Effect of prenatal diagnosis on epidemiologic studies of birth defects.

Prenatal diagnostic technology makes it possible to offer women the option of electively terminating pregnancies affected by birth defects. Excluding these pregnancies from epidemiologic studies may affect study results. We explored this effect using examples from the literature. We calculated the bias in the odds ratio caused by excluding prenatally diagnosed pregnancies when the exposure of interest is not correlated with the likelihood of terminating an affected pregnancy and when it is correlated with an increase or decrease in this likelihood. We assumed that control infants did not have birth defects. When the exposure is not associated with the likelihood of a pregnancy termination, studies excluding terminations suffer a loss of precision. When the exposure is associated with an increase or decrease in this likelihood, the odds ratios are biased toward or away from the null, respectively. The magnitude of the bias will vary according to characteristics of the study population such as the prevalence of the exposure and the frequency with which prenatal diagnosis and elective termination are used. Whenever possible, pregnancies terminated after prenatal diagnosis must be included in epidemiologic studies.

Evaluation of selected characteristics of pregnancy drug registries.

Given that half of U.S. pregnancies are unintended and some prescription drugs are frequently used by reproductive-age women, there is an increasing interest in establishing pregnancy registries to monitor fetal exposures and pregnancy outcomes. Physicians report prenatal exposures and pregnancy outcomes, including birth defects, to these registries. We compared pooled data from four pregnancy registries with data from a population-based birth defects surveillance system, the Metropolitan Atlanta Congenital Defects Program (MACDP); specifically we compared the defect prevalence by organ system and severity, the number of defects per baby, and timeliness. We also compared the number of zidovudine exposures identified by a registry to the number identified by 29 states with HIV surveillance. The registries' overall defect prevalence (41/1471, 2.7%) was slightly lower than MACDP (6157/195642, 3.2%). The defect prevalence by organ system was similar, except for genitourinary defects which had a lower prevalence in the registries than in MACDP (RR = 0.22; 95% CI = 0.07,0.67). The prevalence of having an internal defect or severe defect reported was lower in the registries (RR = 0.75, 95% CI = 0.53,1.06, and RR = 0.82, 95% CI = 0. 57,1.19, respectively). The mean number of defects identified per affected infant was 2.82 in MACDP and 1.68 in the registries. Both systems received 69% of defect reports by 6 months after birth. In similar 6-month periods, U.S. HIV surveillance identified 300 prenatal zidovudine exposures, while the registry received 134 worldwide reports. If registries improve their ascertainment of defects and exposed pregnancies, they will increase their chance of detecting signs of possible teratogenicity. Teratology 60:356-364, 1999. Published 1999 Wiley-Liss, Inc.

Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromcyin: a case review and cohort study.

BACKGROUND: In February, 1999, a local US health department identified a cluster of pertussis cases among neonates born at a community hospital and recommended oral erythromycin for post-exposure prophylaxis for about 200 neonates born at that hospital between Feb 1 and Feb 24, 1999. We investigated a cluster of seven cases of infantile hypertrophic pyloric stenosis (IHPS) that occurred the following month among the neonates who had received erythromycin. METHODS: We obtained a masked, independent review of the IHPS ultrasonography diagnoses, calculated the monthly IHPS incidence, and compared index and historical (1998-99) IHPS cases with respect to several characteristics including erythromycin exposure. We used a retrospective cohort of infants born in January and February, 1999, to investigate further erythromycin exposure and development of IHPS. FINDINGS: An independent review confirmed the ultrasonographic diagnoses of all seven index IHPS cases. All index cases versus none of the historical IHPS cases had been given erythromycin for pertussis prophylaxis. The IHPS rate for infants born in the hospital in February, 1999, was 32.3 per 1000 liveborn infants, representing nearly a seven-fold increase over 1997-98 (relative risk 6.8 [95% CI 3.0-15.7]). Among infants born in January and February, 1999, erythromycin was associated with IHPS (absolute risk 4.5%, relative risk infinity [1.7-infinity]). INTERPRETATION: Neonates receiving oral erythromycin may have an increased risk of IHPS. The risks and benefits of erythromycin for neonatal pertussis prophylaxis should be re-evaluated, and caution should be used in defining risk groups for prophylaxis.

Increased frequency of cystic fibrosis among infants with jejunoileal atresia.

