Clinical and molecular heterogeneity of syndromic hypothalamic hamartoma.

Two children are presented who have a distinct syndrome of multiple buccolingual frenula, a stiff and short fifth finger with small nails, a hypothalamic hamartoma, mild to moderate neurological impairment, and mild endocrinological symptoms. No variant assessed to be pathogenic or likely pathogenic was detected in the GLI3 gene in either child. This syndrome appears to be distinct from the inherited Pallister-Hall syndrome associated with GLI3 variants, which is characterized by hypothalamic hamartoma, mesoaxial polydactyly, and other anomalies. In the individuals described here, manifestations outside of the central nervous system were milder and the mesoaxial polydactyly, which is common in individuals with Pallister-Hall syndrome, was absent. Instead, these children had multiple buccolingual frenula together with the unusual appearance of the fifth digit. It remains unclear whether these two individuals represent a separate nosologic entity or if they represent a milder manifestation of one of the more severe syndromes associated with a hypothalamic hamartoma.

Limited surface examination to evaluate potential teratogens in a resource-limited setting.

BACKGROUND: To determine the frequency of malformations that would be identified in the limited surface examination of a newborn by the delivering nurse midwife in a resource-limited setting. METHODS: The limited surface examination will identify visible external anomalies, but not abnormalities inside the mouth, most heart defects, undescended testes, inguinal hernias, hip dysplasia, peripheral vascular anomalies, and some internal anomalies. The findings in a malformations surveillance program, involving 289,365 births in Boston, have been used to establish the prevalence rate of malformations that would be identified and not identified. In African countries, the number of anomalies to be identified should also be reduced by excluding polydactyly, postaxial, type B, a common minor finding, from the list of potential malformations. RESULTS: Of note, 2.05% (n = 5,941) of the 289,365 births surveyed had one or more malformations. The abnormalities that would have been missed, using surface exam alone, accounted for 0.5% of all of malformations identified and reduced the overall prevalence rate of malformations to 1.5%. In addition, excluding all infants with isolated postaxial polydactyly, type B reduced the expected prevalence rate of malformations to 1.3% in unexposed newborn infants. CONCLUSION: A limited surface examination can detect the majority of malformations among newborn infants.

Iniencephaly.

BACKGROUND: Iniencephaly is a severe developmental abnormality of the craniovertebral junction in which the head is retroflexed dramatically. Anatomic studies have identified striking changes in the vertebrae and skull: marked lordosis of the cervical vertebrae, duplicated cervical vertebrae, irregularly fused cervical vertebrae, a widened foramen magnum and a small posterior fossa. The affected infant appears to have no neck, as the skin of the face is continuous with the chest and the skin of the posterior scalp is continuous with the skin of the back. Iniencephaly is considered a rare neural tube defect. The frequency has been higher in geographic areas in which the rates of occurrence of anencephaly and myelomeningocele were high. Most affected fetuses are either stillborn or die soon after birth. However, one affected individual is an adult with normal intelligence. METHODS: A malformations surveillance program can identify an unselected group of infants with iniencephaly. This approach can determine the prevalence rate, the frequency of associated malformations, and the occurrence of close relatives with other neural tube defects. RESULTS: Over 41 years, the surveillance of 289,365 births identified eight fetuses and newborn infants with iniencephaly. Five of the eight had either an additional encephalocele or a thoracic myelomeningocele. Two of the eight affected infants had a sibling or a cousin with anencephaly. CONCLUSION: These findings suggest a relationship between the occurrence of iniencephaly and the most common neural tube defects, anencephaly and myelomeningocele. Recent experience confirms that this complex neural tube defect is not always lethal. Birth Defects Research 110:128-133, 2018. © 2018 Wiley Periodicals, Inc.

Stillborn Infants: Associated Malformations.

