hyperinsulinemia, which is often associated with diabetes, nearly doubled the risk.19 Women who are obese or have diabetes should consider taking a higher dose of folic acid as soon as pregnancy is planned.19 Dieting. In Brownsville, women on weight loss diets or those who consumed weight loss products prior to or early in their pregnancy had twice the risk of NTDs as their nondieting counterparts.33 Food restriction during the first trimester is believed to be problematic ajnonline.com

­ ecause of the decrease in nutrient intake, specifically b folate. Especially alarming is the use of diuretics during the first trimester as part of a weight-loss strategy, as this can nearly triple the risk of NTDs.34 Taking at least 1 mg of folic acid daily during the periconceptual period has been shown to mitigate the risk of NTDs in women who are dieting.33 Pesticides, nitrates, and solvents. Women exposed to pesticides multiple times—be it at home, at work, or in the communities in which they live—have exhibited a risk of NTDs, and specifically of anencephaly, that increased as the “sources of exposure opportunities” increased.35, 36 In Brownsville, there has been speculation about a possible link between NTDs and exposure to pesticides, herbicides, and nitrates.19 This link is also being investigated in the three affected counties in south central Washington, all of which are rural.

c­ arbamazepine—as well as the dermatologic therapy, isotretinoin.4 A 2007 study also found an association between use of selective serotonin reuptake ­inhibitors and an increased risk of anencephaly; however, more research is needed to confirm this possible connection.40 Previous NTD pregnancies. Women who have had a previous pregnancy that resulted in an NTD are at higher risk for another such pregnancy, but the risk is low: in the United States it is about 3%, compared with 0.006% for women with no prior history. The Centers for Disease Control and Prevention (CDC) advises these women to take at least 4 mg of folic acid daily—10 times the normal recommended daily dose of 0.4 mg.41 Women who have had previous miscarriages and stillbirths may also benefit from a higher dose of folic acid, as NTDs are a common cause of fetal death.41

In the six-year Brownsville case–control study, obesity increased the odds of giving birth to a baby with an NTD by 1.6 times, while hy­perinsulinemia, which is often associated with diabetes, nearly doubled the risk. Nitrate exposure is a common health concern in farming communities, whose private wells may be contaminated by fertilizers and animal waste. In 2006, a meta-analysis by Manassaram and colleagues found mixed results in studies relating nitrate-contaminated water to birth defects, with some showing a connection, others not.37 In Washington State, no relationship has yet been established. Exposure to organic solvents such as benzene has likewise been associated with an increased risk of NTDs.38 Specifically, working in occupations or having hobbies involving cleaning products, spray paints, or paint thinners has been found to double the odds of NTDs or other birth defects.19, 38 Hyperthermia. Women who have experienced a high fever or been exposed to external heat—as from a sauna or hot tub—early in their pregnancy appear to be at higher risk for NTDs, though the reason for this is unclear.39 In Brownsville, mothers who had had a fever or been exposed to external heat during their first trimester had more than three times the risk of NTDs.19 Medications that increase the risk of NTDs ­include two anticonvulsants—valproic acid and [email protected]



Radiation exposure. Popular media and blogs have often linked the Washington State NTD cluster to the Hanford Nuclear Reservation in Benton County, Washington. Although leaks from nuclear power plants have been associated with a higher rate of anencephaly and other NTDs,42 Washington State Department of Health investigators point out that the three counties with the highest prevalence of NTDs were both upwind and upriver of the Hanford site, making the nuclear plant an unlikely cause of the 2012 cluster.7

SURVEILLANCE

Surveillance for NTDs—or any birth defects— in the United States is patchwork at best. Since there is no national system, each state chooses whether and how to study its rate of birth defects, and which birth defects to study. The CDC defines three types of case finding43: • Active case finding, whereby the state health department routinely reviews records from various hospitals and clinics. When a birth defect is noted, information is collected on the mother and baby. • Passive case finding with confirmation, whereby hospitals and clinics are asked to report any AJN ▼ March 2016



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newborns with birth defects to the state health department, which confirms the reported cases and may follow up with an investigation. • Passive case finding, whereby the state health department receives reports of birth defects from hospitals and other health facilities, but neither confirms these nor follows up. The CDC funds 13 states, as well as Puerto Rico, for active case finding.43 Among these, Texas and Georgia have developed model programs: the Texas Neural Tube Defect Project, established after the discovery of the Brownsville cluster, has provided much of our current knowledge about NTDs and their associated risk factors19; and the Metropolitan Atlanta Congenital Defects Program, which has been actively studying births in five counties around Atlanta since 1967, has served as the foundation for the National Birth Defects Prevention Network, an organization that links surveillance programs in several states and publishes annual reports on the prevalence of birth defects.44 The majority of the remaining states use passive case finding, and six states have no birth defect registries.45

age, weight, race/ethnicity, and income, as well as for potential environmental factors such as water source (public water versus private wells, for example). In 2015, investigators also began to interview recently affected mothers using the National Birth Defects Prevention Study questionnaire, a tool to standardize data collection developed by the National Birth Defects Prevention Network.47 Through these efforts, the state of Washington hopes to gain more detailed information regarding the women’s diet, occupation, living circumstances, and environmental exposures. However, the results of these interviews won’t become available for some time.

