Different fetal effects on fingers from exposure to phenytoin, phenobarbital, and carbamazepine.

Exposure at conception to phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) has been associated with several different effects on the fetus, including hypoplasia of the distal phalanges, dysmorphic facial features, and structural abnormalities such as oral clefts and neural tube defects. One question is whether each of these antiepileptic drugs (AEDs) has the same effects or just similar effects. A systematic examination of the fingers of children exposed at conception to PHT, PB, or CBZ, as monotherapy, has been used to address this question. The findings in the examinations of the fingers of 115 AED-exposed children (40, PHT; 34, PB; 41, CBZ) and their parents were compared to the findings in 111 age- and sex-matched children and their parents. The evaluations used were both subjective assessments and objective measurements. Shortening and narrowing of the fifth fingernail and an increased frequency of arch patterns in the dermal ridges were more common in PHT-exposed children. A significant decrease in the length of the nail, but not width, occurred in the PB-exposed children. Stiffness of the interphalangeal joints was more common in the CBZ-exposed children. The findings in children exposed to PHT, PB, or CBZ, as monotherapy, showed that all three exposures in early pregnancy affected the fingers, but the effects were not the same. The most striking effects were present in PHT-exposed children.

Facial dysmorphology in children exposed in pregnancy to anticonvulsant medications correlates with deficits in IQ.

Some children exposed at conception to the antiepileptic drugs (AEDs) phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) have changes in their midface and fingers. It has been suggested that the anticonvulsant-exposed child with these subtle changes in facial features (the "anticonvulsant face") has a greater likelihood of having deficits in IQ in comparison with children exposed to the same anticonvulsants who do not have these features. 115 AED-exposed children (40, PHT; 34, PB; and 41, CBZ) between 6.5 and 16 years of age and 111 unexposed children matched by sex, race, and year in school were evaluated. The evaluations were (WISC-III), physical examination with measurements of facial features and digits and photographs. The AED-exposed children had cephalometric radiographs, but not the unexposed. Each parent had a similar examination of face and hands plus tests of intelligence. These AED-exposed children showed an increased frequency of a short nose and anteverted nares, features of the "anticonvulsant face." Lateral skull radiographs showed a decrease in the angle between the anterior cranial base and nasal bone, which produces anteverted nares. Mean IQs were significantly lower on one or more IQ measures for the children with these facial features. Shortening of the distal phalanges and small fingernails correlated with the presence of a short nose in that child. The findings in 115 children exposed at conception to either phenytoin, phenobarbital, or carbamazepine, as monotherapy, confirmed the hypothesis that those with a short nose and anteverted nares had a lower IQ than exposed children without those features.

Personal journeys to and in human genetics and dysmorphology.

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.

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.

The North American Antiepileptic Drug Pregnancy Registry: A Canadian Subgroup Analysis.

BACKGROUND: The North American AED Pregnancy Registry (NAAPR) provides crucial data for understanding the risks of antiepileptic drug (AED) exposure in pregnancy. This study aims to quantify the Canadian contribution to NAAPR and compare AED usage in pregnancy in Canada and the USA. METHODS: Enrollment rate ratios (ERR) to NAAPR, adjusted for the populations of women of childbearing age, were calculated for the USA, Canada, and for the different Canadian provinces. Methods of enrollment to NAAPR and AED usage were compared between the two countries using chi-squared tests. RESULTS: Between 1997 and 2019, 10,215 pregnant women enrolled into NAAPR: 4.1% were Canadian (n = 432, ERR = 0.39, CI95% = 0.35-0.43). Within Canada, no patients were enrolled from the three northern territories or from Prince Edward Island. While fewer patients than expected enrolled from Quebec (ERR = 0.35, CI95% = 0.19-0.58), Nova Scotia had the highest enrollment rate (ERR = 1.55; CI95% = 0.66-3.11). Compared with their American peers, Canadians were less likely to have been enrolled by their healthcare provider and more likely to have been enrolled via social media (p < 0.01). Canadian women were more likely to be taking carbamazepine (24% vs. 15%; p < 0.01) or valproic acid (8% vs. 4%; p < 0.01). CONCLUSION: The proportion of Canadian enrollees into NAAPR was less than expected based on the relative population size of Canadian women of reproductive age. Greater Canadian enrollment to NAAPR would contribute to ongoing worldwide efforts in assessing the risks of AEDs use in pregnant women and help quantify rates of AED usage, major congenital malformations, and access to subspecialized epilepsy care within Canada.

Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Antiretroviral therapy (ART) during pregnancy is important for both maternal health and prevention of perinatal HIV-1 transmission; however adequate data on the safety and efficacy of different ART regimens that are likely to be used by pregnant women are scarce. In this trial we compared the safety and efficacy of three antiretroviral regimens started in pregnancy: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; and efavirenz, emtricitabine, and tenofovir disoproxil fumarate. METHODS: This multicentre, open-label, randomised controlled, phase 3 trial was done at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Pregnant women (aged ≥18 years) with confirmed HIV-1 infection and at 14-28 weeks' gestation were eligible. Women who had previously taken antiretrovirals in the past were excluded (up to 14 days of ART during the current pregnancy was permitted), as were women known to be pregnant with multiple fetuses, or those with known fetal anomaly or a history of psychiatric illness. Participants were randomly assigned (1:1:1) using a central computerised randomisation system. Randomisation was done using permuted blocks (size six) stratified by gestational age (14-18, 19-23, and 24-28 weeks' gestation) and country. Participants were randomly assigned to receive either once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg; once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; or once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg. The primary efficacy outcome was the proportion of participants with viral suppression, defined as an HIV-1 RNA concentration of less than 200 copies per mL, at or within 14 days of delivery, assessed in all participants with an HIV-1 RNA result available from the delivery visit, with a prespecified non-inferiority margin of -10% in the combined dolutegravir-containing groups versus the efavirenz-containing group (superiority was tested in a pre-planned secondary analysis). Primary safety outcomes, compared pairwise among treatment groups, were the occurrence of a composite adverse pregnancy outcome (ie, either preterm delivery, the infant being born small for gestational age, stillbirth, or spontaneous abortion) in all participants with a pregnancy outcome, and the occurrence of grade 3 or higher maternal and infant adverse events in all randomised participants. This trial was registered with ClinicalTrials.gov, NCT03048422. FINDINGS: Between Jan 19, 2018, and Feb 8, 2019, we enrolled and randomly assigned 643 pregnant women: 217 to the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group, 215 to the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group, and 211 to the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), the median HIV-1 RNA concentration among participants was 902·5 copies per mL (152·0-5182·5; 181 [28%] of 643 participants had HIV-1 RNA concentrations of <200 copies per mL), and the median CD4 count was 466 cells per µL (308-624). HIV-1 RNA concentrations at delivery were available for 605 (94%) participants. Of these, 395 (98%) of 405 participants in the combined dolutegravir-containing groups had viral suppression at delivery compared with 182 (91%) of 200 participants in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (estimated difference 6·5% [95% CI 2·0 to 10·7], p=0·0052; excluding the non-inferiority margin of -10%). Significantly fewer participants in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (52 [24%] of 216) had a composite adverse pregnancy outcome than those in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (70 [33%] of 213; estimated difference -8·8% [95% CI -17·3 to -0·3], p=0·043) or the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (69 [33%] of 211; -8·6% [-17·1 to -0·1], p=0·047). The proportion of participants or infants with grade 3 or higher adverse events did not differ among the three groups. The proportion of participants who had a preterm delivery was significantly lower in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (12 [6%] of 208) than in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (25 [12%] of 207; -6·3% [-11·8 to -0·9], p=0·023). Neonatal mortality was significantly higher in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (ten [5%] of 207 infants) than in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (two [1%] of 208; p=0·019) or the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (three [2%] of 202; p=0·050). INTERPRETATION: When started in pregnancy, dolutegravir-containing regimens had superior virological efficacy at delivery compared with the efavirenz, emtricitabine, and tenofovir disoproxil fumarate regimen. The dolutegravir, emtricitabine, and tenofovir alafenamide fumarate regimen had the lowest frequency of composite adverse pregnancy outcomes and of neonatal deaths. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana.

BACKGROUND: A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies. METHODS: We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals. RESULTS: From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, -0.13 to 0.87). CONCLUSIONS: The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.).

Hypothesis: Symbrachydactyly.

The term symbrachydactyly has been used for the phenotype of two or three short fingers or toes, hypoplasia of the middle and distal phalanges and variable syndactyly of the affected digits. Some clinicians have extended this diagnosis to include other phenotypes, specifically cleft hand, terminal transverse limb defects, hypoplasia of the thumb and fifth finger with nubbins for fingers 2, 3, and 4 and the hand deformity of the Poland anomaly. A malformations surveillance program can identify enough affected infants to characterize a phenotype. In the Active Malformations Surveillance Program in Boston (1972-2012) among 289,365 births, all infants and fetuses with structural abnormalities were identified from reading the examination findings by the pediatricians and pathologists and the results of diagnostic tests. Liveborn and stillborn infants were included, as well as fetuses from elective terminations because of anomalies identified in prenatal testing. We present the findings in 14 infants, all liveborn, who had symbrachydactyly of one or both hands (n = 12) or feet (n = 2). We suggest restricting the term symbrachydactyly to this single phenotype to improve counseling and to focus future research on identifying the cause(s).

