George C. Cunningham

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.

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.

Neural tube defect prevalence in California (1990-1994): eliciting patterns by type of defect and maternal race/ethnicity.

This study presents race/ethnicity-specific prevalence estimates of neural tube defects (NTDs) in California using 5 years of population-based data. NTD prevalence estimates include prenatally diagnosed cases, as well as cases diagnosed at birth. The California NTD Registry contains NTD case reports identified through the California Maternal Serum Alpha-Feto Protein (AFP) Screening Program, the California Birth Defects Monitoring Program, and additional reports from clinicians and clinics throughout the state. These data were used to estimate NTD prevalence in a large population-based study (n = 1,618,279). The overall NTD prevalence among White, Black, Hispanic, and Asian women are reported, as well as race/ethnic prevalence, for anencephaly, spina bifida, and encephalocele. Rates are expressed as the number of cases per 1,000 women screened between 1990 and 1994. Among 1,457 women with an NTD-affected pregnancy, the overall rate for anencephaly, spina bifida, and encephalocele was 0.49 (95% CI 0.46-0.53), 0.42 (95% CI 0.38-0.45), and 0.08 (95% CI 0.07-0.09), respectively. When these types of NTDs are combined, Hispanic women had the highest overall rate (1.12, 95% CI 1.04-1.21), followed by Whites (0.96, 95% CI 0.89-1.04), Blacks (0.75, 95% CI 0.59-0.91), and Asians (0.75, 95% CI 0.60-0.90). Hispanic women were 45% more likely than White women to have a pregnancy affected with anencephaly (odds ratio = 1.45, 95% CI 1.24-1.70), while Asian women were over two times less likely to have a pregnancy affected with spina bifida (odds ratio = 0.44, 95% CI 0.29-0.65). Considerable variation exists in the prevalence of NTDs by race/ethnicity and by type of NTD, with Hispanic women exhibiting the highest overall NTD rate.

Vitamin A and birth defects.

OBJECTIVE Our objective was to determine whether moderate doses of vitamin A are teratogenic. STUDY DESIGN This was a geographically based case-control study. Women whose pregnancies produced offspring with neural tube defects (n = 548) or major malformations other than neural tube defects (n = 387) and normal control subjects (n = 573) were interviewed to determine periconceptional vitamin A supplement exposure levels. RESULTS The proportion of women consuming doses of vitamin A between 8000 and 25,000 IU was no greater in the major malformations group or the group with neural tube defects than in the normal control group. For exposure from supplements and fortified cereals combined, women consuming >8000 and >10,000 IU daily had odds ratios for major malformations of 0.79 (95% confidence interval 0.40 to 1.53) and 0.73 (95% confidence interval 0.27 to 1.96), respectively, compared with women consuming <5000 IU. The results for neural tube defects were similar. For cranial neural crest defects the odds ratios were 0.76 (0.22 to 2.56) and 1.09 (0.24 to 4.98) for exposure to >8000 and >10,000 IU, respectively, versus exposure to <5000 IU. CONCLUSIONS This study found no association between periconceptional vitamin A exposure at doses >8000 IU or >10,000 IU per day and malformations in general, cranial neural crest defects, or neural tube defects. If vitamin A is a teratogen, the minimum teratogenic dose appears to be well above the level consumed by most women during organogenesis.

Cost and effectiveness of the California triple marker prenatal screening program

Purpose: To report the utilization of services offered and pregnancy outcomes for a unique statewide prenatal triple marker screening program and to present a cost-benefit analysis. A state population of 32 million with consider-able ethnic and age distribution and with a wide variety of delivery systems providing prenatal care was considered. The entire pregnant population who appeared for care before 20 weeks gestation, approximately one-half million per year during the years of 1995 to 1997, was included in the study.Methods: Mandatory offering of serum testing, using alpha-fetoprotein from 1986 to 1995, and the addition of human chorionic gonadotropin and unconjugated estriol in 1995, with systematic follow-up of serum screen positives with ultrasound and amniocentesis. This study collected and analyzed the program data and reports of outcomes and collected similar information from the birth defects registry.Results: Triple marker serum screening was accepted by 67.4% of the women eligible and yielded an initial positive rate of 7.3%. More than 90% of the initially screen positive pregnancies were seen at a prenatal diagnostic center. After correction of gestational age, 71.3% had amniocentesis. The overall amniocentesis rate among women screened was 2.6%. The Programs detection rate was predicted to be 85% for neural tube defects, and, based on Monte Carlo modeling, was theoretically calculated to be 62% for Down syndrome. In practice, detection rates were 75% for neural tube defects and 41% for Down syndrome due to lower than expected amniocentesis acceptance rate. Nevertheless, at a 5% discount rate, the screening program was cost beneficial at a ratio of 2.69:1. The cost per case detected was 35,365 and per case prevented was 110,741.Conclusion: It is possible to implement a cost-effective population-based screening in compliance with quality standards in a diverse ethnic population with a variety of health-care providers. Triple marker screening in the second trimester is a cost beneficial program even if utilization of all services is less than ideal.

