The association between maternal use of spermicides, condoms, intra-uterine devices or progesterone and major structural birth defects

Birth defects occur in 1 of every 33 babies born in the United States, and are the leading cause of infant death. Mothers using contraceptives that become pregnant may continue to use their contraceptives after their first missed menstrual period, thus exposing their baby in utero to the contraceptive product. Progesterone is also sometimes prescribed during the first trimester of pregnancy to mothers with a history of miscarriages or infertility problems. To ensure the safety of these products, it is important to investigate whether there is an increased occurrence of babies born with birth defects to mothers using various contraceptive methods or progesterone in early pregnancy. Using data from the National Birth Defects Prevention Study (NBDPS), an ongoing multi-state, population based case-control study, this study assessed maternal exposures to IUDs, spermicides, condoms and progesterone in early pregnancy. ^ Progesterone used for threatened miscarriage during the first three months of pregnancy was associated with an increased occurrence of hypoplastic left heart (adjusted odds ratios (OR) 2.24, 95% CI 1.13-4.21), perimembranous ventricular septal defects (OR 1.64, 95% CI 1.10-2.41), septal associations (OR 2.52, 95% CI 1.45-4.24), esophageal atresia (OR 1.82, 95% CI 1.04-3.08), and hypospadias (OR 2.12, 95% CI 1.41-3.18). Mothers using progesterone for injectable contraception had increased (OR > 2.5), but insignificant odds ratios for anencephaly, septal associations, small intestinal atresias and omphalocel. Progesterone used for fertility was not associated with an increased occurrence of any birth defects examined. ^ Mothers using progesterone for fertility assistance and threatened miscarriage were very similar with respect to their demographics and pregnancy history. They also both reported similar types of progesterone. Thus, if progesterone was a causal risk factor for birth defects we would have expected to observe similar increases in risk among mothers using progesterone for both indications. Because we predominantly observed increased associations among mothers using progesterone for threatened miscarriage but not fertility assistance, it is possible the increased associations we observed were confounded by indication (i.e. progesterone was administered for vaginal bleeding which occurred as a sequelae to the formation of a congenital anomaly. ^ No significant increased associations were observed between maternal spermicide use during pregnancy and 26 of 27 types of structural malformations. While multiple statistical tests were performed we observed first trimester maternal spermicide use to be associated with a significant increased occurrence of perimembranous ventricular septal defects (OR 2.21, 95% CI 1.16-4.21). A decreased occurrence (OR < 1.0) was observed for several categories of birth defects among mothers who conceived in the first cycle after discontinuing the use of spermicides (22 of 28) or male condoms (23 of 33). ^ Overall the percent of IUD use was similar between mothers of controls and mothers of all cases in aggregate (crude OR 1.05, 95% CI 0.61-1.84). Power was limited to detect significant associations between IUD use and birth defects, however mothers using an IUD in the month immediately prior to conception or during pregnancy were not associated with an increase of birth defects. Limb defects and amniotic band sequence previously reported to be associated with IUD use during pregnancy were not found to occur among any mothers reporting the use of an IUD during pregnancy.^

The association between parity and selected structural birth defects

BACKGROUND: Parity is a risk factor in neonatal morbidity and mortality. This dissertation examined the association between first births and selected birth defects. The first aim was to assess the risk of 66 birth defects among first births and third or greater births. The second aim was to determine if maternal race, maternal age, infant sex or infant birth weight modify the association between first births and selected birth defects. METHODS: The Texas Birth Defects Registry provided data for 1999-2009. For the first aim, odds ratios were calculated for each birth defect. For the second aim, analysis was restricted to the ten birth defects significantly associated with first births. Stratified analyses were conducted and interaction terms were added to logistic regression models to assess whether differences in the odds ratios for the effect of first birth were statistically significant across strata. RESULTS: Findings for the first aim showed that first births had significantly increased odds of having an infant with 24 of the 66 birth defects. Third or greater births had significantly increased odds of having four of the 66 birth defects. For the second aim, a number of significant effect modifiers were observed. For patent ductus arteriosis, obstructive urinary defects and gastroschisis, the effect of first births was significantly modified by black or U.S.-born Hispanic mothers. The effect of first birth was also significantly modified among mothers ≥30 years for mitral valve insufficiency, atrial septal defect and congenital hip dislocation. The effect of first births was significantly modified among infants with low birth weight for hypospadias, congenital hip dislocation and gastroschisis. CONCLUSIONS: First births were associated with an elevated risk of 24 categories of birth defects. For some of the birth defects studied, the effect of first birth is modified by maternal age, maternal race and low birth weight. Knowledge of the increased risk for birth defects among women having their first birth allows physicians and midwives to provide better patient care and spur further research into the etiology of associated birth defects. This knowledge may bring about interventions prior to conception in populations most likely to conceive.^

