Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case-control study.

OBJECTIVE: To study previously identified associations between specific maternal hypertensive disorders and/or prenatal exposure to antihypertensive medication and birth defects. DESIGN: Case-control study. SETTING: Slone Birth Defects Study, 1998-2010. POPULATION: A total of 5568 cases with birth defects and 7253 liveborn infants without malformations as controls. METHODS: Adjusted odds ratios (aORs) for birth defects associated with prenatal exposure to maternal hypertensive disorders and/or antihypertensive medication were calculated using multivariable logistic regression analyses. MAIN OUTCOME MEASURES: Specific birth defects previously linked to maternal hypertension or antihypertensive medication use during pregnancy. RESULTS: Non-pharmacologically managed chronic hypertension was associated with a three-fold risk of oesophageal atresia (95% CI 1.2-8.3), and pre-eclampsia superimposed on non-pharmacologically managed chronic hypertension was associated with ventricular septal defects (aOR 3.9, 95% CI 1.3-11.7) and atrial septal defects (aOR 6.5, 95% CI 1.8-23.7). For chronic hypertension that was pharmacologically treated early in pregnancy, increased risks were observed for first-degree hypospadias (aOR 2.9, 95% CI 1.1-7.4). Non-pharmacologically managed pre-eclampsia was related to second-/third-degree hypospadias and ventricular septal defects. Pharmacological treatment for gestational hypertension was associated with a number of congenital heart defects. CONCLUSIONS: Our results confirm some, but not all, previously identified associations between pharmacologically treated and non-pharmacologically managed hypertensive disorders and specific birth defects. They support the hypothesis that physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the aetiology of major birth defects, including congenital heart defects and hypospadias.

Use of a job-exposure matrix to assess occupational exposures in relation to birth defects.

Accurate exposure assessment remains a challenge in occupational epidemiology. We evaluated one approach, use of a job-exposure matrix (JEM), by applying the National Institute for Occupational Safety and Health (NIOSH) JEM to a large case-control birth defects study that included parental occupation information. We investigated the JEM exposure predictions in several ways and found that for a substantial proportion of the parents in the birth defects study, the JEM yielded either no exposure data or nonsense predictions. Among exposure predictions that were plausible, most were of low probability. The high probability exposure predictions were statistically unstable, and neither low nor high probability exposure predictions were reliable. There was considerable discrepancy between the JEM predictions and expert assessments for five exposures of interest. Application of the NIOSH JEM to the birth defects study database (and probably other databases as well) does not provide a useful means of assessing occupational exposures.

A case-control study of use of postmenopausal female hormone supplements in relation to the risk of large bowel cancer.

Postmenopausal female hormone use has been associated with a reduced risk of colon cancer. We assessed the relation of use of these supplements to the risk of large bowel cancer. The data were collected in a case-control study of large bowel cancer conducted in Massachusetts. Control subjects were matched to incident cases of carcinoma of the colon or rectum on age, gender, and town precinct. The analysis was restricted to women who experienced a natural menopause or had had a hysterectomy with or without removal of the ovaries (292 colon cancer cases and 112 rectal cancer cases and their matched controls). Use of female hormone supplements was associated with a decreased risk of colon cancer among recent users (odds ratio, 0.6; 95% confidence interval, 0.4-1.0) and long duration (5+ years) of use (odds ratio, 0.5; 95% confidence interval, 0.3-0.9). The association with long duration of use appeared to be independent of recency of use and screening practices and was apparent for late-stage cancer. Hormone supplement use was not associated with a reduced risk of rectal cancer. Our results add to the evidence for a decreased risk of colon cancer associated with use of female hormone supplements.

NSAIDs and risk of colorectal cancer according to presence or absence of family history of the disease.

