Ensuring the safe and effective use of medications during pregnancy: planning and prevention through preconception care.
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Abnormalities, Drug-Induced↗
Biomedical subjects
Lewis B Holmes
Publications and source records attributed to Lewis B Holmes.
Analysis of reproductive toxicity and classification of glufosinate-ammonium.
CONCLUSION REGARDING CLASSIFICATION OF GLUFOSINATE-AMMONIUM: Science Partners' Evaluation Group (Evaluation Group) has conducted an independent analysis of the herbicide glufosinate-ammonium (GA) relative to its potential to cause reproductive toxicity in humans. Further, the Evaluation Group has evaluated the implementation of Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC) and Council Directive 91/414/EEC, with respect to classification of chemicals posing potential reproductive hazards. After consideration of all information available to us relevant to the potential of glufosinate-ammonium (GA) to cause reproductive toxicity, the Science Partners Evaluation Group concludes that no classification of GA is justified. The following form the basis of this conclusion. There are no human data to suggest that GA causes reproductive toxicity in women or in their conceptus. The issue concerning possible reproductive hazard to humans is raised solely on the basis of positive animal test results that show GA to cause preimplantation or implantation losses in rats. SPECIFICALLY: a. Daily treatment with GA had no detectable effect on the earliest stages of the reproductive sequence including gametogenesis, ovulation, mating and conception; b. Treatment with GA interfered with rat gestation before and at the stage when the conceptus implants into the uterus. This effect occurred at doses of 360 ppm in the feed (corresponding to daily doses of 27.8 mg/kg bw) and above; and c. After implantation, no further effect of GA on prenatal and post-natal development was recognized. Previous concerns that GA might be toxic to embryonic stages after implantation were not supported by the data. Abortions and stillbirth seen were associated with, and regarded as secondary to, maternal toxicity. There was no evidence suggesting the induction of malformations in the offspring. The mechanism underlying this adverse effect in experimental laboratory animals is identified-inhibition of glutamine synthetase. Glutamine is essential to the viability of the embryo. The embryo is dependent on a maternal source of the amino acid. For embryo lethality to occur, a significant reduction of maternal glutamine is required. Such reduction in maternal glutamine depends on a significant inhibition of glutamine synthetase by GA. This can only occur when the mother is exposed to very high levels of GA. SPECIFICALLY: a. The reproductive toxicity of GA is confined to very short, early stages of reproduction, during which the conceptus is dependent on maternal glutamine; and b. In order for the effect to occur, significant reduction in maternal blood glutamine level is required, which in turn depends on a significant inhibition of glutamine synthetase, induced by high levels of GA in the maternal system. There is no evidence for accumulation of GA in the mammalian organism beyond a factor of two and no evidence for its metabolic toxification. To raise a concern in humans, women would have to be exposed to GA during the very limited time frame of preimplantation or implantation and the exposure would have to be to the exceedingly high levels necessary to alter the maternal metabolism and, correspondingly, result in glutamine levels in maternal tissue and blood plasma being drastically reduced. There is no basis to suggest that such exposures would occur under conditions of normal handling and use. SPECIFICALLY: a. Under conditions of normal handling and use, operators would never be exposed to GA levels that could potentially inhibit glutamine synthetase to the extent that this inhibition could impair preimplantation or implantation. b. All acceptable exposure measurements and predictive calculations confirm this conclusion, and in fact demonstrate that reasonably foreseeable exposure of workers would be to levels significantly below the AOEL. c. The evidence is also clear that there is no reproductive toxicity hazard to workers upon reentry tosprayed fields, bystanders, consumers or toddlers. The safety margin compared to the NOAEL in animal studies is sufficiently large to assure protection of the health of workers using GA as well as bystanders, consumers, and toddlers. Pursuant to Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC), to justify a classification of category 2 there must be sufficient evidence to produce a strong presumption that human exposure to the substance may result in impaired fertility in humans. It is the conclusion of the Science Partners Evaluation Group that there is no reasonable evidence to suggest a strong presumption of impairment. To the contrary, there is clear evidence demonstrating a strong presumption that exposure to GA would not cause the adverse effect demonstrated in rats. Pursuant to Annex 6 of Commission Directive 2001/59/EC (28th ATP of Council Directive 67/548/EEC), to justify a classification of category 3, there must be sufficient evidence to provide a strong suspicion of impaired fertility in humans. There is no basis to conclude that the animal data demonstrating impaired preimplantation or implantation has any relevance to humans in that the effect found in rats only occurs at levels which would never be experienced by workers under conditions of normal handling and use or by bystanders, consumers, or toddlers.
