Maternal hereditary hemolytic anemia and birth defects in the National Birth Defects Prevention Study.

OBJECTIVES: Hereditary hemolytic anemia (HHA) results from genetic mutations that cause red blood cell abnormalities. Little research exists on the relationship between HHA and birth defects. Using data from the National Birth Defects Prevention Study (NBDPS), we described characteristics of HHA-exposed women and estimated associations between HHA during pregnancy and specific birth defects. METHODS: The NBDPS was a population-based, case-control study of major birth defects and included pregnancies with estimated delivery dates from October 1997 through December 2011. Participants were ascertained from hospital discharge lists or birth defect registries at 10 sites. Trained interviewers collected information about pregnancy exposures via telephone questionnaire. We described characteristics among HHA-exposed women and calculated crude odds ratios and exact 95% confidence intervals for defects with ≥3 exposed cases. RESULTS: Among 31 HHA-exposed women (28 cases/3 controls), 13 (42%) reported sickle cell anemia, 17 (55%) reported thalassemia, and one (3%) reported hereditary spherocytosis. The average age at delivery for HHA-exposed case women was 27.3 years (range: 17-38). The majority (82%) of HHA-exposed case women reported additional conditions during pregnancy, including hypertension, genitourinary infections, and respiratory illnesses. Additionally, 93% of case women reported using medication during pregnancy. Among the 28 cases, 18 (64%) had isolated birth defects. The defects with ≥3 exposed cases were anencephaly, atrial septal defect, gastroschisis, and cleft palate. Except for anencephaly, the 95% confidence intervals for all estimates were close to or included the null. CONCLUSION: This hypothesis-generating study adds to the sparse literature on the association between HHA and birth defects.

Prevalence of anencephaly in Africa: a systematic review and meta-analysis.

Anencephaly is a severe anomaly of the brain that results from the failure of the cephalic part of the neural tube to close during the fourth week. It occurs at least in one per thousand births and is the major cause of fetal loss and disabilities in newborns. The objective of this review is to determine the birth prevalence of anencephaly in Africa. We identified relevant studies via a search of databases like PubMed Central, PubMed/Medline, Science Direct, Joanna Briggs Institute, African Journals Online, Embase, Google Scholar, Web of Science, and Cochrane Library. After examining the heterogeneity of studies via the Cochran Q test and I2 test (and Forest plot for visual inspection), the prevalence of anencephaly was estimated using the random-effect meta-analysis model. Consequently, we carried out subgroup, sensitivity, meta-regression, trim and fill, time-trend, and meta-cumulative analyses. In this systematic review and meta-analysis, the twenty-four studies reported a total of 4,963,266 births. The pooled birth prevalence of anencephaly in Africa was 0.14% (95% CI: 0.12, 0.15%). Higher burden of anencephaly was detected in Ethiopia (0.37%, CI: 0.15, 0.58%), Algeria (0.24%, CI: 0.24, 0.25%), and Eritrea (0.19%, CI: 0.19, 0.19%). The higher pooled prevalence of anencephaly was observed in the studies that included both live births and stillbirths (0.16%) and in studies done after the year 2010 (0.25%) whereas, the lower burden was detected among countries that had a mandatory folic acid fortification (0.05%). High birth prevalence of anencephaly was detected in Africa. Strong prevention and control measures should be the priority because of an increment in the magnitude of anencephaly. Helping in prevention programs, which should be the ultimate contribution of this study to the field.

Prevalence of open neural tube defects and risk factors related to isolated anencephaly and spina bifida in live births from the "Dr. Juan I. Menchaca" Civil Hospital of Guadalajara (Jalisco, Mexico).