BACKGROUND: We undertook the present analyses to determine whether family history of colorectal cancer in a parent or sibling modifies the inverse association of nonsteroidal anti-inflammatory drug (NSAID) use with colorectal cancer risk. METHODS: We used data from two case-control studies of colorectal cancer. The hospital-based Case Control Surveillance Study included 1526 patients with primary colorectal cancer, 4192 cancer controls and 6036 noncancer controls. A population-based study conducted in Massachusetts enrolled 1201 incident cases of colorectal cancer and 1201 community controls. Data on NSAID use and risk factors for colorectal cancer were collected by interview. RESULTS: In both studies there was a reduction in the odds ratios among subjects who used NSAIDs regularly continuing into the previous year, regardless of family history. In the Case Control Surveillance data, the odds ratio was 0.4 (95% CI 0.2-0.9) among subjects with a family history and 0.5 (95% CI 0.4-0.7) among subjects without a family history. The comparable odds ratios in the Massachusetts data were 0.5 (95% CI 0.3-0.9) and 0.7 (95% CI 0.6-0.9). CONCLUSIONS: These data indicate that regular continuing NSAID use is associated with a reduced risk of colorectal cancer among persons with a family history of the disease, as well as those without such a history.

Achieving a public health recommendation for preventing neural tube defects with folic acid.

OBJECTIVES: This study examined 3 approaches to achieving the public health recommendation that all women of child-bearing age ingest 0.40 mg of folic acid per day to reduce the occurrence of neural tube defects (NTDs). METHODS: A total of 1136 mothers of infants with major malformations from the Boston and Philadelphia areas, whose pregnancies began from 1993 to 1995, were interviewed within 6 months of delivery about vitamin supplementation, dietary intakes, and other factors. RESULTS: Seventy-one percent of the 1136 women in the study did not take folic acid--containing supplements daily before conception, but the proportion decreased over the years of the study. Women not taking supplements consumed an average of 0.25 mg of naturally occurring folates daily. On the basis of dietary intakes reported by women not taking folic acid supplements, a simulation of cereal grain fortification with folic acid at the level required by the US Food and Drug Administration showed that an average of only 0.13 mg of folic acid would be ingested daily. CONCLUSIONS: With consumption of folic acid only through dietary intake, sizeable portions of the childbearing population would receive less than the level of folic acid recommended for preventing NTDs. Even with food fortification, women of childbearing age should be advised to take folic acid--containing supplements on a daily basis.

Multivitamin supplementation and risk of birth defects.

It is widely accepted that supplementation with folic acid, a B vitamin, reduces the risk of neural tube defects (NTDs). This case-control study tested the hypothesis that multivitamins reduce risks of selected birth defects other than NTDs. Infants with and without birth defects and aborted fetuses with birth defects were ascertained in the greater metropolitan areas of Boston, Philadelphia, and Toronto during 1993-1996. Mothers were interviewed within 6 months after delivery about a variety of factors, including details on vitamin use. Eight case groups were included: cleft lip with or without cleft palate, cleft palate only, conotruncal defects, ventricular septal defects, urinary tract defects, limb reduction defects, congenital hydrocephaly, and pyloric stenosis (n's ranged from 31 to 186). Controls were 521 infants without birth defects (nonmalformed controls) and 442 infants with defects other than those of the cases (malformed controls). Daily multivitamin supplementation was evaluated according to gestational timing categories, including periconceptional use (28 days before through 28 days after the last menstrual period). Odds ratios (ORs) below 1.0 were observed for all case groups except cardiac defects, regardless of control type. For periconceptional use, ORs with 95% confidence intervals that excluded 1.0 were estimated for limb reduction defects using both nonmalformed controls (OR = 0.3) and malformed controls (OR = 0.2) and for urinary tract defects using both nonmalformed controls (OR = 0.6) and malformed controls (OR = 0.5). Statistically significant ORs for use that began after the periconceptional period were observed for cleft palate only and urinary tract defects. These data support the hypothesis that periconceptional vitamin supplementation may extend benefits beyond a reduction in NTD risk. However, other than folic acid's protecting against NTDs, it is not clear what nutrient or combination of nutrients might affect risk of other specific defects.

Vasectomy and prostate cancer.