Hypothesis: Central digit hypoplasia.

Limb deficiencies are a common birth defect. A malformations surveillance program among many newborns, stillborn fetuses, and malformed fetuses in elective terminations can identify a sufficient number of infants with the same set of abnormalities to characterize a specific limb deficiency phenotype. The active malformations surveillance program was carried out among 289,365 births at Brigham and Women's Hospital in Boston over a 41-year period (1972-2012). The research assistants identified the affected infants and fetuses from reading the findings recorded in each newborn's medical record by the examining pediatricians and consultants and by the pathologists in autopsies. One hundred ninety-four newborn infants and fetuses were found to have a limb deficiency either as an isolated abnormality or as one of multiple malformations. We identified three phenotypes of limb deficiency. We present here the seventeen infants and fetuses with "central digit hypoplasia," a term we suggest for this phenotype: hypoplasia of the thumb and fifth finger with nubbins of soft tissue in place of fingers 2, 3, and 4 at the level of the metacarpal-phalangeal joint. Central digit hypoplasia is to be distinguished primarily from the terminal transverse limb defect that ends at the wrist. In symbrachydactyly, the middle and distal phalanges of the fingers and toes are hypoplastic. In addition, central digit hypoplasia should be distinguished from the amniotic band syndrome, the most common and incorrect diagnosis suggested by the pediatricians and the consultants in this survey. The affected infant and her/his parents benefit from more accurate and specific counseling.

Neuropsychological effects in children exposed to anticonvulsant monotherapy during gestation: Phenobarbital, carbamazepine, and phenytoin.

OBJECTIVE: Usage during pregnancy of the antiseizure medication (ASM), phenobarbital (PB), carbamazepine (CBZ), and phenytoin (PHT), has been associated with adverse pregnancy outcomes. While morphological effects on offspring are well-documented, inconsistent findings have been reported on neuropsychological development, possibly due to differences in attention to maternal demographics, and other design characteristics. Herein, we report the results of a carefully designed protocol used to examine the effects of gestational monotherapy with PB, CBZ, or PHT upon children's general mental abilities, when compared to age- and gender- matched children born to unexposed women of similar age, education, and socioeconomic status. METHODS: For each ASM, we selected qualifying cases from children born to PB, CBZ, or PHT monotherapy-exposed and unexposed women. Following the application of inclusion, exclusion, and matching criteria, our sample included 34 PB-exposed, 40 PHT-exposed, and 41 CBZ-exposed children along with matched unexposed children for each drug group. Criteria were applied through examination of maternal medical and educational histories, parental socioeconomic characteristics, and child's age and gender. Each child's physical and neuropsychological characteristics were examined, using standardized protocols. We report on the cognitive performance of the children as assessed by the Wechsler Intelligence Scale for Children - III (WISC-III), the leading measure of mental ability in the U.S. RESULTS: An overall mixed model ANOVA of the adjusted performance of the children across all groups controlling for maternal IQ revealed significant effects on verbal IQ, but not full-scale IQ or performance IQ. In the individual drug and unexposed group comparisons, only reduced verbal and full-scale IQ scores in PB-exposed versus matched unexposed children were found. Comparisons between drug groups revealed a significant reduction in verbal IQ and full-scale IQ in PB-exposed versus PHT-exposed children, but not in other drug-drug comparisons. SIGNIFICANCE: These results demonstrate effects on children's mental ability due to prenatal PB exposure, such that analyses adjusted for maternal IQ scores, revealed reduced verbal mental abilities and reduced full-scale IQ scores when scores in exposed children were compared to scores from children of the same age and sex born to demographically similar, healthy unexposed women. When comparisons were made between drug groups, children exposed prenatally to PB performed significantly worse than prenatally PHT-exposed children, but CBZ-exposed children's scores were not significantly different from those of PB or PHT-exposed groups. In light of shared effects on structural teratogenicity, these findings suggest that use of PB monotherapy for the management of seizures during pregnancy may be associated with increased risk in comparison to PHT when neurobehavioral functioning is considered, and that only PB-exposed children have reduced performance compared to matched controls. Attention to these effects is critical in the developing world where use of these older medications remains predominant, and prudent choices can be made to reduce impact on cognitive development.

The Impact of Technology on the Diagnosis of Congenital Malformations.

