D. Kim Waller

Diabetes mellitus and birth defects.

OBJECTIVE The purpose of this study was to examine associations between diabetes mellitus and 39 birth defects. STUDY DESIGN This was a multicenter case-control study of mothers of infants who were born with (n = 13,030) and without (n = 4895) birth defects in the National Birth Defects Prevention Study (1997-2003). RESULTS Pregestational diabetes mellitus (PGDM) was associated significantly with noncardiac defects (isolated, 7/23 defects; multiples, 13/23 defects) and cardiac defects (isolated, 11/16 defects; multiples, 8/16 defects). Adjusted odds ratios for PGDM and all isolated and multiple defects were 3.17 (95% CI, 2.20-4.99) and 8.62 (95% CI, 5.27-14.10), respectively. Gestational diabetes mellitus (GDM) was associated with fewer noncardiac defects (isolated, 3/23 defects; multiples, 3/23 defects) and cardiac defects (isolated, 3/16 defects; multiples, 2/16 defects). Odds ratios between GDM and all isolated and multiple defects were 1.42 (95% CI, 1.17-1.73) and 1.50 (95% CI, 1.13-2.00), respectively. These associations were limited generally to offspring of women with prepregnancy body mass index > or =25 kg/m(2). CONCLUSION PGDM was associated with a wide range of birth defects; GDM was associated with a limited group of birth defects.

Are obese women at higher risk for producing malformed offspring

OBJECTIVE Our purpose was to determine whether obese women and underweight women have an increased risk of birth defects in their offspring. STUDY DESIGN A geographically based case-control study of women living in California and Illinois was performed. There were 499 mothers of offspring with neural tube defects, 337 mothers of offspring with other major birth defects, and 534 mothers of offspring without birth defects who participated. RESULTS Compared with women of normal weight, women who were extremely obese before pregnancy (body mass index > or = 31 kg/m2) showed a significantly increased risk of having an infant with a neural tube defect (odds ratio 1.8, 95% confidence interval 1.1 to 3.0), especially spina bifida (odds ratio 2.6, 95% confidence interval 1.5 to 4.5), after adjustments for age, race, education, and family income. Obese women also had significantly increased risks (p < 0.05) of having an infant with other defects of the central nervous system, great vessel defects, ventral wall defects, or other intestinal defects. CONCLUSION Our data suggest that offspring of obese women (but not underweight women) are at an increased risk of neural tube defects and several other malformations. If these findings are confirmed, further research will be necessary before it can be concluded that weight reduction before pregnancy will lower the risk of birth defects among obese women. Until then, obese women can address their risk of birth defects with the same measures that are recommended for all women, such as adequate daily intake of folic acid and alpha-fetoprotein screening to identify malformed fetuses.

Maternal obesity, gestational diabetes, and central nervous system birth defects.

Background: Maternal obesity and diabetes are both associated with increased risk of congenital central nervous system (CNS) malformations in the offspring and may share a common underlying mechanism. Our objective was to evaluate whether gestational diabetes influenced the association of prepregnancy maternal obesity and risks for CNS birth defects. Methods: This Texas population-based case-control study evaluated births occurring January 1997 through June 2001. Data came from structured telephone interviews. Cases (n = 477) were mothers of offspring with anencephaly (n = 120), spina bifida (n = 184), holoprosencephaly (n = 49), or isolated hydrocephaly (n = 124). Controls (n = 497) were mothers of live infants without abnormalities randomly selected from the same hospitals as cases. Response rates were approximately 60% for both cases and controls. We evaluated maternal obesity (body mass index ≥30.0 kg/m2) and risks for CNS birth defects, as well as whether gestational diabetes influenced the risks. Results: After adjusting for maternal ethnicity, age, education, smoking, alcohol use, and periconceptional vitamin use, obese women had substantially increased risks of delivering offspring with anencephaly (odds ratio = 2.3; 95% confidence interval = 1.2–4.3), spina bifida (2.8; 1.7–4.5), or isolated hydrocephaly (2.7; 1.5–5.0), but not holoprosencephaly (1.4; 0.5–3.8). Odds ratios were higher for the joint effects of maternal obesity and gestational diabetes, with evidence for interaction on a multiplicative scale. Conclusions: Maternal obesity and gestational diabetes may increase the risk of CNS birth defects through shared causal mechanisms.