PURPOSE: Vasectomy has been associated with an increased risk of prostate cancer in some previous studies but not in others. We evaluated the association in a population based, case control study in Massachusetts. MATERIALS AND METHODS: Included in our study were 1,216 patients younger than 70 years with newly diagnosed prostate cancer and 1,400 controls with no history of prostate cancer who were matched to patients by age and town of residence. Data on vasectomy and potential confounding factors were obtained by telephone interview, and confounding was controlled by conditional logistic regression analysis. RESULTS: Overall 16% of patients and 15% of controls had undergone vasectomy. Compared with no vasectomy the odds ratio for ever having undergone vasectomy was 1.0 (95% confidence interval [CI] 0.8 to 1.3), which did not vary significantly by age at or interval since vasectomy. In men who reported urological symptoms and those without symptoms the odds ratio was 0.9 (95% CI 0.7 to 1.2) and 1.4 (1.0 to 1.9), respectively. In men younger than 55 years and those 55 years old or older at diagnosis of prostate cancer the odds ratio was 1.9 (95% CI 1.2 to 3.2) and 1.0 (0.8 to 1.3), respectively [corrected]. In the younger men with stages A or B and C or D disease the odds ratio was 2.3 (95% CI 1.2 to 4.3) and 1.3 (0.5 to 3.5), respectively. CONCLUSIONS: Our findings do not support the hypothesis that vasectomy increases the risk of prostate cancer in men older than 55 years. Further study is needed to determine whether the observed association between vasectomy and prostate cancer in men younger than 55 years is due to chance, detection bias or a causal effect.

Nonsteroidal antiinflammatory drug use and reduced risk of large bowel carcinoma.

BACKGROUND: Animal experiments and epidemiologic data have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the incidence of large bowel carcinoma. Our purpose was to assess the relation of the use of aspirin and nonaspirin NSAIDs with the risk of large bowel carcinoma. METHODS: A population-based case-control study of colon and rectal carcinoma was conducted in Massachusetts from 1992 to 1994. Data on NSAID use and risk factors for large bowel carcinoma were collected by interview from 1201 incident cases of large bowel carcinoma and 1201 controls matched by age, gender, and area of residence. RESULTS: Regular NSAID use that continued into the year before diagnosis was associated with a significantly decreased relative risk estimate overall (0.7; 95% confidence interval [CI], 0.5-0.8) and among Stage II-IV tumors (0.6; 95% CI, 0.4-0.7). There was no reduction in risk for discontinued use. The inverse association with regular continuing use was present across age and gender and for both colon and rectal carcinoma. Similar inverse associations were present for regular continuing use of aspirin and nonaspirin NSAIDs. There was no significant evidence of a trend for the relative risk to decrease as the duration of use increased, nor was there a trend across the dose of aspirin, which ranged from less than one-half of a 325 mg tablet per day to > or = 2 tablets per day. Discontinuation of use in response to symptoms of carcinoma did not appear to explain the inverse association, nor did bias related to diagnosis of the carcinoma. CONCLUSIONS: These data add to the growing body of evidence that suggests a protective effect of NSAIDs against large bowel carcinoma.

Prepregnant weight in relation to risk of neural tube defects.

OBJECTIVE: To examine the relation between prepregnant weight and the risk of neural tube defects (NTDs). DESIGN: Data were collected from 1988 to 1994 in a case-control surveillance program of birth defects. SETTING: Study subjects were ascertained at tertiary care centers and birth hospitals in the greater metropolitan areas of Boston, Mass, and Philadelphia, Pa, and in southeastern Ontario. PARTICIPANTS: Cases were 604 fetuses or infants with an NTD identified within 6 months of delivery. Controls were 1658 fetuses or infants with other major malformations identified within 6 months of delivery. For 1992 to 1994, there were 93 control infants without major malformations. MAIN OUTCOME MEASURE: Relative risk of NTDs in infants or fetuses for different maternal weights. RESULTS: Relative to women who weighed 50 to 59 kg, risk of NTDs increased from 1.9 (95% confidence interval [CI], 1.2 to 2.9) for women weighing 80 to 89 kg to 4.0 (95% CI, 1.6 to 9.9) for women weighing 110 kg or more. When women were classified according to daily intake above or below the recommended level of 400 micrograms of folate, approximate threefold increases in risk were estimated for the heaviest weights in both groups. Intakes of 400 micrograms of folate or more reduced risk of NTDs by 40% among women weighing less than 70 kg, but no risk reduction was observed among heavier women. CONCLUSION: The risk of NTDs increased with increasing prepregnant weight, independent of the effects of folate intake.

A pregnancy-prevention program in women of childbearing age receiving isotretinoin.