We determine the prevalence and trends of open neural tube defects (ONTDs) during 1991 to 2019 at the "Dr. Juan I. Menchaca" Civil Hospital of Guadalajara (Mexico). Also, details of potential risks were obtained in 662 newborns, including those 143 patients with anencephaly and open spina bifida (OSB) classified as isolated (cases) and 519 controls. Data were analyzed using multivariable logistic regression. Among 267 201 live births during the study period, 336 were born with ONTDs, yielding an overall prevalence of 12.6 per 10 000. After folic acid (FA)-related programs began in Mexico (2003-2019), only OSB showed a decline of 20.6%. For anencephaly, associated risks included relatives with neural tube defects (NTDs) (adjusted odds ratio [aOR]: 67.9, 95% confidence interval [95% CI]: 11.3-409.8), pre-pregnancy body mass index (BMI) ≥25 kg/m2 (aOR: 2.6, 95% CI: 1.1-6.0), insufficient gestational weight gain (aOR: 3.0, 95% CI: 1.3-7.1), parity ≥4 (aOR: 3.2, 95% CI: 1.3-7.7), and exposure to analgesic/antipyretic drugs (aOR: 9.0; 95% CI: 2.5-33.0). For OSB, associated risks included consanguinity (aOR: 14.0, 95% CI: 3.5-55.9), relatives with NTDs (aOR: 22.4, 95% CI: 4.5-112.9), BMI ≥25 kg/m2 (aOR: 2.5, 95% CI: 1.6-4.2), insufficient gestational weight gain (aOR: 1.9, 95% CI: 1.1-3.1), and exposures to hyperthermia (aOR: 2.3, 95% CI: 1.2-4.3), common cold (aOR: 6.8, 95% CI: 3.6-12.7), and analgesic/antipyretic drugs (aOR: 3.6, 95% CI: 1.3-10.0). Our high rate probably results from exposures to preventable risks, most related to FA, indicating a need for strengthening existing FA-related programs in Mexico.

Red Blood Cell Folate Likely Overestimated in Australian National Survey: Implications for Neural Tube Defect Risk.

In 2009, the Australian government mandated the addition of folic acid to bread flour to reduce the incidence of neural tube defects (NTD)-affected pregnancies. In 2011-2012, the Australian Health Measures Survey (AHMS) reported a mean red blood cell (RBC) folate in women of reproductive age (16-44 y) of 1647 nmol/L. Over 99% of women had an RBC folate ≥ 906 nmol/L, a concentration consistent with a very low risk of NTDs if a woman became pregnant. However, RBC folate was measured using an immunoassay, which is not a recommended method due to questionable accuracy. The microbiological assay is the preferred method for RBC folate measurement. To determine whether the immunoassay method may have led to spurious conclusions about the folate status of Australian women, we collected fasting blood samples from 74 healthy non-pregnant, non-lactating women (18-44 y) and measured RBC folate using both the immunoassay and microbiological methods. Mean RBC folate (95% confidence interval) concentration measured with the immunoassay method was 1735 (1666, 1804) nmol/L compared with 942 (887, 1012) nmol/L using the microbiological method. No woman had an RBC folate < 906 nmol/L using the immunoassay method, whereas 46% of women had an RBC folate < 906 nmol/L using the microbiological method. The NTD risk was estimated to be 0.06% using the immunoassay method and 0.14% using the microbiological method. RBC folate using AHMS survey may have underestimated NTD risk in Australian women.

Association between maternal periconceptional alcohol consumption and neural tube defects: Findings from the National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Neural tube defects (NTD)s are common birth defects with a multifactorial etiology. Findings from human studies examining environmental (non-inherited) exposures tend to be inconclusive. In particular, although animal studies of alcohol exposure and NTDs support its teratogenic potential, human studies are equivocal. Using data from the National Birth Defects Prevention Study (NBDPS), associations between maternal periconceptional (1 month before through 1 month after conception) alcohol consumption and NTDs in offspring were examined. METHODS: NTD cases and unaffected live born singleton controls with expected dates of delivery from October 1997-December 2011 were enrolled in the NBDPS. Interview reports of alcohol consumption (quantity, frequency, variability, type) from 1,922 case and 11,251 control mothers were analyzed. Crude and adjusted odds ratios (aOR)s and 95% confidence intervals (CI)s for alcohol consumption and all NTDs combined and selected subtypes (spina bifida, anencephaly, encephalocele) were estimated using unconditional logistic regression analysis. RESULTS: Among mothers in the NBDPS, 28% of NTD case and 35% of control mothers reported any periconceptional alcohol consumption. For each measure of alcohol consumption, inverse associations were observed for all NTDs combined (aORs = 0.6-1.0). Results for NTD subtypes tended to be similar, but CIs for spina bifida and encephalocele were more likely to include the null. CONCLUSIONS: These findings suggest a lack of positive associations between maternal periconceptional alcohol consumption and NTDs. Future studies should continue to evaluate the association between maternal alcohol consumption and NTDs in offspring accounting for methodological limitations such as potential misclassification from self-reported alcohol consumption.

The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature.