There appears to be an increased frequency of cystic fibrosis (CF) among infants with jejunoileal atresia (JIA). However, the figures vary widely, and no population-based data exist. The purpose of this study was to quantitate the magnitude of the association between JIA and CF in Atlanta using population-based data from 1968 to 1995. Case subjects included all infants with isolated JIA born during 1968-1995 to mothers residing in the five-county metropolitan Atlanta area at the time of birth. To ascertain cases, we reviewed records of the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based birth defects registry. Caucasian JIA cases were cross-referenced with patients in the CF registry at the Egleston Cystic Fibrosis Center at Emory University to more completely ascertain the diagnosis of CF among JIA cases. During 1968-1995, MACDP ascertained a total of 94 isolated JIA cases, for a birth prevalence of 1.8/10,000 live births. Among the cases, 38 were Caucasian, 52 were African-American, and 4 were of Asian or Hispanic ethnicity. Four of the 38 Caucasian JIA cases (11%) also had CF. The expected number of JIA cases with CF is 0.019 based on the estimated population incidence of 1/ 2,000 for CF. The observed to expected (O/E) ratio of Caucasian JIA cases with CF is greater than 210 (P<0.0001). Caucasian infants with JIA have more than 210 times the risk for CF compared with Caucasian infants in the general population. The results of this study have implications for the management of infants born with JIA and genetic counseling for families with affected infants.

Multivitamin supplementation and multiple births.

It is well established that maternal multivitamin supplementation reduces the risk of neural tube defects and evidence suggests that it may be associated with other reproductive outcomes. The present study was prompted by a report from a randomized trial in Hungary which showed a 40% increase in multiple births among periconceptional vitamin users. Retrospectively collected data on multivitamin supplementation were obtained on multiple and singleton births from three separate studies: Atlanta Birth Defects Case-Control Study (ABDCCS) malformed and nonmalformed infants born 1968-1980, California Birth Defects Monitoring Program (CBDMP) malformed and nonmalformed infants born 1987-1989, and Boston University Slone Epidemiology Unit Birth Defects Study (SEU-BDS) malformed infants born 1987-1994. Supplementation was divided into three mutually exclusive categories based on timing: "periconceptional" use--before through at least the third month after conception; "early" use--beginning in the first month and continuing through at least the third month after conception; and "later" use--beginning in the second or third month after conception. For periconceptional use, four of five datasets showed a 30 to 60% greater prevalence of supplementation among mothers of multiple births. In contrast, this pattern was not evident for "early" and "later" use. Overall, the study findings are tentative, due to a lack of consistency across all five datasets and they should not alter recent recommendations related to folate supplementation for the prevention of neural tube defects.

Trends and outcomes after prenatal diagnosis of congenital cardiac malformations by fetal echocardiography in a well defined birth population, Atlanta, Georgia, 1990-1994.

OBJECTIVES: In this study we used a population-based approach to assess the impact of fetal echocardiography on a well defined birth population with nearly complete ascertainment of cardiac defects. BACKGROUND: Although fetal echocardiography is being used more frequently in the prenatal diagnosis of congenital cardiac malformations, its impact on the diagnosis and surveillance of cardiac defects has not been described in defined populations. METHODS: All stillborn and live-born infants with diagnosed cardiac defects and whose mothers resided in the metropolitan Atlanta area from January 1990 through December 1994 were ascertained through an established birth defects surveillance system. All fetuses with cardiac defects diagnosed prenatally by a pediatric of cardiac defects, diagnostic trends and adverse fetal outcomes were described. RESULTS: We identified 1,589 infants with congenital cardiac malformations, for a live-birth prevalence rate of 8.1/1,000 (95% confidence interval [CI] 7.8 to 8.6). Overall, 97 (6.1%) of these cases of cardiac malformations were diagnosed prenatally. The proportion of cardiac defects diagnosed prenatally rose from 2.6% in 1990 to 12.7% in 1994, a nearly fivefold increase. The proportion of cardiac defects diagnosed prenatally during the study varied by the type of defect, from a low of 4.7% for atrial septal defects to a high of 28% for hypoplastic left heart syndrome. Prenatally diagnosed cardiac malformations were associated with a high incidence of infant mortality (30.9%, 95% CI 2.4 to 5.4) and fetal wastage (17.5%, 95% CI 6.2 to 11.3). CONCLUSIONS: These data show that fetal echocardiography is being used increasingly in the prenatal diagnosis of congenital cardiac malformations in metropolitan Atlanta. Few pregnancy terminations were reported as a result of such diagnoses. However, the study had limited power (10%) to detect a meaningful decrease in birth prevalence rates for congenital heart disease. In addition, survival of infants was not improved after prenatal diagnosis with fetal echocardiography.