BACKGROUND: Isotretinoin is effective in treating severe acne, but it is also teratogenic. To minimize pregnancies among exposed women, the manufacturer, together with the U.S. Food and Drug Administration, implemented a multicomponent Pregnancy Prevention Program in 1988. We report the results of an ongoing survey designed to assess compliance with this program. METHODS: Treated women enrolled in the survey through their physician, by filling out a form in the medication package, or by calling a toll-free telephone number. They were randomly assigned to be followed by telephone or by mail. Telephone interviews were conducted at the start of therapy, in the middle of it, and 6 months after it ended; mailed questionnaires were completed 6 months after therapy ended (median duration of therapy, 20 weeks). RESULTS: Between 1989 and 1993, 177,216 eligible women enrolled in the survey. Interviews with 24,503 women within one month of enrollment revealed that 99 percent had been told to avoid pregnancy. At that time, approximately 54 percent were not sexually active (of whom 37 percent used contraception) and 42 percent were sexually active (of whom 99 percent used contraception); 4 percent were infertile. Among 124,216 women with completed telephone or mail follow-up results, there were 402 pregnancies during therapy (3.4 per 1000 courses of isotretinoin); 72 percent of the pregnant women had elective abortions, 16 percent spontaneous abortions, 3 percent ectopic pregnancies, and 8 percent live births. CONCLUSIONS: The pregnancy rate among women receiving isotretinoin therapy was substantially lower than that in the general population and was compatible with the characteristics and behavior of the enrolled women.

PIP: Isotretinoin is effective in treating severe acne, but it is also teratogenic. To minimize pregnancies among exposed women, the manufacturer, together with the US Food and Drug Administration, implemented a multicomponent Pregnancy Prevention Program in 1988. The results of an ongoing survey designed to assess compliance with this program are reported. Treated women enrolled in the survey through their physician, by filling out a form in the medication package, or by calling a toll-free telephone number. They were randomly assigned to be followed by telephone or by mail. Telephone interviews were conducted at the start of therapy, in the middle of it, and 6 months after it ended; mailed questionnaires were completed 6 months after therapy ended (median duration of therapy, 20 weeks). Between January 1, 1989, and December 31, 1993, 177,216 eligible women enrolled in the survey. First telephone interviews were completed with 24,503 women within 1 month of enrollment. The median age of these women was 26 years, the median number of years of education was 14, and the median duration of acne was 8 years. 99% had been told to avoid pregnancy; 85% were told of the importance of using effective contraception for 1 month before starting isotretinoin. At that time, approximately 54% were not sexually active (of whom 37% used contraception); 42% were sexually active (of whom 99% used contraception); and 4% were infertile. As of June 30, 1994, 124,216 women had completed telephone or mail follow-up. There were 402 pregnancies during therapy (0.3% or 3.4 per 1000 20-week courses of isotretinoin); 46 were pregnant when therapy began, and 356 became pregnant during therapy. 290 (72%) of the 402 pregnant women had elective abortions, 63 (16%) had spontaneous abortions, 13 (3%) had ectopic pregnancies, and 32 (8%) had live births. Of the 32 liveborn infants, the survey teratologist examined 13, of whom 5 were judged to have defects compatible with the isotretinoin embryopathy. The pregnancy rate among women receiving isotretinoin therapy was substantially lower than that in the general population and was compatible with the characteristics and behavior of the enrolled women.

Ovulation induction and risk of neural tube defects.

The relation between use of ovulation-inducing drugs and risk of neural tube defects (NTDs) was studied in a case-control surveillance programme. The frequency of any use of such drugs during the 6 months before the last menstrual period or during pregnancy was 3.0% for 1034 mothers of infants and fetuses with NTDs (cases) and 2.8% for 4081 mothers of those with other major congenital malformations (controls) (relative risk 1.1, 95% CI 0.8-1.7). Relative risks for clomiphene and for hormones were 0.8 (0.5-1.3) and 1.5 (0.7-3.4), respectively. These data suggest that use of ovulation-inducing drugs before conception does not increase the risk of NTDs.

Maternal exposure to spermicides in relation to certain birth defects.