Aminobutyrates↗
Asymmetry of skeletal effects of Dominant hemimelia.
BACKGROUND: Dominant hemimelia (Dh) is a dominant mutation that arose spontaneously in mice; Dh animals exhibit reduced numbers of lumbar vertebrae and preaxial hindlimb defects. Absence of spleen occurs in both Dh/+ and Dh/Dh animals. This study was undertaken to characterize asymmetry of skeletal defects in the Dh mouse, specifically hindlimb asymmetries in association with axial defects. METHODS: A total of 29 Dh/+ and 100 +/+ fetuses (gestational day [GD] 18) were identified by phenotype and linked DNA and their skeletons were analyzed. RESULTS: The results revealed an asymmetry of hindlimb skeletal defects in Dh/+ animals. In +/+ fetuses, the left and right tibia were symmetrical with 99.0% of the animals possessing 6 lumbar vertebrae. However, Dh/+ fetuses showed asymmetry in length of left and right tibia and a reduction to 5 lumbar vertebrae in 86.2% of animals. There was a range from mild to severe asymmetry as evidenced by direct comparison of the length of the left to the right tibia of each animal. Tibial shortening was greater on the left than the right in 65.5% of Dh/+ fetuses; only 20.7% had symmetrical tibia. Oligodactyly, defined as absence of the first or second toe, was similarly more frequent on the left. CONCLUSIONS: Asymmetry is characteristic of many human limb malformations, although analysis of the molecular basis is difficult. Therefore, Dh/+ mice, which exhibit reduced numbers of lumbar vertebrae, asymmetric hindlimb defects, and complete absence of spleen, provide an important model for studying the relationship between axial patterning and asymmetric skeletal defects.
Animals↗
Infants with Bochdalek diaphragmatic hernia: sibling precurrence and monozygotic twin discordance in a hospital-based malformation surveillance program.
Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect. In order to learn more about possible genetic causes, we reviewed and classified 203 cases of the Bochdalek hernia type identified through the Brigham and Women's Hospital (BWH) Active Malformation Surveillance Program over a 28-year period. Phenotypically, 55% of the cases had isolated CDH, and 45% had complex CDH defined as CDH in association with additional major malformations or as part of a syndrome. When classified according to likely etiology, 17% had a Recognized Genetic etiology for their CDH, while the remaining 83% had No Apparent Genetic etiology. Detailed analysis using this largest cohort of consecutively collected cases of CDH showed low precurrence among siblings. Additionally, there was no concordance for CDH among five monozygotic twin pairs. These findings, in conjunction with previous reports of de novo dominant mutations in patients with CDH, suggest that new mutations may be an important mechanism responsible for CDH. The twin data also raise the possibility that epigenetic abnormalities contribute to the development of CDH.
Child, Preschool↗
Case records of the Massachusetts General Hospital. Case 11-2005. A 32-year-old pregnant woman with an abnormal fetal karyotype.
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Adult↗
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.
Abnormalities, Multiple↗
The correlation of deficits in IQ with midface and digit hypoplasia in children exposed in utero to anticonvulsant drugs.
OBJECTIVE: Children exposed during pregnancy to the anticonvulsant drugs phenytoin, phenobarbital, and carbamazepine as monotherapy and polytherapy have an increased frequency of midface and digit hypoplasia. Some children also have cognitive dysfunction. The hypothesis tested is that the anticonvulsant drug-exposed child with midface and digit hypoplasia is more likely to have cognitive dysfunction. METHODS: Children exposed to anticonvulsant drugs (n = 80) were recruited for a follow-up evaluation, which included testing cognitive function and a physical examination for head size, height, and the presence of midface and digit hypoplasia. Microcephaly, midface and digit hypoplasia, and major malformations were correlated with full scale (FSI), performance (PIQ) and verbal (VIQ) intelligence. RESULTS: The presence of the 3 anticonvulsant-exposed children with microcephaly had a deficit of 23.7 IQ points in FSI in comparison with the other children with a normal head size. Either midface or digit hypoplasia, after excluding the persons with microcephaly and with the Bonferroni correction, correlated significantly with deficits in VIQ (-12.7), PIQ (-10) and FSI (-12.8) IQ points ( P = .0061). There was no decrease in IQ in association with major malformations. CONCLUSION: The presence of midface and digit hypoplasia in a child exposed to anticonvulsant drugs in pregnancy is an indication for a systematic developmental evaluation.