As technology improves and becomes more widely accessible, more subclinical congenital malformations are being detected. Using a cohort of 1,780,156 pregnant women and their offspring nested in the 2000-2013 US Medicaid Analytic eXtract, we contrasted time trends in malformations which do not necessarily present with overt clinical symptoms early in life and are more likely to be diagnosed via imaging (secundum atrial septal defect, patent ductus arteriosus, ventricular septal defect, pulmonary artery anomalies, pulmonary valve stenosis, hydrocephalus) with trends in malformations that are unlikely to escape clinical diagnosis (tetralogy of Fallot, coarctation of the aorta, transposition of the great vessels, hypoplastic left heart syndrome, oral cleft, abdominal wall defect). Logistic regression was used to account for trends in risk factors while assessing the impact of increased screening intensity. Prevalence of the diagnosis of secundum atrial septal defect rose from 2.3‰ in 2000-2001 to 7.5‰ in 2012-2013, of patent ductus arteriosus from 1.9‰ to 4.1‰, and of ventricular septal defect from 3.6‰ to 4.5‰. Trends were not explained by changes in the prevalence of risk factors but were attenuated when accounting for screening tests. The other malformations showed no temporal trends. Findings suggest that increased screening partially explains the observed increase in diagnosis of milder cases of select common malformations.

Fetal growth and premature delivery in pregnant women on antiepileptic drugs.

OBJECTIVE: To evaluate the effects of epilepsy and antiepileptic drugs (AEDs) used during pregnancy on fetal growth and preterm delivery. METHODS: This study included singleton liveborn infants born to women enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2016. Data were collected prospectively through telephone interviews. The prevalence of preterm birth (<37 weeks) and small for gestational age status (SGA) among infants exposed prenatally to AEDs when used by women with epilepsy (WWE) or women without epilepsy (WWOE) was compared with that among infants unexposed to AEDs and born to WWOE. Multivariate log-binomial regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: The study population included infants born to 6,777 AED-WWE, 696 AED-WWOE, and 486 no-AED-WWOE. The risk of prematurity was 6.2% for no-AED-WWOE, 9.3% for AED-WWE (RR = 1.5, 95% CI = 1.0-2.1), and 10.5% for AED-WWOE (RR = 1.5, 95% CI = 1.0-2.4). Prenatal exposure to AEDs in WWE and WWOE was associated with a mean lower birth weight of 110 and 136g, respectively, as compared to no-AED-WWOE. The prevalence of SGA was 5.0% for no-AED-WWOE, 10.9% for AED-WWE (RR = 2.0, 95% CI = 1.3-3.0), and 11.0% for AED-WWOE (RR = 1.9, 95% CI = 1.2-2.9). Within users of AEDs in monotherapy, the prevalence of SGA ranged from 7.3% for lamotrigine to 18.5% for topiramate. INTERPRETATION: Women on AEDs during pregnancy, whether for epilepsy or for other neuropsychiatric indications, are at a higher risk of delivering prematurely and giving birth to SGA newborns. The risk may vary by drug. Ann Neurol 2017;82:457-465.

Antidepressant use in pregnancy and the risk of cardiac defects.

BACKGROUND: Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects. METHODS: We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders. RESULTS: A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41). CONCLUSIONS: The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.).

Impact of elective termination on the occurrence of severe birth defects identified in a hospital-based active malformations surveillance program (1999 to 2002).

BACKGROUND: The number of affected infants and the types of malformations identified by a malformation surveillance programs can be impacted if elective terminations for malformations are not included. METHODS: The occurrence of malformations in all newborn infants was determined in a daily review of the findings in the pediatricians' examinations and those of all consultants. In addition, the findings in autopsies of all elective terminations were reviewed to identify all fetuses with structural abnormalities. A severity scale was used to subdivide the malformations. To establish the impact of elective termination, the malformed infants identified in the Active Malformations Surveillance Program at Brigham and Women's Hospital in Boston were analyzed for the 2 years before and after the hospital decreased significantly the number of elective terminations temporarily (1999-2000 vs. 2001-2002). The effect on the number of malformations identified at birth, as well as malformations of greater severity, was determined. RESULTS: The number of terminated fetuses with malformations decreased dramatically after termination services were interrupted (p < 0.0001). There were no differences in the prevalence rates of all malformations in the 2 years before and after the change in access to elective terminations. However, there were significant decreases in the number of infants identified with lethal/life-limiting and severe/handicapping malformations. CONCLUSION: In the surveillance for malformations among newborn infants, the inclusion of malformed fetuses from elective terminations had a significant effect on the number of infants with the more severe malformations identified. Birth Defects Research (Part A) 106:659-666, 2016. © 2016 Wiley Periodicals, Inc.

Effects of gestational age at enrollment in pregnancy exposure registries.

