Specific Pattern Of Malformations Research Articles

Reproductive Safety of Lurasidone and Quetiapine: Update from the National Pregnancy Registry for Psychiatric Medications.

Background: Second-generation antipsychotics (SGAs), also called atypical antipsychotics, are common therapies for women with a spectrum of psychiatric disorders. No systematically ascertained human reproductive safety data are available for lurasidone, and prospective data for quetiapine are limited, making decisions regarding use of these medications during pregnancy complicated. Materials and Methods: The National Pregnancy Registry for Psychiatric Medications is a prospective cohort study designed to collect reproductive safety data relative to SGAs. Pregnant women aged 18-45 years, with psychiatric illness and prenatal psychotropic medication exposure completed three phone interviews during pregnancy and the postpartum period. Cases of presumed malformations are abstracted from medical records for adjudication by a teratologist blinded to medication exposure. Results: Of 2,293 women enrolled at the time of analysis, 134 in the lurasidone group, 264 in the quetiapine group, and 886 controls completed the postpartum interview and were therefore eligible for inclusion. Dropped or lost-to-follow-up participants (13%) and those currently pregnant were excluded. Participants were predominantly White, college-educated, and married (lurasidone = 88.1%, 76.9%, 77.6%; quetiapine = 89.8%, 71.2%, 75.0%; controls = 92.7%, 86.7%, 89.1%). Absolute risks of major malformations were 2.19% (lurasidone), 1.85% (quetiapine), and 1.77% (controls). Odds ratios comparing lurasidone and quetiapine with controls were 1.24 (95% confidence interval [CI] = 0.36-4.32) and 1.04 (95% CI = 0.38-2.85), respectively. Conclusions: No specific patterns of malformations were observed in infants exposed to the medications of interest. Lurasidone and quetiapine did not appear to be major teratogens, but further information is needed to refine risk estimates. Food and Drug Administration guidance underscores the importance of pregnancy registries. Clinical trial number: NCT01246765.

First trimester COVID-19 and the risk of major congenital malformations-International Registry of Coronavirus Exposure in Pregnancy.

There is limited information about the effects of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection during the first trimester of pregnancy on the risk of major congenital malformations (MCMs). The International Registry of Coronavirus Exposure in Pregnancy (IRCEP) was designed to estimate the relative risk of adverse perinatal outcomes among women with Coronavirus Disease 2019 (COVID‐19) at specific times during gestation. Adult women were eligible to enroll if they had a SARS‐CoV‐2 test, regardless of the results, or clinically confirmed COVID‐19 during pregnancy. Self‐administered questionnaires collected data on SARS‐CoV‐2 infection, pregnancy outcomes (including detailed questions on MCMs), and potential confounders. The analysis of MCMs includes women with either a positive SARS‐CoV‐2 PCR test or a clinical diagnosis of COVID‐19 during the first trimester (exposed group) or a negative SARS‐CoV‐2 test (reference) that enrolled while pregnant. Sensitivity analyses were restricted to participants who enrolled before the availability of informative prenatal screening tests and extended to those enrolled after end of pregnancy. Generalized linear models were used to estimate relative risks (RR) and 95% confidence intervals (CI). Of 17,163 participants enrolled between June 2020 and July 2021, 1727 had a SARS‐CoV‐2 infection during the first trimester, of whom 1,675 enrolled during pregnancy. Of 10,235 controls with a negative test during pregnancy, 4,172 enrolled during pregnancy. Restriction to participants with complete follow‐up reduced the sample size to 92 exposed and 292 unexposed reference pregnancies. MCMs were reported in 3 (3.3%) exposed and 8 (2.7%) unexposed (RR 1.2; 95% CI 0.32–4.2) newborns. The RR was 2.5 (95%CI 0.23–27) among those enrolled before prenatal screening, and 2.2 (95%CI 0.89–5.3) in the overall study population including those enrolled post‐pregnancy. No specific pattern of malformations was observed. Although results are compatible with no major teratogenic effects associated with maternal SARS‐CoV‐2 infection, RR estimates were imprecise and larger studies are warranted.