Anencephaly is a severe malformation of the central nervous system (CNS), being one of the most common types of neural tube defects. It is defined as total or partial absence of the calvarium, with absence of the brain. Anencephaly has an incidence of 1 to 5 in every 1000 births, and the mortality rate is 100% during intrauterine life or within hours or days after birth. The etiology of anencephaly remains unclear, but various maternal-related environmental and genetic risk factors have been reported, which include diabetes, obesity, exposure to different drugs or toxins, genetic polymorphisms and mutations, as well as positive family history for neural tube defects. One of the most important nutritional factors in the development of anencephaly is folate deficiency. Methylenetetrahydrofolate reductase (MTHFR) gene codes the enzyme involved in the intracellular metabolism of folic acid; the 677C-T polymorphism of this gene causes the thermolability of the enzyme and decreased enzymatic activity, which is also dependent of folate plasmatic level. Etiopathogenesis of anencephaly includes several mutations in various other genes, such as: platelet-derived growth factor receptor alpha (PDGFRA), cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1), Vang-like 1 (VANGL1) and Vang-like 2 (VANGL2), the last two being involved in the process of neurulation. Screening tests include maternal serum alpha-fetoprotein level and ultrasound (US) examination. During the first trimester US screening, anencephaly is now detected in all cases, but in order to decrease the complication rate of pregnancy termination, the diagnosis should be established as soon as possible, during the pregnancy confirmation US. We conclude that given that anencephaly is a severe malformation of the CNS, morphological characterization could improve the screening by US that is mandatory in the first trimester in order to plan the best, safe and early management.

Dynamic acetylation profile during mammalian neurulation.

BACKGROUND: Neural tube defects (NTDs) result from failure of neural tube closure during embryogenesis. These severe birth defects of the central nervous system include anencephaly and spina bifida, and affect 0.5-2 per 1,000 pregnancies worldwide in humans. It has been demonstrated that acetylation plays a pivotal role during neural tube closure, as animal models for defective histone acetyltransferase proteins display NTDs. Acetylation represents an important component of the complex network of posttranslational regulatory interactions, suggesting a possible fundamental role during primary neurulation events. This study aimed to assess protein acetylation contribution to early patterning of the central nervous system both in human and murine specimens. METHODS: We used both human and mouse (Cited2 -/- ) samples to analyze the dynamic acetylation of proteins during embryo development through immunohistochemistry, western blot analysis and quantitative polymerase chain reaction. RESULTS: We report the dynamic profile of histone and protein acetylation status during neural tube closure. We also report a rescue effect in an animal model by chemical p53 inhibition. CONCLUSIONS: Our data suggest that the p53-acetylation equilibrium may play a role in primary neurulation in mammals.

Maternal antihypertensive medication use and selected birth defects in the National Birth Defects Prevention Study.

BACKGROUND: There are limited data on the relationship between antihypertensive medication use in early pregnancy and risk of birth defects. METHODS: Using data from the National Birth Defects Prevention Study, we examined associations between specific antihypertensive medication classes and 28 noncardiac birth defects. We analyzed self-reported data on 17,038 case and 11,477 control pregnancies with estimated delivery dates during 1997-2011. We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals, adjusted for maternal age, race/ethnicity, body mass index, parity, pregestational diabetes, and study site, for associations between individual birth defects and antihypertensive medication use during the first trimester of pregnancy. We compared risk among women reporting early pregnancy antihypertensive medication use to normotensive women. RESULTS: Hypertensive women who reported early pregnancy antihypertensive medication use were more likely to be at least 35 years old, non-Hispanic Black, obese, multiparous, and to report pregestational diabetes than normotensive women. Compared to normotensive women, early pregnancy antihypertensive medication use was associated with increased risk of small intestinal atresia (adjusted OR 2.4, 95% CI 1.2-4.7) and anencephaly (adjusted OR 1.9, 95% CI 1.0-3.5). Risk of these defects was not specific to any particular medication class. CONCLUSIONS: Maternal antihypertensive medication use was not associated with the majority of birth defects we analyzed, but was associated with an increased risk for some birth defects. Because we cannot entirely rule out confounding by the underlying hypertension and most ORs were based on small numbers, the increased risks observed should be interpreted with caution.

Neuropathology of holoprosencephaly.

