Publications by authors named "Lewis B Holmes"

84 Publications

Terminal transverse limb defects.

Authors:
Lewis B Holmes

Birth Defects Res 2021 Aug 14;113(13):1029-1030. Epub 2021 Jul 14.

Medical Genetics and Metabolism Unit, MassGeneral Hospital for Children, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1002/bdr2.1933DOI Listing
August 2021

Terminal transverse limb defects with "nubbins".

Birth Defects Res 2021 Aug 8;113(13):1007-1014. Epub 2021 Jul 8.

Medical Genetics and Metabolism Unit, MassGeneral Hospital for Children, Boston, Massachusetts, USA.

Background: A terminal transverse limb defect with absence of the forearm and hand or just the hand is an uncommon limb deformity in an otherwise healthy newborn. Most of the affected infants also have tiny digit-like nubbins on the stump of the affected limb, a finding that could represent an attempt at regeneration following vascular obstruction in early limb development.

Methods: One hundred ninety-four newborn infants with a limb deficiency were identified among 289,365 births in an active malformations surveillance program at Brigham and Women's Hospital in Boston, MA from 1972 to 2012. Twenty-eight infants with terminal transverse limb defects were identified.

Results: Twenty-four had tiny digit-like nubbins (0.5 cm in length) on the stump at one of three levels: the proximal portion of the forearm, the wrist or the forefoot. The examination of the placentas of eight affected infants showed no evidence of amnion rupture. Three of these 28 infants had associate chromosome abnormalities: trisomy 21, chromosome 11q deletion and the deletion of 22q11.2.

Conclusion: Terminal transverse limb defects reflect failure of early limb development. Awareness of this phenotype at birth, or when identified by ultrasound screening, can provide more accurate counseling than occurs with the more common misdiagnosis of "amniotic band syndrome."
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http://dx.doi.org/10.1002/bdr2.1931DOI Listing
August 2021

Global birth defects app: An innovative tool for describing and coding congenital anomalies at birth in low resource settings.

Birth Defects Res 2021 Aug 5;113(14):1057-1073. Epub 2021 May 5.

National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA.

Background: Surveillance programs in low- and middle-income countries (LMICs) have difficulty in obtaining accurate information about congenital anomalies.

Methods: As part of the ZikaPLAN project, an International Committee developed an app for the description and coding of congenital anomalies that are externally visible at birth, for use in low resource settings. The "basic" version of the app was designed for a basic clinical setting and to overcome language and terminology barriers by providing diagrams and photos, sourced mainly from international Birth Defects Atlases. The "surveillance" version additionally allows recording of limited pseudonymized data relevant to diagnosis, which can be uploaded to a secure server, and downloaded by the surveillance program data center.

Results: The app contains 98 (88 major and 10 minor) externally visible anomalies and 12 syndromes (including congenital Zika syndrome), with definitions and International Classification of Disease v10 -based code. It also contains newborn examination videos and links to further resources. The user taps a region of the body, then selects among a range of images to choose the congenital anomaly that best resembles what they observe, with guidance regarding similar congenital anomalies. The "basic" version of the app has been reviewed by experts and made available on the Apple and Google Play stores. Since its launch in November 2019, it has been downloaded in 39 countries. The "surveillance" version is currently being field-tested.

Conclusion: The global birth defects app is a mHealth tool that can help in developing congenital anomaly surveillance in low resource settings to support prevention and care.
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http://dx.doi.org/10.1002/bdr2.1898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349897PMC
August 2021

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.

Lancet 2021 04;397(10281):1276-1292

Division of Global Women's Health, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Project Malawi, Lilongwe, Malawi.

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.
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http://dx.doi.org/10.1016/S0140-6736(21)00314-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132194PMC
April 2021

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

Birth Defects Res 2021 05 28;113(9):702-707. Epub 2021 Mar 28.

Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, USA.

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.
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http://dx.doi.org/10.1002/bdr2.1887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148051PMC
May 2021

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

Birth Defects Res 2021 Jul 15;113(12):995-1000. Epub 2021 Mar 15.

Medical Genetics and Metabolism Unit, Massachusetts General Hospital for Children, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1002/bdr2.1890DOI Listing
July 2021

Memories of the Teratology Society: 1972-2020.