Abnormalities, Drug-Induced↗
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.
Adrenal Hyperplasia, Congenital↗
The AED (antiepileptic drug) pregnancy registry: a 6-year experience.
BACKGROUND: Pregnancy registries are a new method for assessing the fetal risks from exposures in pregnancy. We present the findings of the North American AED (antiepileptic drug) Pregnancy Registry for phenobarbital sodium-exposed pregnancies. OBJECTIVE: To determine whether exposure during pregnancy to anticonvulsant drugs as monotherapy, and phenobarbital in particular, is associated with an increased risk of major malformations in comparison with unexposed controls. DESIGN: Evaluation of registry data. SETTING: The North American AED Pregnancy Registry. PATIENTS: Pregnant women throughout the United States and Canada who were taking an anticonvulsant drug and who called a toll-free telephone number to enroll. INTERVENTIONS: Each woman was interviewed by telephone at enrollment, at 7 months' gestation, and post partum. With the mother's written permission, her medical records and those of her infant were obtained. MAIN OUTCOME MEASURES: Major malformations identified by 5 days of age. Criteria for the release of findings were established by the independent Scientific Advisory Committee on the basis of malformations identified in infants of women who had enrolled prospectively before having had any prenatal screening ("pure" enrollees). RESULTS: Five (6.5%) of 77 pure pregnancies with exposure to phenobarbital monotherapy were associated with major malformations (95% confidence interval of proportion, 2.1%-14.5%). When compared with the background rate (1.62%), there was a significantly increased risk (relative risk, 4.2; 95% confidence interval, 1.5-9.4). CONCLUSIONS: A hospital-based pregnancy registry can establish the fetal risk of major malformations for a commonly used drug. Prenatal exposure to phenobarbital is associated with a significantly increased risk of fetal abnormalities.
Abnormalities, Drug-Induced↗
Mutations in SALL4 in malformed father and daughter postulated previously due to reflect mutagenesis by thalidomide.
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Duane Retraction Syndrome↗
Clonazepam use in pregnancy and the risk of malformations.
BACKGROUND: Clonazepam (Klonopin) is a benzodiazepine that has been used widely to treat seizures and conditions such as panic attacks and anxiety disorder. However, the current findings about its use in pregnancy are derived from limited studies of small sample size. Because it is commonly prescribed during pregnancy, more information about its safety is needed. METHODS: The medical records of 28,565 infants were surveyed as part of a hospital-based malformation surveillance program to identify those who had been exposed prenatally to an anticonvulsant, including clonazepam. RESULTS: During a 32-month period, 166 anticonvulsant-exposed infants were identified; 52 had been exposed to clonazepam, 43 as monotherapy. A total of 33 (76.7%) of the monotherapy infants were exposed during the first trimester. One (3.0%) infant had dysmorphic features, growth retardation, and a heart malformation (tetralogy of Fallot). CONCLUSIONS: This study did not observe an increase in major malformations in births exposed to clonazepam monotherapy. However, this study is not large enough to have adequate power to determine whether or not the rate of major malformations is increased in clonazepam-exposed pregnancies. No increase has been identified in three other case series. Although the number of patients in this series was larger than previous reports, continued monitoring of pregnancies is needed to determine whether or not clonazepam is teratogenic.
Abnormalities, Drug-Induced↗
Is antenatal vitamin K prophylaxis needed for pregnant women taking anticonvulsants?
The objective of this cohort study of a consecutive sample of infants exposed during pregnancy to anticonvulsant drugs was to determine if the mother received late pregnancy prophylaxis with vitamin K, and if any infants had signs of hemorrhagic disease. The medical records of 204 neonates exposed to anticonvulsant drugs in utero and 77 unexposed control neonates were retrospectively reviewed. No hemorrhagic disease was observed, and the incidence of bleeding tendencies was not higher in infants exposed to these drugs compared with control infants, despite no prenatal vitamin K supplementation in all but 1 epileptic woman.
Anticonvulsants↗
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.
Abnormalities, Multiple↗
Trends in congenital malformations, 1974-1999: effect of prenatal diagnosis and elective termination.