Several studies have found no increase in the overall frequency of birth defects in association with the use of spermicides, but the possibility of an increase in specific defects remains. We evaluated this possibility in a large case-control study. Infants with certain malformations (265 with Down's syndrome, 396 with hypospadias, 146 with limb reduction defects, 116 with neoplasms, and 215 with neural-tube defects) were compared with 3442 control infants with a wide variety of other defects. Exposure to spermicides was assessed for three periods: use during the periconceptional period (one month before through one month after the last menstrual period), use during the first trimester (the first four lunar months of pregnancy), and any use during the lifetime. For the five groups of cases and for each interval, the odds ratios were close to 1.0 (range, 0.7 to 1.3); the upper 95 percent confidence bounds were 2.2 or lower. Risks did not increase with the duration of exposure. When each of the active ingredients in currently available spermicides was considered separately, no differences in odds ratios were apparent between the types of spermicides. With the possible exception of a subgroup of cases (limb reduction defects of unknown cause), these results suggest that risks for the five specific birth defects evaluated are not increased by exposure to spermicides.

PIP: Several studies have found no increase in the overall frequency of birth defects in association with the use of spermicides, but the possibility of an increase in specific defects remains. This possibility was evaluated in a large case-control study. Infants with certain malformations (265 with Downs syndrome, 396 with hypospadias, 146 with limb reduction defects, 116 with neoplasms, and 215 with neural-tube defects) were compared with 3442 control infants with a wide variety of other defects. Exposure to spermicides was assessed for 3 periods: use during preconceptional period (1 month before through 1 month after the last menstrual period), use during the 1st trimester (the 1st 4 lunar months of pregnancy), and any use during the lifetime. For the 5 groups of cases and for each interval, the odds ratios were close to 1.0 (range 0.7 to 1.3); the upper 95% confidence bounds were 2.2 or lower. Risks did not increase with the duration of exposure. When each of the active ingredients in currently available spermicides was considered separately, no differences in odds ratios were apparent between the types of spermicides. With the possible exception of a subgroup of cases (limb reduction defects of unknown cause), these results suggest that risks for the 5 specific birth defects evaluated are not increased by exposure to spermicides.

Heparin use as a risk factor for intraventricular hemorrhage in low-birth-weight infants.

In a systematic review of data on drug use and adverse clinical events in infants with birth weights under 2000 g, we observed an association between germinal matrix-intraventricular hemorrhage and the use of heparin to maintain the patency of vascular catheters. Sixty-six infants with germinal-matrix (periventricular) or intraventricular hemorrhage or both (cases) were matched with 254 infants with other conditions (controls), and analysis, taking the matching factors into account, yielded an odds ratio of 14.0 (95 percent confidence interval, 5.4 to 34). When potential confounding factors were taken into account, the odds ratio was 3.9 (1.4 to 11). The association did not appear to vary according to the severity of hemorrhage or to the method of administration or dose of heparin. The data suggest that the routine use of heparin in neonatal intensive care units is associated with a four-fold increase in the risk of germinal matrix-intraventricular hemorrhage. Because of the possibility that confounding may have been incompletely controlled for, the true risk cannot be determined from these data, and a controlled clinical trial of heparin use in low-birth-weight infants is recommended.

Risk factors for neonatal hyperglycemia associated with 10% dextrose infusion.

As part of an intensive drug surveillance program, we identified rates and associated risk factors for hyperglycemia related to intravenous 10% dextrose solution in a population of 1,157 newborns in two neonatal intensive care units. Hyperglycemia related to 10% dextrose solution was observed in 64 exposed infants (5.5%), a rate similar to that observed for hypoglycemia (6.7%) in this population. There was a highly significant trend toward an increasing risk of hyperglycemia with decreasing body weight, such that the risk of hyperglycemia among infants weighing less than 1,000 g was 18 times greater than the risk among infants weighing more than 2,000 g. The risk of hyperglycemia also increased with increasing dextrose dose. The effects of weight and dose were independent. Certain measures of disease severity also were associated with increased risks of hyperglycemia. Because increases in blood glucose levels may affect renal function or possibly lead to intraventricular hemorrhage, it is important that glucose levels in neonates receiving 10% dextrose solution be carefully monitored, and the total dextrose dose be adjusted accordingly.

A study of adverse reaction algorithms in a drug surveillance program.

To improve agreement among observers, several investigators have recently proposed methods (algorithms) to standardize assessments of causality for presumed adverse drug reactions. We evaluated one such method in the context of an intensive pediatric drug surveillance program. Four observers rated 50 randomly selected case reports drawn from the program, first using only general guidelines and then, several months later, using the strict criteria of the algorithm. Agreement among observers was poor in both study phases. The presence of selected characteristics of adverse events (e.g., major severity) did not improve agreement in either phase of the study. We conclude that routine use of such algorithms in drug surveillance programs is not likely to be of benefit.