Authors:
Lewis B Holmes

Birth Defects Res 2020 07;112(12):935-941

Medical Genetics and Metabolism Unit, MassGeneral Hospital for Children, Boston, Massachusetts, USA.

Background: My career goal in 1971 was to learn about the causes of malformations. Attending the annual meetings of the Teratology Society and reading the articles in Teratology exposed me to the scientists and clinicians involved in this research and the methods being used.

Methods: Over a period of 49 years (1972-2020), I heard many presentations about several exposures in pregnancy that can cause birth defects. Symposia and platform presentations provided unique and stimulating information on the fetal effects of the teratogen thalidomide.

Results: I developed research studies and presented the results from our studies on teratogenic exposures, such as anticonvulsant drugs, the prenatal diagnosis procedure chorionic villus sampling, and the abortifacient misoprostol. The annual Pregnancy Registry Workshop was developed as a forum for discussing issues related to this new method of evaluating potential teratogenic exposures in pregnancy.

Conclusion: Attending the annual meetings and reading the articles in the journal Teratology (now Birth Defects Research) have been an instructive and enjoyable way to learn about the causes of malformations.
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http://dx.doi.org/10.1002/bdr2.1667DOI Listing
July 2020

The Impact of Technology on the Diagnosis of Congenital Malformations.

Am J Epidemiol 2019 11;188(11):1892-1901

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1093/aje/kwz153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825822PMC
November 2019

Levetiracetam Pregnancy Registry: Final results and a review of the impact of registry methodology and definitions on the prevalence of major congenital malformations.

Birth Defects Res 2019 08 23;111(13):872-887. Epub 2019 May 23.

UCB Pharma, Raleigh, North Carolina.

Background: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs).

Methods: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria.

Results: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs.

Conclusion: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates.
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http://dx.doi.org/10.1002/bdr2.1526DOI Listing
August 2019

Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study.

Lancet Glob Health 2018 07 4;6(7):e804-e810. Epub 2018 Jun 4.

Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Global rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana.

Methods: In this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofovir-emtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes were the combined endpoints of any adverse outcome (stillbirth, preterm birth [<37 weeks' gestation], small for gestational age [SGA; less than the tenth percentile of birthweight by gestational age], or neonatal death [within 28 days of age]) and severe adverse outcomes (stillbirth, neonatal death, very preterm birth [<32 weeks' gestation], and very SGA [less than the third percentile of birthweight by gestational age]). We fitted log-binomial regression models, controlling for maternal age, gravidity, and education, to estimate adjusted risk ratios (aRRs).

Findings: Our analysis included 1729 pregnant women who initiated dolutegravir-based ART and 4593 who initiated efavirenz-based ART. The risk for any adverse birth outcome among women on dolutegravir versus efavirenz was similar (33·2% vs 35·0%; aRR 0·95, 95% CI 0·88-1·03), as was the risk of any severe birth outcome (10·7% vs 11·3%; 0·94, 0·81-1·11). We found no significant differences by regimen in the individual outcomes of stillbirth, neonatal death, preterm birth, very preterm birth, SGA, or very SGA.

Interpretation: Adverse birth outcomes were similar among pregnant women who initiated dolutegravir-based and efavirenz-based ART. Dolutegravir-based ART can be safely initiated in pregnancy.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2214-109X(18)30218-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071315PMC
July 2018

Stillborn Infants: Associated Malformations.

Birth Defects Res 2018 01;110(2):114-121

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1002/bdr2.1097DOI Listing
January 2018

Iniencephaly.

Birth Defects Res 2018 01;110(2):128-133

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1002/bdr2.1082DOI Listing
January 2018

The Active Malformations Surveillance Program, Boston in 1972-2012: Methodology and demographic characteristics.

Birth Defects Res 2018 01;110(2):148-156

Active Malformations Surveillance Program, Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Malformations surveillance programs have been carried out in consecutive populations of newborn infants at single hospitals, as well as in several hospitals in defined populations. A surveillance program begins with the review of the findings recorded by the examining pediatrician in each infant's medical record. The results of diagnostic tests, consultations, and imaging studies are obtained, also, from that infant's medical record. Some malformations surveillance programs identify additional malformations over several months, as the infants have hospitalizations and additional diagnostic testing.