California's Experience Implementing a Pilot Newborn Supplemental Screening Program Using Tandem Mass Spectrometry

OBJECTIVE. In response to a California legislative mandate, a pilot tandem mass spectrometry (MS/MS) screening program was undertaken by the Genetic Disease Branch of the California Department of Health Services between January 2002 and June 2003. This article outlines the Genetic Disease Branch approach to implementing the MS/MS pilot program and the program evaluation strategies used. METHODS. Through the use of multiple data collection methods, we were able to describe hospital participation patterns, screening test uptake, screening test performance, follow-up services utilization, and provider and family satisfaction with the educational materials and follow-up services provided. RESULTS. During the 18-month pilot program, just more than one half of Californias 755698 newborns were offered MS/MS screening; among this group, 90% of parents chose to have their newborns screened. Fifty-one newborns were identified with MS/MS-detectable disorders, among 461 patients referred for follow-up testing (0.13% of the screened population). One disorder was diagnosed successfully for every 6939 newborns screened and for every 9 infants referred (excluding phenylketonuria). The overall California population prevalence of MS/MS-detectable disorders was 1 case per 6500 infants (excluding phenylketonuria). The positive predictive value for medium-chain acyl-CoA dehydrogenase deficiency was 86.7%, whereas the positive predictive value for short-chain acyl-CoA dehydrogenase deficiency was 21.6%. For a sample from Hawaii, 1 isovaleric aciduria case was detected among 6132 newborns. CONCLUSIONS. Evaluation of the California MS/MS screening pilot program demonstrated that this technology was effective in identifying additional metabolic disorders. The positive predictive value of screening was particularly good for medium-chain acyl-CoA dehydrogenase deficiency. Overall, patient referral rates were very acceptable. The utility of the program was also demonstrated by positive reviews from patients and providers.

Risk of neural tube defects in relation to maternal fertility and fertility drug use

In a case-control study to investigate whether women who use drugs to induce ovulation are at increased risk of conception of a child with a neural tube defect, 571 women who had a fetus or child with a neural tube defect, 546 women who had a fetus or child with other abnormalities, and 573 women who had an apparently normal fetus or child were questioned about infertility, fertility drug use, and related obstetric problems. The rate of maternal fertility drug use around the time of conception was not significantly higher for neural tube defects than for other abnormalities (odds ratio 1.28; 95% confidence interval 0.39, 4.51) or no abnormalities (odds ratio 0.80; 95% Cl 0.27, 2.27). Fertility drug use at any time was not significantly more frequent for neural tube defects than for other abnormalities (odds ratio 1.37; 95% Cl 0.70, 2.74) or no abnormalities (odds ratio 1.05; 95% Cl 0.56, 1.98).

Economic Evaluation of Tandem Mass Spectrometry Screening in California

OBJECTIVE. On the basis of California’s experience implementing a pilot tandem mass spectrometry (MS/MS) screening program, an economic evaluation was conducted to determine the economic benefits and costs of a statewide MS/MS screening program. METHODS. Cost-effectiveness, benefit/cost, and cost-utility analyses were conducted with a base-case set of assumptions. The base-case assumptions were varied by using a set of more-favorable and less-favorable assumptions to test the robustness of the analysis findings. RESULTS. The total estimated, annualized, incremental costs of MS/MS screening of 540000 births in California were nearly

The California Maternal Serum α-Fetoprotein Screening Program: The role of ultrasonography in the detection of spina bifida

5.7 million; 83 affected newborns would be identified. Screening would reduce the expected lifetime costs of medical care for affected newborns by

Providers and Consumers of Prenatal Genetic Testing Services: What Do the National Data Tell Us?

7.2 million (