BACKGROUND: Stillbirth, defined as death of a fetus in utero after 20 weeks of gestation, occurs in 1 to 2% of pregnancies in the United States. Many of these stillborn infants have associated malformations, including chromosome abnormalities, neural tube defects, and malformation syndromes. Other causes are abnormalities of the placenta and maternal conditions, such as pre-eclampsia and obesity. A consecutive sample of malformed stillborn infants can establish the relative frequency and severity of the associated malformations. METHODS: Stillbirths were identified in the Active Malformations Surveillance Program at Brigham and Women's Hospital (1972-2012). The findings at autopsy, including the findings in the placenta and the results of diagnostic studies, were compiled. RESULTS: One hundred twenty-seven stillborn infants with malformations were identified at autopsy among 289,365 pregnancies, including trisomies 21, 18, and 13; 45,X; triploidy; anencephaly; lower urinary tract obstruction; holoprosencephaly and severe heart defects, such as hypoplastic left heart syndrome and tetralogy of Fallot with pulmonary atresia. The severity of the abnormalities in stillborn infants was more severe than the spectrum of abnormalities identified in live-born infants. CONCLUSION: An autopsy of the stillborn fetus, including chromosome microarray and an examination of the placenta, can identify the underlying causes of the stillbirth. This review of stillborn fetuses with malformations showed that several different lethal malformations and heart defects are more common than among live-born infants. These postmortem examinations can improve the counseling of the parents about risks in future pregnancies. Birth Defects Research 110:114-121, 2018.© 2018 Wiley Periodicals, Inc.

Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine.

OBJECTIVES: To evaluate adaptive behavior outcomes of children prenatally exposed to lamotrigine, valproate, or carbamazepine, and to determine if these outcomes were dose-dependent. METHODS: Data were collected from women enrolled in the North American Anti epileptic Drug (AED) Pregnancy Registry who had taken lamotrigine, valproate, or carbamazepine monotherapies throughout pregnancy to suppress seizures. The adaptive behavior of 252 exposed children (including 104 lamotrigine-exposed, 97 carbamazepine-exposed, and 51 valproate-exposed), ages 3- to 6-years-old, was measured using the Vineland-II Adaptive Behavior Scales, administered to each mother by telephone. Mean Adaptive Behavior Composite (ABC), domain standard scores for communication, daily living, socialization and motor skills, and adaptive levels were analyzed and correlated with first trimester drug dose. RESULTS: After adjusting for maternal age, education, folate use, cigarette and alcohol exposure, gestational age, and birth weight by propensity score analysis, the mean ABC score for valproate-exposed children was 95.6 (95% CI [91, 101]), versus 100.8 (95% CI [98, 103]) and 103.5 (95% CI [101, 106]) for carbamazepine- and lamotrigine-exposed children, respectively (ANOVA; p=0.017). Significant differences were observed among the three drug groups in the ABC (p=0.017), socialization (p=0.026), and motor (p=0.018) domains, with a trend toward significance in the communication domain (p=0.053). Valproate-exposed children scored lowest and lamotrigine-exposed children scored highest in every category. Valproate-exposed children were most likely to perform at a low or moderately low adaptive level in each category. Higher valproate dose was associated with significantly lower ABC (p=0.020), socialization (p=0.009), and motor (p=0.041) scores before adjusting for confounders. After adjusting for the above variables, increasing VPA dose was associated with decreasing Vineland scores in all domains, but the relationships were not statistically significant. No dose effect was observed for carbamazepine or lamotrigine. CONCLUSIONS: Unlike carbamazepine and lamotrigine, prenatal valproate exposure was associated with adaptive behavior impairments with specific deficits in socialization and motor function, along with a relative weakness in communication. Increasing valproate dose was associated with a decline in adaptive functioning. This finding of a linear dose-dependent teratogenic effect suggests that valproate should be avoided at any dose during pregnancy. However, some women with epilepsy controlled only by valproate will decide, in consultation with their provider, that the benefits of continuing valproate during pregnancy outweigh the fetal risks. Faced with difficult choices, clinicians should be supportive as these patients consider their options.

Triploidy: Variation of Phenotype.