Isolation and analysis of regulatory and structural mutations in the {\it recA\/} gene of {\it Escherichia coli}

The recA gene is essential for homologous recombination and for inducible DNA repair in Escherichia coli. The level of recA expression is important for these functions. The growth defect of a lambda phage carrying a recA-lacZ fusion was used to select mutations that reduced recA expression. Nine of these mutations were single base changes in the recA promoter; each reduced both induced and basal (repressed) levels of expression, indicating that only one promoter is used under both circumstances. Deletion analysis of the promoter region and S1 mapping of transcripts confirmed that there is only one promoter responsible for both basal and induced expression. Some of the mutants, however, displayed a ratio of induced to repressed expression that was much lower than wild-type. For one of these mutants (recA1270) LexA binding studies showed that this was not due to a change in the affinity of LexA repressor for the operator site. The extent of binding of RNA polymerase to this mutant promoter, however, was much reduced, and the complexes formed were qualitatively different. Further binding experiments provided some evidence that LexA does not block RNA polymerase binding to the recA promoter, but inhibits a later step in initiation. Behavior of the mutants with altered induction ratios could be explained if LexA binding to the operator actually increases RNA polymerase binding to the promoter in a closed complex compensating for defects in polymerase binding caused by the mutations.^ In a study of mutations in the recA structural gene, site-directed mutagenesis was used to replace cysteine codons at positions 90, 116, and 129 with a number of different codons. In vivo analysis of the replacements showed that none of the cysteines is absolutely essential and that they do not have a direct role as catalysts in ATP hydrolysis. Some amino acid substitutions abolished all RecA functions, while a few resulted in partial or altered function. Amino acids at positions 90 and 129 tended to affect all functions equally, while the amino acid at position 116 appeared to have a particular effect on the protease activity of the protein. ^

Prevention of birth defects in a national study

The following analyses covered two main objectives focused on the prevention of and identification of risk factors for birth defects, the leading cause of infant mortality. All analyses utilized data from the National Birth Defects Prevention Study (NBDPS), an ongoing, population-based, case-control study of major structural birth defects. ^ The first objective was to identify predictors of folic acid supplementation among women of reproductive age. To meet this objective, a previous analysis of potential predictors of periconcecptional folic acid use in the NBDPS was repeated using data from more recent years (1997-2000 versus 2001-2005). The results of these analyses were consistent with the initial analyses, indicating that folic acid use is associated with maternal race/ethnicity, age, education, pregnancy awareness, smoking status, first prenatal care visit, previous live births, and fertility treatments). In addition, data from NBDPS controls were used to identify predictors of preconceptional folic acid use, since supplementation is optimally initiated prior to pregnancy (rather than after conception). These analyses indicated that maternal race/ethnicity, education, age, nativity, employment status, income, number of dependents, smoking, and birth control are significantly associated with preconceptional folic acid supplementation. Ultimately the results of these analyses can be used to guide the development of targeted interventions for preconceptional folic acid use. ^ The second objective was to investigate the association between parental Hispanic acculturation and the risk of gastroschisis, a congenital malformation of the abdominal wall, in offspring. Significant association were not observed for mothers < 20 years of age at conception. Among mothers ≥ 20 years of age, white parents were at a decreased risk of having a child with gastroschisis as compared to Hispanic parents who were born in the United States (US) [odd ratios (ORs) ranging from 0.60 to 0.55] and Hispanics parents who predominantly spoke English (ORs ranging from 0.65 to 0.58). Compared to Hispanic mothers born in the US, the risk of gastroschisis was lower among Hispanic mothers who had lived in the US < 5 years (OR=0.36, 95% CI: 0.42, 0.81) at the time of delivery and Hispanic mothers who migrated to the US at ≥ 20 years of age (OR=0.48, 95% CI: 0.26, 0.89). The results of these analyses provide further evidence that the risk of gastroschisis in offspring is associated with parent Hispanic ethnicity and, among Hispanics, with the degree of parental acculturation. Future studies should focus on characteristic differences between less and more acculturated parents to better understand the relationship between acculturation and gastroschisis.^