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.

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.

Physical features of newborns exposed during pregnancy to anticonvulsant medication and developmental monitoring.

BACKGROUND: Antiepileptic drug (AED) use during pregnancy can affect the physical features, intelligence, and behavior in the exposed infants and children. Identifying these AED-related effects early makes intervention in childhood possible. To examine the accuracy of the identification of AED effects on the physical features of newborn infants, the written findings in routine physical examinations in medical records can be evaluated. METHODS: Documentation of AED exposure and the physical findings recorded was obtained from the hospital medical records of 207 infants at a large birthing hospital. Comparison was made of the findings in these infants by private pediatricians and two study pediatricians who were unaware of infant exposure status. The comparisons of the findings were analyzed using the Kappa statistic. RESULTS: The level of agreement in the assessment of the presence of facial features characteristic of midface hypoplasia by private pediatricians and the study pediatricians was poor (Kappa = 0.04; 95 CI-0.07 to 0.01); for microcephaly was fair (Kappa = 0.39; CI-0.14 to 0.93); and for growth restriction was fair (Kappa-0.22; CI-0.18 to 0.63). CONCLUSIONS: Findings recorded by hospital pediatricians in medical records during routine medical care showed that most (74%) of the pediatricians were aware of the infant's exposure to AED during pregnancy. Pediatricians did not do well in identifying the physical signs of midface or digit hypoplasia or microcephaly or growth restriction. Better early identification of the physical effects from AED exposure would make it possible for infants to benefit from developmental monitoring.

Polydactyly, postaxial, type B.

BACKGROUND: Postaxial polydactyly, type B is the most common type of polydactyly. The vestigial sixth finger is attached by a narrow neurovascular pedicle to the lateral aspect of the hand or foot at the level of the metacarpal-phalangeal joint or the metatarsal-phalangeal joint. The occurrence of this type of polydactyly varies among racial groups, by sex and sidedness. Postaxial polydactyly, type A is a fully developed extra digit on the lateral aspect of the hand or foot with a bifid fifth or sixth metacarpal/metatarsal and is much less common. METHODS: In a malformations surveillance program, the frequency in racial groups, sex ratio and the frequency of other anomalies can be established. RESULTS: Five hundred forty-five affected infants were identified from 1972 to 2012 in the surveillance of 289,365 liveborn and stillborn infants and elective terminations because of fetal anomalies detected prenatally. Postaxial polydactyly, type B was an isolated anomaly in 95% of the affected newborns. There were more affected males than females. Black infants were affected more often than White infants: 0.91/100 vs. 0.035/100 infants. The dangling extra digit was much more common in the hands than in the feet. CONCLUSIONS: Postaxial polydactyly, type B is almost always an isolated, mild malformation with no medical significance. Postaxial polydactyly, types B and A occurred in several infants, suggesting that either the underlying mutation(s) can cause both types of postaxial polydactyly or that some affected infants have more than one mutation. Autosomal dominant inheritance with variable expressivity is postulated.

Malformations among infants of mothers with insulin-dependent diabetes: Is there a recognizable pattern of abnormalities?

BACKGROUND: Infants of diabetic mothers have been shown in several studies to have an increased frequency of malformations. In previous studies, an increased frequency of several specific malformations has been noted, including anencephaly, bilateral renal agenesis, and double outlet right ventricle. Surveillance, used to identify all malformed infants in a consecutive sample of births, can identify a distinctive pattern of malformations among the affected infants. METHODS: The infants of insulin-dependent, pregestational diabetic mothers were identified in the daily review of the medical records of each newborn infant with a malformation and her/his mother's medical record. Infants of mothers with gestational diabetes were excluded. The frequency of each malformation was compared to that among the malformed infants of nondiabetic mothers. RESULTS: One hundred and eighty-three malformed infants of diabetic mothers were identified among the 289,365 births. The most notable malformations were: neural tube defects (anencephaly, 9%), heart defects (transposition of great arteries, 4%), bilateral renal agenesis or dysgenesis (6%), and vertebral anomalies (hemivertebrae, 4%). CONCLUSIONS: There was a recognizable pattern of malformations and characteristics of infants of diabetic mothers, although there was variation in the pattern among affected infants. Some of the malformations in the diabetic embryopathy can be identified in prenatal screening by ultrasound. More important, their occurrence can be reduced significantly by the mother achieving much better control of her diabetes mellitus prior to conception.

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.

Hypospadias, Intrauterine Growth Restriction, and Abnormalities of the Placenta.

BACKGROUND: Hypospadias is more common among male infants with growth restriction, defined as a birth weight less than the 10th centile, than in infants with a normal birth weight. Intrauterine growth retardation (IUGR) has been associated, also, with abnormalities of the placenta, such as maternal vascular malperfusion. In a consecutive sample of newborn infants, the association between hypospadias, IUGR and abnormalities of the placenta could be analyzed. METHODS: Affected infants were identified among 289,365 liveborn and stillborn infants in the Active Malformations Surveillance Program between 1972 and 2012. The four anatomic locations of the ectopic urethral opening, based on the recorded physical examination findings, were: (1) glandular; (2) subcoronal; (3) penile; (4) penoscrotal. Affected infants with associated malformations, a chromosome abnormality, teratogenic exposure, maternal diabetes mellitus, or multiple gestations were excluded. RESULTS: Three hundred sixteen affected infants were identified: 52.2% glandular, 11.7% subcoronal, 27.8% penile, and 8.2% penoscrotal. The highest frequency of IUGR (34.6%) was in the infants with the most severe hypospadias (penoscrotal). The 39 reports of placenta findings showed a high frequency of abnormalities. CONCLUSION: An increased rate of occurrence of hypospadias and abnormalities of the placenta were present in infants with intrauterine growth restriction. The postulated cause of this association is a deficiency in the function of the placenta during weeks 10 to 14 of gestation when normal masculinization occurs due to an increase in the level of placental human chorionic gonadotropin and fetal testosterone. The cause of the placental deficiency has not been established. Birth Defects Research 110:122-127, 2018.© 2017 Wiley Periodicals, Inc.

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.