Holoprosencephaly (HPE) is a primary disorder of neural induction and patterning of the rostral neural tube resulting in noncleavage of the forebrain with failure to form two separate distinct hemispheres. The spectrum of HPE is very broad and encompasses various neuropathological phenotypes of different severity. The recent literature has demonstrated that the phenotypic variability of HPE ranges from aprosencephaly-atelencephaly, at the most severe end, to milder forms such as the "middle interhemispheric variant" of HPE at the less severe end of the spectrum. Between them, different intermediate forms demonstrate a continuum in a wide phenotypic spectrum rather than well-defined categories. Although the term "HPE" suggests a disorder affecting only the prosencephalon, other brain structures are involved, underlining the complexity of the malformation. Because of close spatiotemporal interactions and common signaling pathways contributing to the development of both brain and face, concomitant facial and ocular anomalies are associated with brain malformation. In this review, the characteristic neuropathological features of the various forms of HPE are described as well as their associated brain, face, and ocular malformations, to delineate the different phenotypes.

Neural tube closure and embryonic metabolism.

Neural tube closure (NTC) is an embryonic process during formation of the mammalian central nervous system. Disruption of the dynamic, sequential events of NTC can cause neural tube defects (NTD) leading to spina bifida and anencephaly in the newborn. NTC is affected by inherent factors such as genetic mutation or if the mother is exposed to certain environmental factors such as intake of harmful chemicals, maternal infection, irradiation, malnutrition, and inadequate or excessive intake of specific nutrients. Although effects of these stress factors on NTC have been intensively studied, the metabolic state of a normally developing embryo remains unclear. State-of-the art mass spectrometry techniques have enabled detailed study of embryonic metabolite profiles and their distribution within tissues. This approach has demonstrated that glucose metabolism is altered during NTC stages involving chorioallantoic branching. An understanding of embryonic metabolic rewiring would help reveal the etiology of NTD caused by environmental factors.

Maternal periconceptional occupational pesticide exposure and neural tube defects.

BACKGROUND: Adverse associations between maternal pesticide exposure and neural tube defects (NTDs) have been suggested but not consistently observed. This study used data from the multisite National Birth Defects Prevention Study to examine associations between maternal periconceptional (1 month preconception through 2 months postconception) occupational pesticide exposure and NTDs. METHODS: Mothers of 502 NTD cases and 2950 unaffected live-born control infants with estimated delivery dates from 1997 through 2002 were included. Duration, categorical intensity scores, and categorical frequency scores for pesticide classes (e.g., insecticides) were assigned using a modified, literature-based job-exposure matrix and maternal-reported occupational histories. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated based on fitted multivariable logistic regression models that described associations between maternal periconceptional occupational pesticide exposure and NTDs. The aORs were estimated for pesticide exposure (any [yes/no] and cumulative exposure [intensity × frequency × duration] to any pesticide class, each pesticide class, or combination of pesticide classes) and all NTD cases combined and NTD subtypes. RESULTS: Positive, but marginally significant or nonsignificant, aORs were observed for exposure to insecticides + herbicides for all NTD cases combined and for spina bifida alone. Similarly, positive aORs were observed for any exposure and cumulative exposure to insecticides + herbicides + fungicides and anencephaly alone and encephalocele alone. All other aORs were near unity. CONCLUSION: Pesticide exposure associations varied by NTD subtype and pesticide class. Several aORs were increased, but not significantly. Future work should continue to examine associations between pesticide classes and NTD subtypes using a detailed occupational pesticide exposure assessment and examine pesticide exposures outside the workplace.

Is folate involved in the pathogenesis of inflammatory bowel disease?

The inflammatory bowel diseases, Crohn's and ulcerative colitis, are common and a significant cause of morbidity. They were rare before the 1930's but the incidence has been increasing in both developed and developing countries. We have recently reported that the incidence in Nova Scotia, the area with one of the highest reported burden globally, is decreasing since 1997. We postulate that this decrease may be due to the addition of folate to cereals. This was mandated in 1998 but the process of fortification began in 1997. There is circumstantial evidence from epidemiology studies that a diet deficient in folate may have contributed to the global rise in these diseases. This hypothesis, if proven to be correct, has important implications for the prevention and treatment of these diseases.

Proportion of neural tube defects attributable to known risk factors.