Methods: 289,365 infants (liveborn, stillborn, and fetuses in pregnancies terminated because of anomalies) were surveyed from 1972 to 2012 at an urban maternity center in Boston to identify each infant with one or more malformations. Each mother was interviewed to obtain demographic characteristics, results of prenatal testing, family history, and information about exposures in pregnancies. Specific diagnoses were established by the study geneticists.

Results: 7,020 (2.4%) of the 289,365 infants surveyed had one or more malformations. The etiologies identified included chromosome abnormalities, phenotypes attributed to dominant or recessive autosomal or X-linked mutations, vascular disruption, environmental factors, and complications of twinning.

Conclusion: The surveillance of a large consecutive population of newborn infants, stillbirths, and aborted fetuses can identify with high reliability all infants with one or more malformations. This process of ascertainment of affected newborns can be used to improve genetic counseling, identify "new" phenotypes, and serve as a system for testing new technologies to establish more causes of congenital malformations.
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http://dx.doi.org/10.1002/bdr2.1156DOI Listing
January 2018

Causes of Congenital Malformations.

Birth Defects Res 2018 01;110(2):87-91

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston.

Background: Many different causes of malformations have been established. The surveillance of a consecutive population of births, including stillbirths and elective terminations of pregnancy because of fetal anomalies, can identify each infant with malformations and determine the frequency of the apparent etiologies. This report is a sequel to the first such analysis in the first 10 years of this Active Malformations Surveillance Program (Nelson and Holmes, ).

Methods: The presence of malformations was determined among 289,365 births over 41 years (1972-2012) at the Brigham and Women's Hospital in Boston. The abnormalities were identified from the review of the examination findings of the pediatricians and consultants and diagnostic testing for the live-born infants and the autopsies of the fetuses in elective terminations and stillbirths.

Results: A total of 7020 (2.4%) infants and fetuses with one or more malformations were identified with these apparent etiologies in 26.6%: Mendelian disorders, including infants with postaxial polydactyly, type B; chromosome abnormalities; vascular disruption; complications of monozygous twinning; and environmental factors. The malformations of unknown etiology were a much larger group.

Conclusion: While several causes of malformations have been identified, many remain unexplained. Combining the ascertainment in a future surveillance programs with genome sequencing and chromosome microarray analysis will increase significantly the number of malformations attributed to genetic mechanisms. Birth Defects Research 110:87-91, 2018.© 2018 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdr2.1105DOI Listing
January 2018

Malformations among 289,365 Births Attributed to Mutations with Autosomal Dominant and Recessive and X-Linked Inheritance.

Birth Defects Res 2018 01;110(2):92-97

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston.

Background: The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders.

Methods: The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well.

Results: One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents.

Conclusion: It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdr2.1101DOI Listing
January 2018

Malformations attributed to the process of vascular disruption.

Birth Defects Res 2018 01;110(2):98-107

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Background: Several malformations have been attributed to the process of vascular disruption. The central hypothesis for this etiology is that blood flow to a structure has been altered after that structure had formed normally. The decreased blood flow leads to hypoxia, endothelial cell damage, hemorrhage, tissue loss, and repair. After recovery, some structures are normal and others show either tissue loss or structural abnormalities, such as syndactyly and constriction rings.

Methods: The phenotypic features of the 7,020 infants with one or more malformations, who were born to women who had always planned to deliver at Brigham and Women's Hospital (BWH) between, 1972 and 2012, that is, maternal nontransfers, were reviewed. The phenotypes associated with vascular disruption, such as the amniotic band syndrome and terminal transverse limb defects (TTLD), were identified.

Results: One hundred and five fetuses and infants had malformations attributed to the process of vascular disruption. Some specific causes of the amniotic band limb deformity were identified. TTLD with associated small digit-like nubbins occurred at three levels: proximal forearm, wrist, and metacarpal-phalangeal joint. Other causes included severe hemoglobinopathies and exposures to misoprostol and to prenatal procedures.

Conclusions: Malformations attributed to the process of vascular disruption were a distinctive entity, among the recognized etiologies. The timing of the causative event in the first trimester was established for infants with exposures to either the prostaglandin misoprostol or the prenatal diagnosis procedure chorionic villus sampling. One challenge is to identify the developmental steps in vascular disruption when no causative exposure can be identified.
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http://dx.doi.org/10.1002/bdr2.1160DOI Listing
January 2018

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

Birth Defects Res 2018 01;110(2):108-113

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1002/bdr2.1155DOI Listing
January 2018

Polydactyly, postaxial, type B.