OBJECTIVES: Triploidy (69, XXX; 69, XXY; 69, XYY) accounts for 1% of conceptions, but the affected fetus often does not survive past the first trimester. Fetal development in triploidy is rare. A consecutive series was used to describe the fetal and placental phenotypes and compare them with previous publications. METHODS: Fifty-four triploid fetuses were identified in the Active Malformations Surveillance Program between 1972 and 2012 at Brigham and Women's Hospital in Boston. The phenotype was described from prenatal imaging and autopsy findings. RESULTS: The diagnosis was confirmed by chromosome analysis in 53 of the 54 fetuses. Twenty-seven (50%) of the affected fetuses were identified during pregnancy. The abnormalities identified by prenatal ultrasound included renal malformations, heart defects, hydrocephalus, holoprosencephaly, and myelomeningocele. At autopsy, syndactyly, usually between fingers 3 and 4, was identified in 37 (69%) of the fetuses. Thirteen (24%) of the infants had the histologic features of a partial hydatidiform mole in the placenta. CONCLUSIONS: The presence of major malformations and growth restriction during pregnancy makes triploidy a potential diagnosis. There are no obligate clinical features in triploidy. Syndactyly, especially 3-4 syndactyly of the hands, is a distinctive feature. Cystic changes in the placenta can be seen by ultrasound during pregnancy. There was no difference in the phenotype between triploid infants associated with partial moles and those with nonmolar placentas.

Congenital talipes equinovarus: frequency of associated malformations not identified by prenatal ultrasound.

OBJECTIVES: To establish the frequency of prenatally undetected associated malformations (identified at birth) in infants with apparent "isolated" club foot deformity. METHODS: A cohort study of all infants with unilateral or bilateral club foot deformity identified at birth among 311 480 infants surveyed between 1972 and 2012 at Brigham and Women's Hospital in Boston. Those with talipes equinovarus were divided into "isolated" and "complex", based on the findings in examination and by chromosome analysis. RESULTS: One hundred and forty-two infants had "isolated" talipes equinovarus (TEV), and 66 had the "complex" type. Six (4.2%) of the 142 infants with "isolated" TEV were found at birth to have associated malformations that had not been identified by imaging during pregnancy. These abnormalities included hip dislocation (n = 2), bilateral post-axial polydactyly of the feet (n = 1), penile chordee (n = 1), and hypospadias (n = 2). CONCLUSION: In this consecutive series of infants with isolated talipes equinovarus, 95.8% had no additional malformations identified by examination at birth. None of the additional findings were severe enough to affect the medical prognosis of the affected infant. © 2014 John Wiley & Sons, Ltd.

Vascular limb defects and maternal age.

BACKGROUND: The prenatal diagnosis procedure chorionic villus sampling is associated with increased risk of vascular disruption limb defects. Some studies have suggested that these defects are more common among infants born to women 35 years and older while other studies have shown a correlation with younger mothers. METHODS: All infants with vascular disruption defects were identified in the Active Malformations Surveillance Program at Brigham and Women's Hospital in the years 1972-1974, 1979-2011. We compared the rate of occurrence of infants with vascular limb defects among women in theses age groups: ≤19, 20 to 34, and ≥35 years to the rate of occurrence of infants with preaxial polydactyly, adjusting for race. Infants with an identifiable cause of their defects were excluded. RESULTS: 106 infants with vascular disruption defects and 67 with preaxial polydactyly were identified. Seventeen percent of the infants with vascular disruption defects and 25% of the infants with preaxial polydactyly were born to women 35 and older (p = 0.23). In contrast, 16% of the infants with vascular disruption defects were born to young mothers (≤19 years) compared with 6.0% of the mothers of infants with preaxial polydactyly (adjusted odds ratio vs. 35+ years = 5.3, 95% confidence interval 1.4-21, p = 0.017). CONCLUSION: Women 35 years old or older did not have increased risk for having a child with vascular disruption defects, but these defects were more common among infants of young (≤19) mothers, compared with the preaxial polydactyly group.

Maternal periconceptional exposure to cigarette smoking and congenital limb deficiencies.