PURPOSE: This study aims to explore the influence of gestational age at enrollment, and enrollment before or after prenatal screening, on the estimation of drug effects in pregnancy exposure registries. METHODS: We assessed the associations between first trimester antiepileptic drug (AED) exposure and risk of spontaneous abortion and major congenital malformations in the North American AED Registry (1996-2013). We performed logistic regression analyses, conditional or unconditional on gestational age at enrollment, to estimate relative risk (RR) for first trimester AED users compared with non-users. We also compared first trimester users of valproic acid and lamotrigine. Analyses were repeated in women who enrolled before prenatal screening. RESULTS: Enrollment occurred earlier among 7029 AED users than among 581 non-users; it was similar among AEDs. Comparing AED users with non-users, RR (95% confidence interval) of spontaneous abortion (n = 359) decreased from 5.1 (2.3-14.1) to 2.0 (0.9-5.6) after conditioning on gestational week at enrollment and to 1.9 (0.8-5.4) upon further restriction to before-screening enrollees. RR of congenital malformations (n = 216) changed from 3.1 (1.4-8.5) to 3.2 (1.4-9.0) after conditioning on gestational week at enrollment and to 2.0 (0.7-10.1) upon further restriction to before-screening enrollees. When comparing valproic acid users and lamotrigine users, the RR of congenital malformations was not substantially changed by conditioning or restricting. CONCLUSIONS: Spontaneous abortion rates were sensitive to gestational age at enrollment. Estimates of congenital malformation risks for AED users relative to non-users were sensitive to before/after-screening enrollment. This difference was not apparent between active drugs, likely due to similar gestational age at enrollment.

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.

Laser light scan analysis of the "anticonvulsant face".

BACKGROUND: The "anticonvulsant face," with a short nose, broad nasal bridge, epicanthal folds, and wide mouth, was described in the 1970s in children who had been exposed during pregnancy to the anticonvulsant drugs phenytoin and phenobarbital. The laser light scan makes it possible to establish three-dimensional positions of physical features and to determine more objectively the changes in the size and shape of the affected soft tissues of the faces of children exposed to these anticonvulsant drugs during pregnancy. METHODS: Thirteen individuals, exposed throughout pregnancy to phenytoin as either monotherapy or polytherapy, were identified in a previous analysis as having significant changes in their craniofacial features based on measurements of cephalometric radiographs. Those changes were associated with midface hypoplasia and a short nose, features of the "anticonvulsant face." The soft tissues of their faces have been evaluated with laser light scans. RESULTS: The notable changes in soft tissues identified by laser light scans were a wide philtrum (cph-cph), narrow mouth (ch-ch), short nasal bridge (n-prn), shortened nose height (n-sn), and flattened orbits (orbital protrusion index). CONCLUSION: This analysis of the facial features of phenytoin-exposed individuals, selected because of changes in their craniofacial bony structures, showed that there were several significant changes, two of which, widening of the philtrum and a small mouth, have not been described previously as part of this phenotype.

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 alcohol consumption and congenital limb deficiencies.

BACKGROUND: Women of childbearing age report high rates of alcohol consumption, which may result in alcohol exposure during early pregnancy. Epidemiological research on congenital limb deficiencies (LDs) and periconceptional exposure to alcohol is inconclusive. METHODS: Data from the National Birth Defects Prevention Study (NBDPS) were examined for associations between LDs and patterns of maternal periconceptional (1 month before conception through the first trimester) alcohol consumption among LD case (n = 906) and unaffected control (n = 8352) pregnancies with expected delivery dates from 10/1997 through 12/2007. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated from unconditional logistic regression analysis for all LDs combined, specific LD subtypes (preaxial/terminal transverse), and LD anatomic groups (upper/lower limbs); interactions with folic acid (FA) supplementation were tested. RESULTS: When compared with nondrinkers, inverse associations were found between all LDs combined, preaxial, and upper LDs and any reported periconceptional alcohol consumption (aORs ranged from 0.56-0.83), drinking without binging (aORs: 0.53-0.75), and binge drinking (≥4 drinks/occasion) (aORs: 0.64-0.94); however, none of the binge drinking aORs were statistically significant. Stratification by alcohol type showed inverse associations between all LDs combined, preaxial, transverse, and upper and lower LDs for drinking without binging of wine only (aORs: 0.39-0.67) and between all LDs combined and upper LDs for drinking without binging of combinations of alcohol (aORs: 0.63-0.87). FA did not modify observed associations. CONCLUSION: Maternal periconceptional alcohol consumption did not emerge as a teratogen for selected LDs in the NBDPS. Future studies should evaluate additional rare LDs among more highly exposed populations.