Birth Defects Res 2018 01;110(2):134-141

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston.

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.
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http://dx.doi.org/10.1002/bdr2.1184DOI Listing
January 2018

What is the risk of major congenital abnormalities among women on antiretroviral therapy?

AIDS 2018 01;32(3):403-404

Medical Genetics Unit, MassGeneral Hospital for Children, Department of Pediatrics, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1097/QAD.0000000000001711DOI Listing
January 2018

Setting Standards for Pregnancy Registries.

Authors:
Lewis B Holmes

Drug Saf 2018 01;41(1):7-9

Medical Genetics Unit, MassGeneral Hospital for Children, 175 Cambridge Street, Fifth Floor, Boston, MA, 02114, USA.

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http://dx.doi.org/10.1007/s40264-017-0600-8DOI Listing
January 2018

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

Ann Neurol 2017 Sep;82(3):457-465

North American Antiepileptic Drug Pregnancy Registry, MassGeneral Hospital for Children, Boston, MA.

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.
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http://dx.doi.org/10.1002/ana.25031DOI Listing
September 2017

Malformations Surveillance: Comparison between Findings at Birth and Age 1 Year.

Birth Defects Res 2018 01 10;110(2):142-147. Epub 2017 Aug 10.

Active Malformations Surveillance Program, Department of Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Background: Malformations surveillance programs among newborn infants are used to determine the prevalence of congenital anomalies. A comparison in the same group of infants between the malformations detected at birth and those detected at 1 year of age will identify errors in the surveillance process and, also, the abnormalities more likely not to be detected at birth, but later in the first year of life.

Methods: The malformations identified at birth by Brigham and Women's Hospital (BWH) in the years 2000 and 2005 have been compared with the abnormalities detected in the same infants up to age 1 year by the Massachusetts Birth Defects Monitoring Program.

Results: The Massachusetts Birth Defects Monitoring Program identified 557 malformed infants in 2000 and 415 in 2005. Of these, 34 (3.5%) of the malformed infants were missed at birth by BWH Surveillance Program. An additional 22 (2.3%) malformed infants had delayed detection, as they were identified later in the first year. The reasons were the fact that: (1) the Surveillance staff reviewed the physicians' recorded findings only on the first day of life; (2) failure of the examining pediatrician to record the presence of a malformation in her/his notes. The most common abnormalities with delayed detection were mild heart defects, such as atrial septal defects.

Conclusion: These findings emphasize the importance in a newborn malformations surveillance program of continued follow up in the first days of life, especially in small, premature infants. Birth Defects Research 110:142-147, 2018. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdr2.1096DOI Listing
January 2018

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

Birth Defects Res 2018 01 29;110(2):122-127. Epub 2017 Jul 29.

Active Malformations Surveillance Program, Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Hypospadias is more common among male infants with growth restriction, defined as a birth weight less than the 10 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.
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http://dx.doi.org/10.1002/bdr2.1087DOI Listing
January 2018

Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism.

Birth Defects Res 2017 Aug 21;109(14):1134-1143. Epub 2017 Jun 21.

The Medical Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts.

Background: Valproic acid (VPA) is the most teratogenic anticonvulsant drug in clinical use today. Children exposed prenatally to VPA have previously been shown to have dysmorphic craniofacial features, identified subjectively but not by anthropometric methods. Exposure to VPA has also been associated with an increased frequency of autism spectrum disorder (ASD). An increased cephalic index (the ratio of the cranial lateral width to the cranial anterior-posterior length) has been observed in children with ASD.

Methods: Forty-seven children exposed to VPA during the first trimester of pregnancy were evaluated for dysmorphic facial features, identified subjectively and by measurements. Each VPA-exposed child was evaluated for ASD using the Social Communication Questionnaire, Autism Diagnostic Interview-Revised, and Autism Diagnostic Observation Schedule. The same physical examination was carried out on an unexposed comparison group of 126 children. The unexposed children also had testing for cognitive performance by the Wechsler Intelligence Scale for Children.