BACKGROUND: Recognized risk factors for neural tube defects (NTDs) poorly predict population-level NTD risk. However, the proportion of NTDs that can be attributed to these risk factors is uncertain. METHODS: To determine the proportion of NTD cases that is attributable to known or suspected risk factors (i.e., female infant sex, family history of NTDs, and maternal Hispanic ethnicity, obesity, pregestational diabetes, gestational diabetes, low dietary folate intake, lack of folic acid supplementation, anticonvulsant use, and hot tub or sauna use), we estimated the adjusted population attributable fraction (aAF) for each factor, using the method of Eide and Geffler and data from the National Birth Defects Prevention Study. RESULTS: Our analyses of these data indicate that the proportion of cases of spina bifida and anencephaly that can be attributed to known risk factors is 28% and 44%, respectively. For spina bifida, the factor with the greatest attributable fraction was maternal obesity (aAF, 10%), whereas for anencephaly it was Hispanic ethnicity (aAF, 15%). CONCLUSION: Our analyses indicate that known risk factors account for <50% of NTD cases. Hence, the majority of NTD cases are attributable to, as yet, unidentified factors. These findings highlight the need for continued research to identify genetic and additional nongenetic risk factors for NTDs. Further, these findings suggest that strategies that aim to reduce the risk of NTDs associated with maternal Hispanic ethnicity and obesity may have the greatest impact on the population prevalence of these conditions.

Association between reported venlafaxine use in early pregnancy and birth defects, national birth defects prevention study, 1997-2007.

BACKGROUND: Few epidemiologic studies have investigated the use of venlafaxine (Effexor XR capsules, Product Monograph, Wyeth, Montreal, Canada), an antidepressant used to treat major depression and anxiety disorders in adults, during pregnancy. Our objective was to determine whether use of venlafaxine during pregnancy is associated with specific birth defects. METHODS: We used data from the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study in the United States. Our analysis included mothers with pregnancies affected by one of 30 selected birth defects (cases) and babies without birth defects (controls) with estimated dates of delivery between 1997 and 2007. Exposure was any reported use of venlafaxine from 1 month preconception through the third month of pregnancy. We calculated adjusted odds ratios (aORs) and 95% Fisher Exact confidence intervals (CIs) for 24 birth defect groups for which at least 400 case mothers were interviewed. Our adjusted analyses controlled for maternal age and race/ethnicity. RESULTS: Among the 27,045 NBDPS participants who met inclusion criteria, 0.17% (14/8002) of control mothers and 0.40% (77/19,043) of case mothers reported any use of venlafaxine from 1 month preconception through the third month of pregnancy. Statistically significant associations were found for anencephaly, atrial septal defect (ASD) secundum, or ASD not otherwise specified, coarctation of the aorta, cleft palate, and gastroschisis. CONCLUSIONS: Our data suggest associations between periconceptional use of venlafaxine and some birth defects. However, sample sizes were small, CIs were wide, and additional studies are needed to confirm these results.

Marijuana, Spice 'herbal high', and early neural development: implications for rescheduling and legalization.

Marijuana is the most widely used illicit drug by pregnant women in the world. In utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), a major psychoactive component of marijuana, is associated with an increased risk for anencephaly and neurobehavioural deficiencies in the offspring, including attention deficit hyperactivity disorder (ADHD), learning disabilities, and memory impairment. Recent studies demonstrate that the developing central nervous system (CNS) is susceptible to the effects of Δ9-THC and other cannabimimetics, including the psychoactive ingredients of the branded product 'Spice' branded products. These exocannabinoids interfere with the function of an endocannabinoid (eCB) system, present in the developing CNS from E12.5 (week 5 of gestation in humans), and required for proliferation, migration, and differentiation of neurons. Until recently, it was not known whether the eCB system is also present in the developing CNS during the initial stages of its ontogeny, i.e. from E7.0 onwards (week 2 of gestation in humans), and if so, whether this system is also susceptible to the action of exocannabinoids. Here, we review current data, in which the presence of an eCB system during the initial stage of development of the CNS is demonstrated. Furthermore, we focus on recent advances on the effect of canabimimetics on early gestation. The relevance of these findings and potential adverse developmental consequences of in utero exposure to 'high potency' marijuana, Spice branded products and/or cannabinoid research chemicals during this period is discussed. Finally, we address the implication of these findings in terms of the potential dangers of synthetic cannabinoid use during pregnancy, and the ongoing debate over legalization of marijuana.

Association between weight gain during pregnancy and neural tube defects and gastroschisis in offspring.