Birth defects in relation to Bendectin use in pregnancy. II. Pyloric stenosis.

To test the hypothesis that the use of Bendectin in pregnancy increases the risk of pyloric stenosis, we determined rates of antenatal Bendectin exposure among 325 infants with pyloric stenosis and among two control groups comprising infants with other defects; one consisted of 3,153 infants with other conditions, and the other, a subset of that group, consisted of 724 infants with defects that may have had their origins at any time in pregnancy. Comparisons between the cases and the two control series yielded estimated relative risks of 0.9 (95% confidence interval, 0.6 to 1.2) and 1.0 (0.7 to 1.4), respectively. The findings from this large case-control study suggest that Bendectin does not increase the risk of pyloric stenosis.

Lack of relation of oral clefts to diazepam use during pregnancy.

The hypothesis that in utero exposure to diazepam increases the risk of oral-cleft anomalies was evaluated in a case-control study, in which 445 infants with cleft lip with or without cleft palate and 166 with cleft palate without cleft lip (cleft palate alone) were compared with 2498 control infants having other birth defects. For exposure to diazepam during lunar months 1 through 4 relative to no exposure during pregnancy, the estimated relative risks were 1.0 for cleft lip with or without cleft palate (95 per cent confidence interval, 0.5 to 2.1) and 0.8 for cleft palate alone (0.3 to 2.7). After control for all identified potential confounding factors, the corresponding estimates were 0.8 (0.4 to 1.7) and 0.8 (0.2 to 2.5), respectively. The findings were unchanged when maternal suspicion that diazepam might be a teratogen was taken into account. The data suggest that first-trimester exposure to diazepam does not materially affect the risk of cleft lip with or without cleft palate or of cleft palate alone.

Risks to children from computed tomographic scan premedication.

We observed serious adverse reactions after premedication for computed tomographic (CT) head scans and therefore determined rates and risk factors for such reactions among 106 hospitalized children monitored by an intensive drug surveillance program. Reactions occurred in 13 patients (13%), including four cases of life-threatening cardiorespiratory depression or arrest after narcotic premedication. Other reactions included CNS depression, behavior changes, voiding problems, and vomiting. The risk of reaction was elevated in subjects who received high doses of a premedication drug (relative risk, 5.2) and in those who received four or more premedication (relative risk, 3.7). All life-threatening reactions occurred among infants younger than 3 months, and two of these followed medication with only morphine sulfate, in the recommended dose. Risks of adverse reactions from premedication should be considered by physicians who order CT scans for hospitalized children.

Mortality and cancer morbidity among workers in the rubber tire industry.

A retrospective follow-up study was conducted to evaluate mortality and cancer incidence between 1954 and 1976 among 1,792 white male production workers employed for at least 2 years at a tire manufacturing plant. There were no marked excesses in overall or site-specific cancer deaths or incident cases. Compared to U.S. white males, men employed for at least 10 years experienced small increases in deaths from cancers of the large intestine, pancreas, and lung. Results obtained by comparing observed incident cancer cases to the numbers expected based on age- and calendar time-specific incidence rates of Connecticut males also suggested excesses of these three malignancies. These findings were based on small numbers and therefore do not necessarily indicate causal associations between cancer excesses and employment in the rubber tire industry. However, because the workers studied comprised a relatively young population that may not have experienced the full impact of carcinogenic occupational exposures, further follow-up is warranted.

Oral contraceptives and birth defects.

We reviewed the birth certificates and hospital records of 7723 infants those mothers had reported using oral contraceptives. The overall frequency of malformation was 4.3 per cent for infants whose mothers terminated use of oral contraceptives shortly before conception, as compared with 3.3 per cent for infants whose mothers did not take oral conceptives diring the three years before conception. The 90 per cent confidence limits for the prevalence ratio were 1.0 and 1.7. No difference was apparent for major malformations. For specific malformations the most notable difference was for undescented testis, but this excess, like the overall excess, could be explained by sampling variability. Despite the slightly greater rate of minor malformations in the short-interval group, a reasonable interpretation of these data would be that oral contraceptives present no major teratogenic hazard.