HOW NURSES CAN HELP

Nurses can play a significant role not only in noticing, but also in addressing, a puzzling rise in NTDs. Counseling. Families that have experienced the often traumatic birth of a baby with an NTD need counseling—not just to cope with their grief, but also to receive information regarding possible genetic defects that may be raising their NTD risk. They need reassurance that with proper measures and precautions, a normal pregnancy is possible in the future.

Anencephaly is an extremely rare birth defect. For this reason, if nurses perceive what appears to be an excessive occurrence of anencephaly—or of any NTD—they should report it to their state’s health department. Since Washington is among the passive case-finding states and has thus far conducted active follow-up only in the three counties where the NTD cluster occurred, it is difficult to determine exactly when that cluster began and how widespread the problem may be. The most recent officially recognized national birth defect prevalence estimates are for 2004 to 2006, and these did not include any information about the northwest part of the country.6

WASHINGTON’S ONGOING INVESTIGATION

Since 2012, cases of anencephaly have continued to rise in Washington State. As of November 2015, there have been 41 cases, and the current rate is estimated at 9.5 per 10,000 live births—nearly five times the national rate.46 Investigators have studied medical records from hospitals and clinics to match cases and controls for such demographic indicators as 64

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In addition, nurses should routinely stress the importance of folic acid intake—both as a supplement and in the diet—for every woman of child-bearing age. Reporting. Anencephaly is an extremely rare birth defect. For this reason, if nurses perceive what appears to be an excessive occurrence of anencephaly—or of any NTD—they should report it to their state’s health department. In the case of Washington State, when the number of anencephaly cases first started to rise, hospitals and physicians did not initially notice; it took a nurse to say “this is too many.” Helping with research. Nurses can help ongoing research by continuing to examine possible causes of and factors associated with birth defects. In addition, once a family’s initial shock regarding the loss of a baby has lessened, a nurse can put the family in touch with researchers. This would not only help increase the current data regarding birth defects, it would ajnonline.com

also offer the families an opportunity to discuss their experience and feel like they are helping to spare others from a similar outcome. Advocating policy change. Nurses can advocate policy change at the local and national levels to help protect patients from having pregnancies that result in preventable birth defects. ▼ Sara Barron is a nursing instructor at Washington State University Tri-Cities in Richland, WA. Contact author: [email protected] com. The author has disclosed no potential conflicts of interest, financial or otherwise.

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14. Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Final rule. Washington, DC: Federal Register: Rules and Regulations 1996 8781-97. https://www.gpo.gov/fdsys/pkg/FR-1996-03-05/pdf/ 96-5014.pdf. 15. Centers for Disease Control and Prevention. Spina bifida and anencephaly before and after folic acid mandate—United States, 1995-1996 and 1999-2000. MMWR Morb Mortal Wkly Rep 2004;53(17):362-5. 16. Canfield MA, et al. Hispanic origin and neural tube defects in Houston/Harris County, Texas. II. Risk factors. Am J Epidemiol 1996;143(1):12-24. 17. Shaw GM, et al. Risk for neural tube defect-affected pregnancies among women of Mexican descent and White women in California. Am J Public Health 1997;87(9):1467-71. 18. Fleischman AR, Oinuma M. Fortification of corn masa flour with folic acid in the United States. Am J Public Health 2011; 101(8):1360-4. 19. Suarez L, et al. Neural tube defects on the Texas-Mexico border: what we’ve learned in the 20 years since the Brownsville cluster. Birth Defects Res A Clin Mol Teratol 2012;94(11): 882-92. 20. Aleccia J. FDA weighs adding folic acid to corn masa to halt birth defects. Seattle Times 2015 Dec 12. http://www.seattletimes.com/seattle-news/health/fda-weighs-adding-folic-acid-tocorn-masa-to-halt-birth-defects. 21. Wasserman CR. Anencephaly investigation, central Washington, 2010-2015, Advisory committee meeting [PowerPoint]. Olympia, WA: Washington State Department of Health; 2015 Jan 15. www.doh.wa.gov/Portals/1/Documents/5500/AACPresentation-1-15-2015.pdf. 22. Beaver T. Washington ranked no. 1 in U.S. sweet corn production. Tri-City Herald 2012 Sep 18. http://www.tri-cityherald. com/news/local/article32083404.html. 23. Gelineau-van Waes J, et al. Maternal fumonisin exposure as a risk factor for neural tube defects. Adv Food Nutr Res 2009; 56:145-81. 24. Gelineau-van Waes J. Food safety and pregnancy: investigating the relationship between maize mycotoxins and birth defects. Cornhusker Family Physician 2010;55(4):22-4. 25. Missmer SA, et al. Exposure to fumonisins and the occurrence of neural tube defects along the Texas-Mexico border. Environ Health Perspect 2006;114(2):237-41. 26. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 2000;151(9):862-77. 27. Kirke PN, et al. Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study. BMJ 2004; 328(7455):1535-6. 28. Muñoz JB, et al. Methylenetetrahydrofolate reductase gene polymorphisms and the risk of anencephaly in Mexico. Mol Hum Reprod 2007;13(6):419-24. 29. Wilcken B, et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet 2003;40(8):619-25. 30. International Centre for Birth Defects of the International Clearinghouse for Birth Defects Monitoring Systems, in collaboration with the Human Genetics Programme of the World Health Organization. World atlas of birth defects. 2nd ed. Geneva: World Health Organization; 2003. http://apps.who. int/iris/bitstream/10665/42630/1/9241580291_eng.pdf. 31. Texas Department of State Health Services, Birth Defects Epidemiology and Surveillance. Texas birth defects registry, reports of defects among 1999-2011 deliveries. Table 4: prevalence of selected birth defects by mother’s race/ethnicity, Texas,