OBJECTIVE: To examine trends in congenital malformations, elective terminations for malformations and correlates for the decision to terminate a pregnancy with a malformation. METHODS: All malformed liveborn and stillborn infants and elective terminations for malformations were identified in a large urban tertiary center and general hospital for the years 1974, 1979, 1984, 1989, 1994, and 1999. Nine hundred and fifty-four women with malformed infants, who had always planned to deliver at the hospital, were identified. Prenatal screening by ultrasonography or amniocentesis before 24 weeks of gestation, severity rating of the malformation, parity, marital status, race, level of education, insurance status, and pregnancy history were determined RESULTS: In each of these 6 years, about 2% of newborn infants had a major malformation. The rate of prenatal screening by ultrasonography and amniocentesis before 24 weeks increased from 7% in the years 1974 and 1979 to 61% in the years 1984 and 1989 to 89% in the years 1994 and 1999. Elective termination increased from less than 1% in the years 1974 and 1979 to 18% to 20% in the years 1984, 1989, 1994, and 1999. Pregnancies with fatal and severe conditions were much more likely to be terminated electively than pregnancies with moderate or mild conditions (odds ratio 53.3; 95% confidence interval 22.7-124.7) CONCLUSION: The introduction of routine prenatal screening and the subsequent increase in elective termination for malformed fetuses means that the inclusion of terminated pregnancies in malformation surveillance programs is necessary to study prevalence and risk factors in the epidemiology of malformations.
Abortion, Induced↗
North American antiepileptic drug pregnancy registry.
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Abnormalities, Drug-Induced↗
Guidelines for case classification for the National Birth Defects Prevention Study.
BACKGROUND: Previous studies have suggested that etiologic heterogeneity may complicate epidemiologic analyses designed to identify risk factors for birth defects. Case classification uses knowledge of embryologic and pathogenetic mechanisms to make case groups more homogeneous and is important to the success of birth defects studies. METHODS: The goal of the National Birth Defects Prevention Study (NBDPS), an ongoing multi-site case-control study, is to identify environmental and genetic risk factors for birth defects. Information on environmental risk factors is collected through an hour-long maternal interview, and DNA is collected from the infant and both parents for evaluation of genetic risk factors. Clinical data on infants are reviewed by clinical geneticists to ensure they meet the detailed case definitions developed specifically for the study. To standardize the methods of case classification for the study, an algorithm has been developed to guide NBDPS clinical geneticists in this process. RESULTS: Methods for case classification into isolated, multiple, and syndrome categories are described. Defects considered minor for the purposes of case classification are defined. Differences in the approach to case classification for studies of specific defects and of specific exposures are noted. CONCLUSIONS: The case classification schema developed for the NBDPS may be of value to other clinicians working on epidemiologic studies of birth defects etiology. Consideration of these guidelines will lead to more comparable case groups, an important element of careful studies aimed at identifying risk factors for birth defects.
Adult↗
Anticonvulsant teratogenesis 5: observer bias in a cohort study.
BACKGROUND: The most common physical effects of prenatal exposure to the anticonvulsant drugs phenytoin and phenobarbital are midface and digit hypoplasia. These features are subjective in nature, which makes their detection vulnerable to any bias the examiner has, such as an increased expectation that the infant being examined has been exposed prenatally to an anticonvulsant drug. The purpose of this analysis was to determine whether or not there was evidence of observer bias in the detection of presumed anticonvulsant drug-related physical features. METHODS: The presence or absence of three groups of features were compared: 1) midface hypoplasia, such as anteverted nostrils; 2) digit hypoplasia, e.g., tapered fingers, and 3) other features, e.g., prominent occiput, not known to be affected by exposure to anticonvulsants. These infants were examined by one masked physician examiner, using a study protocol, in three time periods: in two similar time periods, the masked examiner knew that one in four (25%) of the infants to be examined had been exposed to an anticonvulsant drugs; in the third time period, the chance was 50%. RESULTS: The frequencies of the subjective features of midface (odds ratio [OR] = 2.6) and digit hypoplasia (OR = 3.9), but not the other features, were significantly more common in the time periods when the masked examiner knew that there was a 50% chance of exposure to anticonvulsant drugs, compared to the time periods when there was a 25% chance. CONCLUSIONS: The findings suggest the effect of observer bias. In addition, there was evidence of context bias, meaning that a study that focuses on determining the presence of specific features will identify them more often.
Abnormalities, Drug-Induced↗
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.
Child↗