Results: Several dysmorphic craniofacial features, including telecanthus, wide philtrum, and increased length of the upper lip were identified subjectively. Anthropometric measurements confirmed the increased intercanthal distance and documented additional findings, including an increased cephalic index and decreased head circumference/height index. There were no differences between the craniofacial features of VPA-exposed children with and without ASD.

Conclusion: An increased frequency of dysmorphic craniofacial features was identified in children exposed to VPA during the first trimester of pregnancy. The most consistent finding was a larger cephalic index, which indicates a disproportion of increased width of the skull relative to the shortened anterior-posterior length. Birth Defects Research 109:1134-1143, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdr2.1052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555794PMC
August 2017

Detecting congenital malformations - Lessons learned from the Mpepu study, Botswana.

PLoS One 2017 24;12(3):e0173800. Epub 2017 Mar 24.

Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.

Introduction: A large and increasing number of HIV-infected women are conceiving on antiretroviral treatment (ART). While most antiretrovirals are considered safe in pregnancy, monitoring for rare pregnancy and infant adverse outcomes is warranted.

Methods: We conducted a retrospective secondary analysis nested within a clinical trial of infant cotrimoxazole vs. placebo prophylaxis in Botswana (the Mpepu Study). Infants were examined at birth, and at least every 3 months through 18 months of age. Abnormal physical findings and diagnostic testing revealing malformations were documented. Post hoc, a geneticist classified all reported malformations based on available documentation. Structural malformations with surgical, medical or cosmetic importance were classified as major malformations. We present a descriptive analysis of identified malformations.

Results: Between 2011 and 2014, 2,933 HIV-infected women who enrolled in the Mpepu study delivered 2,971 live-born infants. Study staff conducted 2,944 (99%) newborn exams. One thousand eighty-eight (38%) women were taking ART at conception; 1,147 (40%) started ART during pregnancy; 442 (15%) received zidovudine monotherapy; and 223 (7%) received no antiretroviral during pregnancy. Of 33 reported anomalies, 25 (76%) met congenital malformations criteria, 10 (30%) were classified as major malformations, 4 (40%) of which were identified after the birth exam.

Discussion: Our results highlight the importance of staff training on identification of congenital malformations, programmatic monitoring beyond the birth examination and the value of geneticist involvement in the malformations classification process in resource-limited settings. These elements will be important to fully define antiretroviral drug safety in pregnancy.

Significance: Surveillance systems for monitoring the safety of antiretroviral use during pregnancy among HIV-infected women in resource-limited setting are lacking. The World Health Organization's published programmatic recommendations for such surveillance systems represents the gold standard. We employed data from a clinical trial in Botswana, a country with a generalized HIV epidemic and high antiretroviral uptake by HIV-infected women, to highlight practical opportunities to strengthen congenital malformation surveillance systems in these settings where over 1 million HIV infected pregnant women reside.

Trial Registration: Clinical Trials.gov NCT01229761.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173800PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365099PMC
August 2017

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

Birth Defects Res A Clin Mol Teratol 2016 Aug 26;106(8):659-66. Epub 2016 Apr 26.

Active Malformations Surveillance Program, Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1002/bdra.23510DOI Listing
August 2016

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

Neurotoxicol Teratol 2016 Mar-Apr;54:5-14. Epub 2016 Jan 12.

MassGeneral Hospital for Children, United States; University of Massachusetts, Boston, United States; Brigham and Women's Hospital, United States.

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.
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http://dx.doi.org/10.1016/j.ntt.2016.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340722PMC
December 2016

Triploidy: Variation of Phenotype.

Am J Clin Pathol 2016 Jan;145(1):86-95

From the Medical Genetics Unit, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

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.
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http://dx.doi.org/10.1093/ajcp/aqv012DOI Listing
January 2016

Effects of gestational age at enrollment in pregnancy exposure registries.

Pharmacoepidemiol Drug Saf 2015 Apr 20;24(4):343-52. Epub 2015 Feb 20.

Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.

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.
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April 2015

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

Prenat Diagn 2015 Mar 29;35(3):254-7. Epub 2014 Dec 29.

Medical Genetics Unit, MassGeneral Hospital for Children, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

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.
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http://dx.doi.org/10.1002/pd.4534DOI Listing
March 2015
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