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1999-2011 [Excel spreadsheet]. n.d. http://www.dshs.state. tx.us/WorkArea/DownloadAsset.aspx?id=8589994163. 32. Yazdy MM, et al. Maternal dietary glycemic intake and the risk of neural tube defects. Am J Epidemiol 2010;171(4): 407-14. 33. Suarez L, et al. Dieting to lose weight and occurrence of neural tube defects in offspring of Mexican-American women. Matern Child Health J 2012;16(4):844-9. 34. Carmichael SL, et al. Dieting behaviors and risk of neural tube defects. Am J Epidemiol 2003;158(12):1127-31. 35. Brender JD, et al. Maternal pesticide exposure and neural tube defects in Mexican Americans. Ann Epidemiol 2010; 20(1):16-22. 36. Rull RP, et al. Neural tube defects and maternal residential proximity to agricultural pesticide applications. Am J Epidemiol 2006;163(8):743-53. 37. Manassaram DM, et al. A review of nitrates in drinking water: maternal exposure and adverse reproductive and developmental outcomes. Environ Health Perspect 2006;114(3):320-7. 38. Desrosiers TA, et al. Maternal occupational exposure to organic solvents during early pregnancy and risks of neural tube defects and orofacial clefts. Occup Environ Med 2012; 69(7):493-9. 39. Moretti ME, et al. Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and metaanalysis. Epidemiology 2005;16(2):216-9. 40. Alwan S, et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007; 356(26):2684-92.

41. Arth A, et al. Supplement use and other characteristics among pregnant women with a previous pregnancy affected by a neural tube defect—United States, 1997-2009. MMWR Morb Mortal Wkly Rep 2015;64(1):6-9. 42. Wertelecki W. Malformations in a chornobyl-impacted region. Pediatrics 2010;125(4):e836-43. 43. Centers for Disease Control and Prevention. Birth defects: state-based tracking systems. 2015. http://www.cdc.gov/ ncbddd/birthdefects/states. 44. Correa-Villaseñor A, et al. The Metropolitan Atlanta Congenital Defects Program: 35 years of birth defects surveillance at the Centers for Disease Control and Prevention. Birth Defects Res A Clin Mol Teratol 2003;67(9):617-24. 45. National Birth Defects Prevention Network. State programs and related links: population-based birth defects surveillance programs. 2016. http://www.nbdpn.org/state_programs_ and_related_lin.php. 46. Wasserman CR. Anencephaly investigation, central Washington, 2010-2016. Advisory committee meeting [PowerPoint]. Olympia, WA: Washington State Department of Health; 2015 Nov 19. http://www.doh.wa.gov/Portals/1/Documents/5500/ AAC-Presentation-11-19-2015.pdf. 47. Wasserman CR. Anencephaly in central Washington: investigation findings, ongoing surveillance and prevention activities [PowerPoint]. Olympia, WA: Washington State Department of Health; 2015 Feb 11. Governor’s interagency council on health disparities; http://healthequity.wa.gov/Portals/9/Doc/ Meetings/2015/02-11/HDC-02-11-15-Tab05a.pdf.

Anencephaly: An Ongoing Investigation in Washington State.

: In the spring of 2012, a nurse in Washington State detected a cluster of babies born with anencephaly-a fatal condition in which infants are born wi...
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