BACKGROUND: Congenital limb deficiencies (LD)s are characterised by the failure or disruption in formation of limbs or digits. Epidemiological research on maternal exposure to cigarette smoke and LDs is inconclusive. METHODS: Data from the National Birth Defects Prevention Study were used to examine LDs and maternal exposure to active or passive cigarette smoke. Mothers of LD case (n = 906) and unaffected control (n = 8352) pregnancies from October 1997 through December 2007 reported on exposure type and quantity. Logistic regression was used to estimate adjusted odds ratio (OR) and 95% confidence interval [95% CI]; interactions with folic acid (FA) intake were tested. RESULTS: For any LD, ORs were elevated for active (1.24 [95% CI 1.01, 1.53]), passive (home) (1.28 [95% CI 1.03, 1.59]), and 'active and passive' (1.34 [95% CI 1.05, 1.70]) exposures. The ORs for longitudinal LDs were elevated for passive (home) (1.62 [95% CI 1.14, 2.31]) and 'active and passive' (1.62 [95% CI 1.09, 2.41]) exposures. The OR for pre-axial LDs were elevated for any (1.39 [95% CI 1.01, 1.90]), active (1.53 [95% CI 1.03, 2.29]), passive (home) (1.82 [95% CI 1.23, 2.69]), and 'active and passive' (1.87 [95% CI 1.20, 2.92]) exposures. For lower limbs, ORs were elevated for passive (home) (1.44 [95% CI 1.01, 2.04]) and smoking 15 or more cigarettes/day (2.25 [95% CI 1.27, 3.97]). Interactions showed that ORs for any passive smoke exposure were 0.43 and 0.59 higher in the absence of FA intake for any and terminal transverse LDs. CONCLUSIONS: Maternal active smoking and exposure to passive cigarette smoke emerged as a potential teratogen that affects limb and digit formation. FA was not found to mitigate the impact.

Quantitative assessment of craniofacial morphology in Johanson-Blizzard syndrome.

BACKGROUND: Here we apply objective, reliable methods of dysmorphology diagnosis to a patient with Johanson-Blizzard syndrome (MIM #243800). Using an extensive normative database, we computed standardized scores on a graded continuum for operational definitions of nasal alar hypoplasia, a commonly observed feature of this condition. CASE: Most of these measurements in this case were greater than 2 standard deviations below the mean, adjusted for age, gender, and ethnicity. CONCLUSION: This report provides a worked example of quantitative anthropometric assessment in the context of a case report, using tools that may find general application in clinical genetics.

The association of a dysmorphic pelvis, absence of pubic rami, hip dysplasia, and genitourinary anomalies.

BACKGROUND: There have been reports of children who had absence of the pubic rami, hip dysplasia, and genitourinary anomalies. CASE REPORT: We describe a 44-year-old woman with severe hip dysplasia, bilateral chronic congenital hip dislocations, abnormal development of the entire pelvis, and absence of the pubic rami in association with absence of the uterus. CONCLUSION: We present an individual who has abnormal development of the entire pelvis, including absence of the pubic rami, and genitourinary anomalies. We suggest that this is a rare pattern of associated anomalies confined to a localized region of the body. Potential underlying developmental abnormalities include somatic mutations which affected the mesodermal cells from which the pelvis and mullerian structures develop.

Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations.

OBJECTIVE: To determine the frequency of malformations among infants born to women who had taken lamotrigine or carbamazepine as part of polytherapy during the first trimester of pregnancy. DESIGN: A cohort of women enrolled during pregnancy in the North American AED (Antiepileptic Drug) Pregnancy Registry between February 1, 1997, and June 1, 2010. Information on AED use and demographic characteristics was collected in 3 telephone interviews. SETTING: United States and Canada. PATIENTS: A total of 6857 pregnant women taking an AED for any reason. MAIN OUTCOME MEASURES: Major congenital malformations were identified at birth and through the first 12 weeks after delivery. Diagnoses were based on the mother's report and confirmed by medical records. The risks of malformations were compared between polytherapy and monotherapy groups, using exact odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The risk of malformations was 1.9% among infants exposed to lamotrigine as monotherapy (n = 1441). Among the infants exposed to lamotrigine as polytherapy (n = 505), the risks were 9.1% for lamotrigine plus valproate sodium (OR, 5.0; 95% CI, 1.5-14.0) and 2.9% for lamotrigine plus any other AEDs (1.5; 0.7-3.0). The risk of malformations was 2.9% for the infants exposed to carbamazepine monotherapy (n = 1012). For the infants exposed to carbamazepine as polytherapy (n = 365), the risks were 15.4% for carbamazepine plus valproate (OR, 6.2; 95% CI, 2.0-16.5) and 2.5% for carbamazepine plus any other AEDs (0.8; 0.3-1.9). Confounding by factors such as periconceptional vitamin use, cigarette smoking, alcohol use, and chronic maternal diseases did not explain the results. CONCLUSIONS: The risk of malformations among infants exposed to lamotrigine and carbamazepine as polytherapy was higher than the corresponding monotherapies only when the polytherapy includes valproate. These findings suggest that counseling for fetal risks from AED polytherapy should be based on the specific drugs included.