The association between maternal serum alpha-fetoprotein and preterm birth, small for gestational age infants, preeclampsia, and placental complications

Objective To determine whether high levels of serum alphafetoprotein (AFP) predict increased risk of adverse pregnancy outcomes, including preterm birth (before 37 weeks), preterm birth occurring at or before 28 weeks, small for gestational age (SGA) infant, preeclampsia, and placental abnormalities, and to determine whether low levels of serum AFP predict increased or decreased risk of these outcomes. Methods Using the mothers first name, last name, and zip code, we linked the records of 51,008 women who participated in the California Alpha-Fetoprotein Screening Program between June 15, 1986, and October 31, 1987, with California birth certificates for singleton infants born in 1987. The accuracy of the data linkage was confirmed by manually examining complete names, mothers ethnicity, and mothers age for a sample of 500 of the mother-infant linkages. Blood samples were obtained at 15–19 weeks. Results A strong gradient of increasing risk of preterm birth with increasing levels of serum AFP was observed (test for trend, P <.01). Among women with high levels of serum AFP (at least 2.5 multiples of the median [MoM]), 24.3% had preterm births, compared with 3.8% of women with low levels of serum AFP (0.81 MoM or less), odds ratio 8.7, 95% confidence interval 7.1-10.7). This gradient persisted when preterm infants of 28 weeks or less were examined separately. Similar gradients were observed for the risk of preeclampsia and placental abnormalities. There was a weaker U-shaped relation between serum AFP level and the risk of an SGA infant. Conclusion Low levels of second-trimester maternal serum AFP are associated with a very low risk of preterm birth, preeclampsia, and placental complications. High levels of serum AFP are strongly associated with preterm birth, preeclampsia, and placental abnormalities. There is a modest association between AFP levels (both low and high) and SGA birth.

Second-Trimester Maternal Serum Alpha-Fetoprotein Levels and the Risk of Subsequent Fetal Death

Abstract Background. The finding of an elevated level of maternal serum alpha-fetoprotein during the second trimester of pregnancy may indicate that the fetus has died or is about to die. It is uncertain, however, whether the finding is associated with an increased risk of fetal death later in gestation independent of known causes of elevation, such as the presence of neural-tube defects or multiple gestation. Methods. To address this question, we performed a case–control study of 612 women whose pregnancies ended in fetal death and 2501 women who gave birth to live infants, using reports from California vital statistics for 1987. All the women had singleton pregnancies and alpha-fetoprotein screening in the second trimester. Results. Women with elevated levels of serum alpha-fetoprotein in the second trimester of pregnancy had an increased risk of fetal death, and the risk was increased until term. Women with the highest levels of serum alpha-fetoprotein — ≥3.0 times the median value — had a very high ri...

Prevalence of nonsyndromic oral clefts in Texas: 1995–1999

Nonsyndromic cleft lip with/without cleft palate (NSCLP) and nonsyndromic cleft palate only (NSCPO) are common complex birth defects affecting 4,000 newborns annually. We undertook a descriptive study of oral clefts in Texas, focusing on the effect of folic acid fortification and Hispanic ethnicity on the prevalence of oral clefts as these factors have not previously been described. Data on 896 infants with NSCLP and NSCPO born between 1995 and 1999 in Texas were compared to all births in Texas during the same period. Prevalence odds ratios (POR) were calculated for maternal ethnicity, race, age, parity, public health region of residence, highest level of education, and infant gender. The effect of folic acid fortification on oral clefts was also examined. Compared with whites, adjusted POR were 0.97 (95% CI = 0.77–1.23) and 0.90 (95% CI 0.72–1.14) for NSCLP and 0.46 (95% CI = 0.30–0.72) and 0.62 (95% CI = 0.42–0.90) for NSCPO in foreign‐born and US‐born Hispanics, respectively. After fortification was implemented, the rate of NSCLP did not decrease. However, there was a 13% decrease in the prevalence of NSCPO (adjusted POR = 0.87, 95% CI = 0.68–1.15). Compared to whites, the rates in US‐born and foreign‐born Hispanic women were similar for NSCLP and much lower for NSCPO. The small reduction of 13% in NSCPO after folic acid fortification is imprecise and should be interpreted cautiously. Overall, it appears that folic acid fortification has had very little or no effect on the prevalence of oral clefts in infants born in Texas.

Differences in exposure assignment between conception and delivery: the impact of maternal mobility.

In studies of reproductive outcomes, maternal residence at delivery is often the only information available to characterise environmental exposures during pregnancy. The goal of this investigation was to describe residential mobility during pregnancy and to assess the extent to which change of residence may result in exposure misclassification when exposure is based on the address at delivery. Maternal residential mobility was compared between neural tube defect cases and unaffected controls from Texas participants in the National Birth Defects Prevention Study (NBDPS). Maternal residential information was obtained from the NBDPS interview. Data from the U.S. EPA National Air Toxics Assessment [Assessment System for Population Exposure Nationwide (ASPEN)], modelled at the census tract level, were used to estimate benzene exposure based on address at conception and address at delivery. Quartiles of exposure were assigned based on these estimates and the quartile assignments based on address at conception and address at delivery were compared using traditional methods (kappa statistics) and a novel application of mixed-effects ordinal logistic regression. Overall, 30% of case mothers and 24% of control mothers moved during pregnancy. Differences in maternal residential mobility were not significant between cases and controls, other than case mothers who moved did so earlier during pregnancy than control mothers (P = 0.01). There was good agreement between quartiles of estimated benzene exposure at both addresses (kappa = 0.78, P < 0.0001). Based on the mixed-effects regression model, address at delivery was not significantly different from using address at conception when assigning quartile of benzene exposure based on estimates from ASPEN (odds ratio 1.03, 95% confidence interval 0.85, 1.25). Our results indicate that, in this Texas population, maternal residential movement is generally within short distances, is typically not different between cases and controls, and does not significantly influence benzene exposure assessment.