BACKGROUND: Limited information is available about the association of maternal weight gain during pregnancy and birth defects. The objective of this study was to investigate the association of maternal weight gain with neural tube defects (NTDs) and gastroschisis among offspring. METHODS: We used data from the National Birth Defects Prevention Study, an ongoing multicenter, population-based, case-control study. Mothers of cases and controls were interviewed by telephone. Analyses included 255 anencephaly, 577 spina bifida, 648 gastroschisis cases, and 5587 controls with deliveries from 1999 to 2005. After subtracting birth weight, the associations of total and average weekly weight gain (kg) with each phenotype were estimated, stratified by gestational age (<37 vs. ≥37 weeks) and adjusted for relevant covariates. RESULTS: Among deliveries <37 weeks gestation, mothers of infants with anencephaly and spina bifida had lower weight gains compared to control mothers; no association between weight gains and gastroschisis was observed. Among deliveries ≥37 weeks, mothers of infants with anencephaly had lower weight gains during pregnancy; a similar association was not observed for spina bifida; mothers of infants with gastroschisis were twice as likely to have weight gains in the highest quartile. Stratification by maternal age (gastroschisis) or body mass index (BMI) or race/ethnicity (all phenotypes) did not alter odds ratio estimates. CONCLUSION: Altered weight gain during pregnancy may be a consequence of carrying an NTD/gastroschisis affected fetus or a marker for underlying factors common to the etiology of these birth defects. It is possible that whatever mechanisms influence weight gain may also influence the development of NTDs and gastroschisis, but in opposite directions.

Mouse as a model for multifactorial inheritance of neural tube defects.

Neural tube defects (NTDs) such as spina bifida and anencephaly are some of the most common structural birth defects found in humans. These defects occur due to failures of neurulation, a process where the flat neural plate rolls into a tube. In spite of their prevalence, the causes of NTDs are poorly understood. The multifactorial threshold model best describes the pattern of inheritance of NTDs where multiple undefined gene variants interact with environmental factors to cause an NTD. To date, mouse models have implicated a multitude of genes as required for neurulation, providing a mechanistic understanding of the cellular and molecular pathways that control neurulation. However, the majority of these mouse models exhibit NTDs with a Mendelian pattern of inheritance. Still, many examples of multifactorial inheritance have been demonstrated in mouse models of NTDs. These include null and hypomorphic alleles of neurulation genes that interact in a complex fashion with other genetic mutations or environmental factors to cause NTDs. These models have implicated several genes and pathways for testing as candidates for the genetic basis of NTDs in humans, resulting in identification of putative pathogenic mutations in some patients. Mouse models also provide an experimental paradigm to gain a mechanistic understanding of the environmental factors that influence NTD occurrence, such as folic acid and maternal diabetes, and have led to the discovery of additional preventative nutritional supplements such as inositol. This review provides examples of how multifactorial inheritance of NTDs can be modeled in the mouse.

Acephaly: further evidence for disruption but not for amniotic bands.

Complete absence of the fetal head in singleton pregnancies is a very rare defect; to our knowledge there are only 7 reported cases. Decapitation by amniotic bands has been considered as the most probable cause. However, in none of the described cases except one were amniotic bands, constriction rings, or other related findings observed, raising the possibility that mechanisms other than amputation by amniotic bands are involved. We present a further case of acephaly and discuss the role of amniotic bands and alternative mechanisms of decapitation and a possible sequence of events leading to acephaly.

Working towards a risk prediction model for neural tube defects.

BACKGROUND: Several risk factors have been consistently associated with neural tube defects (NTDs). However, the predictive ability of these risk factors in combination has not been evaluated. METHODS: To assess the predictive ability of established risk factors for NTDs, we built predictive models using data from the National Birth Defects Prevention Study, which is a large, population-based study of nonsyndromic birth defects. Cases with spina bifida or anencephaly, or both (n = 1239), and controls (n = 8494) were randomly divided into separate training (75% of cases and controls) and validation (remaining 25%) samples. Multivariable logistic regression models were constructed with the training samples. The predictive ability of these models was evaluated in the validation samples by assessing the area under the receiver operator characteristic curves. An ordinal predictive risk index was also constructed and evaluated. In addition, the ability of classification and regression tree (CART) analysis to identify subgroups of women at increased risk for NTDs in offspring was evaluated. RESULTS: The predictive ability of the multivariable models was poor (area under the receiver operating curve: 0.55 for spina bifida only, 0.59 for anencephaly only, and 0.56 for anencephaly and spina bifida combined). The predictive abilities of the ordinal risk indexes and CART models were also low. CONCLUSION: Current established risk factors for NTDs are insufficient for population-level prediction of a women's risk for having affected offspring. Identification of genetic risk factors and novel nongenetic risk factors will be critical to establishing models, with good predictive ability, for NTDs.