Human teratogens: update 2010.

A wide variety of human teratogens have been identified. The characteristics of human teratogens can be used in the assessment of apparent "new" teratogens, when postulated. Information is available through online databases, such as TERIS and Reprotox, telephone-based counseling resources (e.g., Organization of Teratogen Information Systems [OTIS] and European Network Teratology Information Services [ENTIS]), reference books, annual meetings of the Teratology Society, and published articles. There are significant deficiencies in the information available: (1) lack of knowledge about the molecular and cellular basis for most teratogenic effects; (2) the inability to genetically identify more susceptible women before pregnancy; (3) little information is available on dermal and airborne exposures during pregnancy; and (4) most clinicians receive little, if any, training in the identification of or counseling for exposure to potential teratogens. There are many current dilemmas in counseling about exposures in pregnancy, including: (1) Is exposure to specific drugs, such as selected serotonin re-uptake inhibitors (SSRIs) and the inhibitors of tumor necrosis factor-alpha, teratogenic in the first trimester of pregnancy? (2) Are the increased risks of birth defects associated with assisted reproductive technology due, in part, to epigenetic effects? (3) What are the "safe" levels of exposure to the plasticizers phthalates during pregnancy? (4) How do we convince busy physicians, nurses, and pharmacists not to use the drug categories A, B, C, D, and X in counseling and to use more accurate sources? There is a need for a national advisory center for pregnancy registries to provide guidance when new registries are being developed.

Chorionic villus sampling and hemangiomas.

Chorionic villus sampling (CVS) is a widely used and safe method of prenatal diagnosis. In the 1990s, concerns were raised at several medical centers that there was an increased risk to the exposed fetus for the occurrence of limb deficiencies, hemangiomas, and other vascular disruption defects. The risk was greater when the procedure was performed earlier in pregnancy, such as 8 or 9 weeks of gestation. The postulated mechanisms for the fetal injury included blood loss, hypoperfusion, hypoxia, endothelial cell damage, hemorrhage, and tissue loss. The effect was most common in tissues with end arteries, such as digits, tongue, brain stem, and intestine. The associated hemangiomas were infantile hemangiomas. They were more common on the head, neck, and thorax and more often multiple in infants exposed to CVS. One postulated mechanism for the occurrence of these hemangiomas is embolization of angioblasts or endothelial cells from the placenta to the fetal skin. A question to be answered is whether the infantile hemangiomas in children exposed to CVS differ in immunohistologic characteristics from similar hemangiomas in children not exposed to CVS during pregnancy.

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Evaluating the accuracy of Malformations Surveillance Program in detecting virilization due to congenital adrenal hyperplasia.

Malformations surveillance programs of newborn infants have been developed as a method for identifying serious and relatively common birth defects. The virilization of newborn infants with the classic 21-hydroxylase form of congenital adrenal hyperplasia must be identified early if the associated metabolic crisis in the perinatal period is to be prevented. We compared the detection of virilization associated with 21-hydroxylase congenital adrenal hyperplasia in infants by three methods: an 'active' malformations surveillance of medical records at a large urban hospital; routine medical care by examining physicians; and newborn biochemical screening of blood samples. The experience at a large maternity center in Boston, since 1972, showed that pediatricians often recognized affected females (6/6), but not males (0/2); the state newborn screening program, begun in 1990, identified correctly all affected males and females. The Active Malformations Surveillance Program was the least effective screening method, identifying four of six affected females and neither of the affected males. The low rate of detecting affected females by the Surveillance Program was attributed to a failure to sensitize the research assistants to the importance of physicians' notations regarding the signs and symptoms of virilization. The failure of examining physicians, and thereby, the malformations surveillance program, to detect virilized newborn males was due to the lack of consistent associated physical features. These comparisons between these three methods of detection can be used to design and improve malformations surveillance programs.

Axial mesodermal dysplasia sequence: autopsy findings.