Impact of prenatal diagnosis on the birth prevalence of neural tube defects, Atlanta, 1990-1991.

OBJECTIVE: To determine the impact of prenatal diagnosis on the birth prevalence of neural tube defects (NTDs) in Atlanta during 1990 through 1991. METHODS: Live-born and stillborn infants with NTDs who were at least 20 weeks' gestation were ascertained by the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based birth defects registry. Prenatally diagnosed NTD-affected pregnancies were ascertained from the four perinatal centers and the three genetic laboratories operating in Atlanta during 1990 through 1991. Fetal death certificates were also reviewed for potential cases. RESULTS: During 1990 through 1991, MACDP ascertained 59 NTD cases, for a birth prevalence of 0.77/1000 live births. During this period, an additional 28 NTD-affected pregnancies were detected prenatally and terminated before 20 weeks' gestation. The adjusted NTD rate during 1990 through 1991, which includes prenatally diagnosed cases, was 1.13/1000 live births. CONCLUSIONS: Prenatal diagnosis is making a substantial impact on the birth prevalence of NTDs in Atlanta. However, since NTD rates in Atlanta were 2 to 2.5 per 1000 live births in 1970, prenatal diagnosis and termination of pregnancy does not completely account for the declining rate of NTDs.

Surveillance for anencephaly and spina bifida and the impact of prenatal diagnosis--United States, 1985-1994.

PROBLEM/CONDITION: The reported prevalence of anencephaly and spina bifida in the United States has steadily declined since the late 1960s. During this time, the ability to diagnose these defects prenatally has progressed rapidly. Many U.S. birth defects surveillance systems ascertain defects only among live-born infants or among infants and fetuses beyond a certain gestational age, thus excluding defects among pregnancies prenatally diagnosed as being affected by a neural tube defect (NTD) and electively terminated before the gestational age limit. The impact of prenatal diagnosis and subsequent pregnancy termination on the reported prevalence of anencephaly and spina bifida in the United States has not been well established. However, assessment of this impact is crucial to the use of surveillance data to monitor trends in the occurrence of NTDs and the effectiveness of interventions for these defects (e.g., increased consumption of folic acid). REPORTING PERIOD: This report presents data from birth defects surveillance systems in six states over different time periods: Arkansas, 1985-1989; California, 1989-1991; Georgia, 1990-1991; Hawaii, 1988-1994; Iowa, 1985-1990; and South Carolina, 1992-1993. DESCRIPTION OF SYSTEMS: Population-based data about a) live-born and stillborn infants with anencephaly and spina bifida and b) pregnancies electively terminated after prenatal diagnosis of these defects were analyzed from the Arkansas Reproductive Health Monitoring System; the California Birth Defects Monitoring Program; CDC's Metropolitan Atlanta Congenital Defects Program; the Iowa Birth Defects Registry, the University of Iowa, and the Iowa Department of Public Health; and the Greenwood Genetic Center in South Carolina. Data also were analyzed from the Hawaii Birth Defects Monitoring Program, which includes data for some women who were not residents of the state. The systems differed in the size and racial/ethnic composition of the populations studied, the surveillance methods used, the completeness of ascertainment, and the availability and utilization of prenatal testing and pregnancy termination. RESULTS AND INTERPRETATION: Among all pregnancies ascertained in which the infant or fetus had anencephaly or spina bifida, the percentages that were electively terminated ranged from 9% in Arkansas to 42% in Atlanta and Hawaii, with a corresponding increase in the adjusted prevalence of these defects compared with the prevalence at birth. In each system, pregnancies associated with anencephaly were terminated more frequently than were those associated with spina bifida. These data indicate that the impact of prenatal diagnosis and subsequent pregnancy termination on the prevalence at birth of anencephaly and spina bifida differs among geographic areas and populations. Comprehensive surveillance for these defects requires inclusion of pregnancies that are prenatally diagnosed and then terminated. ACTIONS TAKEN: CDC will use these data to promote the inclusion of prenatally diagnosed and terminated pregnancies in estimates of the prevalence of anencephaly and spina bifida generated by birth defects surveillance programs in the United States. Including such pregnancies is crucial to the ability of these programs to monitor trends accurately and to establish the effectiveness of interventions, including the use of folic acid, for these defects.