Risk factors for congenital hypothyroidism: An investigation of infant's birth weight, ethnicity, and gender in California, 1990–1998

BACKGROUND Approximately 85% of primary congenital hypothyroidism (CH) is sporadic and due to malformations of the thyroid gland. Past studies have reported an increased birth weight among infants with CH. We have attempted to replicate and expand these observations, examining the association between different birth weight categories and CH stratified by infants sex. We have also examined the prevalence of CH by mothers age and infants ethnicity, gender, and year of birth. METHODS A cross-sectional study was conducted on 5, 049,185 infants screened by the statewide California Newborn Screening Program between 1990 and 1998, an estimated 98.6% of all newborns in the state. Dried blood spots from a heel stick were assayed for thyroxine (T4), and presumptive positives had follow-up assays of thyroid-stimulating hormone (TSH) to determine definite positives. RESULTS A total of 1,806 cases of CH were identified. The following findings are unlikely to be due to chance. Compared with infants with birth weights of 3,000-3,499 g, infants weighing <2,000 g and those weighing >/=4,500 g had a twofold or greater increase in the prevalence of CH. This was not explained as a result of confounding by the infants ethnicity or gender. Compared with whites, elevated prevalence rates were found in most ethnic groups, which include the following: Hispanics, Chinese, Vietnamese, Asian Indians, Filipinos, Middle Easterners, and Hawaiians. As reported previously, black infants had about one-third the prevalence rate of whites. We also observed the frequently described female preponderance of CH. The female excess was maintained at all birth weights, however it varied by infants ethnicity. Trends in the prevalence of CH were not associated with mothers age or with the time interval between 1990 and 1998. CONCLUSIONS We observed an increased risk of CH in both low-birth-weight (<2,000-g) and macrosomic (>/=4,500-g) infants. This U-shaped association has not been described in past studies. We have also expanded the previously described ethnic differences in CH risk to include ethnic groups not previously studied. The unique pattern of CH occurrence suggests that further studies to define modifiable risk factors may be useful.

Maternal Exposure to Ambient Levels of Benzene and Neural Tube Defects among Offspring: Texas, 1999–2004

Background Previous studies have reported positive associations between maternal exposure to air pollutants and several adverse birth outcomes. However, there have been no studies assessing the association between environmental levels of hazardous air pollutants, such as benzene, and neural tube defects (NTDs), a common and serious group of congenital malformations. Objective Our goal was to conduct a case–control study assessing the association between ambient air levels of benzene, toluene, ethylbenzene, and xylene (BTEX) and the prevalence of NTDs among offspring. Methods The Texas Birth Defects Registry provided data on NTD cases (spina bifida and anencephaly) delivered between 1999 and 2004. The control group was a random sample of unaffected live births, frequency matched to cases on year of birth. Census tract–level estimates of annual BTEX levels were obtained from the U.S. Environmental Protection Agency 1999 Assessment System for Population Exposure Nationwide. Restricted cubic splines were used in mixed-effects logistic regression models to determine associations between each pollutant and NTD phenotype. Results Mothers living in census tracts with the highest benzene levels were more likely to have offspring with spina bifida than were women living in census tracts with the lowest levels (odds ratio = 2.30; 95% confidence interval, 1.22–4.33). No significant associations were observed between anencephaly and benzene or between any of the NTD phenotypes and toluene, ethylbenzene, or xylene. Conclusion In the first study to assess the relationship between environmental levels of BTEX and NTDs, we found an association between benzene and spina bifida. Our results contribute to the growing body of evidence regarding air pollutant exposure and adverse birth outcomes.

Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus–associated birth defects

OBJECTIVE The purpose of this study was to examine the risk of birth defects in relation to diabetes mellitus and the lack of use of periconceptional vitamins or supplements that contain folic acid. STUDY DESIGN The National Birth Defects Prevention Study (1997-2004) is a multicenter, population-based case-control study of birth defects (14,721 cases and 5437 control infants). Cases were categorized into 18 types of heart defects and 26 noncardiac birth defects. We estimated odds ratios for independent and joint effects of preexisting diabetes mellitus and a lack of periconceptional use of vitamins or supplements that contain folic acid. RESULTS The pattern of odds ratios suggested an increased risk of defects that are associated with diabetes mellitus in the absence vs the presence of the periconceptional use of vitamins or supplements that contain folic acid. CONCLUSION The lack of periconceptional use of vitamins or supplements that contain folic acid may be associated with an excess risk for birth defects due to diabetes mellitus.