We describe an infant with the phenotype of the "axial mesodermal dysplasia spectrum" who had the oculo-auriculo-vertebral sequence and caudal dysgenesis. Postmortem studies identified anomalies of the middle ear ossicles, and muscles, in association with microtia and atresia of the external auditory canals, but no cerebral abnormalities.

Chorionic villus sampling: a distinctive teratogenic effect on fingers?

BACKGROUND: An increased frequency of major limb malformations, especially terminal transverse limb defects, have been described in several studies of birth defects in children who had been exposed to the prenatal diagnosis procedure known as chorionic villus sampling (CVS). Vascular disruption has been proposed as the mechanism behind the fetal effect. We postulate that this mechanism is more likely to affect one or two middle fingers, rather than all five fingers. A recent report of the frequency of defects in any or all fingers in an unexposed control population enabled us to assess whether CVS is associated with an increased frequency of defects involving one or two fingers, as well as terminal transverse limb defects. METHODS: The frequency of limb-reduction defects affecting one or more fingers or toes, including those with constriction rings and tissue loss, in published studies of 20,236 children who had been exposed to CVS was compared with the frequency in 161,252 newborn infants who had not been exposed to CVS. Children with recognized genetic disorders were excluded. RESULTS: Several aspects of the limb deficiencies were more common in the CVS-exposed infants than in unexposed controls. The former were more likely to have: 1) any type of limb deficiency involving one or more fingers (p < .001); 2) absence/ hypoplasia of two fingers (p < .001); and 3) absence/hypoplasia of all five fingers (p = .015). The absence of the distal portion of the third finger was a distinctive type of limb-reduction defect in CVS-exposed infants. CONCLUSIONS: The occurrence of deficiencies in one or two fingers, including those designated as "amniotic band deformities," are as common as terminal transverse limb defects in CVS-exposed infants, and both are much more common than in unexposed infants. The absence of the distal portion of the third finger, with tapering and stiff joints, appears to be a distinctive effect of exposure to CVS.

Multiple congenital anomalies associated with in utero exposure of phenytoin: possible hypoxic ischemic mechanism?

BACKGROUND: The characteristics of the phenotype of the malformed phenytoin-exposed infant can help to clarify the mechanism of the drug's teratogenesis. One postulated mechanism is vascular disruption. CASE: An infant who was exposed to phenytoin as monotherapy throughout pregnancy was born with the following abnormalities: midface hypoplasia, digit hypoplasia with syndactyly in the hands and feet, meningomyelocele, talipes equinovarus, and a long skin pedicle on the back. The mother was also exposed to cigarette smoking and alcohol during the pregnancy. CONCLUSIONS: The malformations of the hands and feet, and the talipes deformity are potential effects of vascular disruption, a postulated fetal effect of both phenytoin and cigarette smoking. The mechanism of the teratogenicity of phenytoin may have included episodes of bradyarrhythmia in the fetus; however, no such episodes were documented.

Alcohol dehydrogenase 2 genotypes, maternal alcohol use, and infant outcome.

OBJECTIVE: To determine whether different alleles of the ADH2 gene (ADH2-1, ADH2-2 and ADH2-3) with differing levels of enzymatic activity can alter the risk of fetal alcohol effects. STUDY DESIGN: ADH2 genotypes were performed on 404 pregnant high-risk women and 139 infants as part of a larger study of alcohol use in pregnancy. Mothers were interviewed about alcohol use during pregnancy, and their infants were examined for alcohol-related features without knowledge of the exposure status. RESULTS: The ADH2-1/3 genotype was more prevalent among black women (46%) than expected (33%); the rate among white women was low as expected (2%). More black women who reported high alcohol use during the pregnancy had the ADH2-1/3 genotype compared with those who reported no alcohol use (70% vs 44%). Sixty percent of the affected black infants had the ADH2-1/3 genotype compared with 29% of the unaffected infants (P <.045). The maternal genotype correlated with her chance of having an infant with alcohol-related physical features (odds ratio = 2.49). This association remained significant after accounting for confounders, such as smoking and maternal weight gain. Alcohol exposure was not significantly associated with infant outcome in black infants after accounting for genotype, smoking, and maternal weight gain, but this association could only be tested in 10 infants of mothers with high exposure. CONCLUSION: Women with the ADH2-1/3 genotype may be at greater risk for having an affected infant, which may be the result of greater ingestion of alcohol.