High incidence of congenital rubella syndrome after a rubella outbreak.

Previous studies of the incidence of congenital rubella syndrome (CRS) after rubella outbreaks have been limited because most women with infection during the first trimester elected to have their pregnancies terminated. After a rubella outbreak in 1991 we measured prospectively the impact of maternal infection on CRS among the Amish in one county in Pennsylvania. We compared rubella serology of Amish women delivering before and after the outbreak and cord blood rubella IgM from Amish and non-Amish infants. Before the outbreak 20% of Amish women were susceptible to rubella; after the outbreak 4% were (P = 0.001). Of Amish infants 15% tested positive for rubella IgM; no non-Amish infants did (P < 0.001). This rubella outbreak in a largely unimmunized community led to a high rate of CRS. The annual CRS rate among the Amish was 2130/100,000 live births. Health care providers should promote immunization in all clients and intensify efforts among the Amish.

Increased risk of small intestinal atresia among twins in the United States.

OBJECTIVE: To compare the prevalence of small intestinal atresia among twins and singletons in the United States. DESIGN: Descriptive analysis. MEASUREMENTS: The McDonnell Douglas Health Information System (MDHIS), a national registry of newborn diagnoses, 1982 through 1988; and the Metropolitan Atlanta Congenital Defects Program (MACDP), a registry of defects among infants in Atlanta, 1968 through 1989. PATIENTS: Live-born infants with small intestinal atresia. INTERVENTIONS: None. MAIN RESULTS: In both systems, the rate of small intestinal atresia was higher among twins than singletons (MDHIS: 5.5 per 10,000 vs 2.0, relative risk [RR] = 2.8, 95% confidence interval [CI] = 1.9 to 4.0; MACDP: 7.3 vs 2.5, RR = 2.9, 95% CI = 1.5 to 5.7). The increase was more notable among same-sex twins than opposite-sex twins, suggesting an increase among monozygotic twins. It was also more notable among twins with jejunoileal atresia than those with duodenal atresia, suggesting a vascular cause in many cases. CONCLUSION: Twins have a higher rate of small intestinal atresia than singletons, possibly due to vascular disruption in monozygotic twins.

Descriptive epidemiology of small intestinal atresia, Atlanta, Georgia.

To describe the epidemiology of small intestinal atresia (SIA) in Atlanta, Georgia, from 1968 through 1989, we used the Metropolitan Atlanta Congenital Defects Program, an active, population-based surveillance system for birth defects diagnosed during the first year of life. We identified 176 infants with SIA, a prevalence of 2.8 per 10,000 livebirths. Among black infants, the prevalence was 3.7 per 10,000 livebirths, significantly higher than the prevalence of 2.4 per 10,000 among white infants [relative risk (RR) = 1.6, 95% confidence interval (CI) = 1.1,2.1]. Nine infants were each one member of a unique pair of twins. The prevalence among twin infants was 7.3 per 10,000, significantly higher than the prevalence of 2.8 per 10,000 among singletons (RR = 2.7, 95% CI = 1.4,5.2). Forty-nine percent of the infants had duodenal atresia, 36% had jejunal atresia, and 14% had ileal atresia. Two infants (1%) had atresia at an unspecified site in the small intestine. We grouped the infants by anatomic location of SIA into four categories: isolated SIA (53%), SIA with multiple unrelated defects (21%), sequences (16%), and syndromes (10%). We then compared the isolated and multiple unrelated defects groups by gender, race, maternal age, birth weight and one-year mortality for each location of SIA. Among black infants the prevalence of isolated jejunal atresia was 1.4 per 10,000, significantly higher than the prevalence of 0.2 per 10,000 among white infants (RR = 6.3, 95% CI = 2.9, 13.5). The increased prevalence of these defects among twins was a particularly interesting finding.