Zonisamide safety in pregnancy: Data from the UK and Ireland epilepsy and pregnancy register

BackgroundAnimal data suggest teratogenic effects with zonisamide use and risk of pregnancy losses. Human data following zonisamide exposure are presently limited, but suggest low risk of malformation with elevated risk of low birth weight. ObjectiveTo calculate the major congenital malformation (MCM) rate of zonisamide in human pregnancy and assess for a signal of any specific malformation pattern and associations with birth weight. Methods and materialsData were obtained from the UK and Ireland Epilepsy and Pregnancy register (UKIEPR) which is an observational, registration, and follow up study from December 1996 to July 2020. Eligibility criteria were use of zonisamide and to have been referred to the UKIEPR before the outcome of the pregnancy was known. Primary outcome was evidence of MCM. ResultsFrom December 1996 through July 2020 there were 112 cases of first trimester exposure to zonisamide, including 26 monotherapy cases. There were 3 MCM for monotherapy cases (MCM rate 13.0% (95% confidence interval 4.5–32.1)), and 5 MCM for polytherapy cases (MCM rate 6.9% (95% confidence interval 3.0–15.2)). While the median birth weight was on 71st and 44th centile for monotherapy and polytherapy cases respectively, there was a high rate of infants born small for gestational age (21% for both). ConclusionThese data raise concerns about a signal for potential teratogenicity with zonisamide in human pregnancy. Given the low numbers reported, further data will be required to adequately counsel women who use zonisamide in pregnancy.

Sella Turcica Morphology in Patients With Genetic Syndromes: Protocol for a Systematic Review.

BackgroundThe sella turcica is an important anatomical reference used in orthodontics and the evaluation of craniofacial growth. Studies have found an association between variations in sella turcica morphology in patients with certain syndromes affecting the craniofacial complex. It is hypothesized that each related syndrome or pathological condition is associated with a specific pattern of malformation of the sella turcica.ObjectiveThis study outlines the protocol for a systematic review that aims to determine if genetic syndromes involving the craniofacial complex are associated with abnormal radiographic sella turcica morphology and if there is a pattern of malformation that is consistent with each syndrome.MethodsAn electronic database search was conducted using a planned search strategy to identify relevant studies. We included primary studies evaluating the morphology of the sella turcica based on imaging from a lateral view. Specifically, only studies with postnatal human participants with genetic syndromes involving the craniofacial complex were included in this review. We placed no restrictions on the language or time frame of these studies. Based on the search findings, studies were further screened for relevance and eligibility by two independent reviewers. Data were extracted from the selected studies. We assessed the selected studies for risk of bias and quality by using risk of bias tools from the Joanna Briggs Institute. We will provide a narrative synthesis of our findings and a structured summary based on prespecified themes.ResultsThe protocol is registered with PROSPERO (#CRD42019148060) and approved by the University of Western Cape Biomedical Science Research Ethics Committee (BM205/3). The literature search was conducted in September 2019 and updated in July 2020. The study was completed in August 2020, and the findings will be published in an open-access journal.ConclusionsThe results of this systematic review are expected to provide a comprehensive list of morphological variations of the sella turcica, which will aid in the identification of syndromes associated with the craniofacial complex. We also expect to identify patterns of sella turcica morphology that highlight genotype-phenotype correlations, thus adding to the body of evidence relating to genetics and craniofacial malformations.Trial RegistrationPROSPERO International Prospective Register of Systematic Reviews CRD42019148060; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=148060International Registered Report Identifier (IRRID)RR1-10.2196/16633

Update on the gestational effects of maternal hyperthermia.

I plan to review the types of defects caused by gestational hyperthermia. Hyperthermia-induced malformations in animals and humans involve many organs and structures, particularly the central nervous system, as well as other defects. The type of defect is related to the timing of the hyperthermic insult, and the underlying mechanisms include cell death, membrane disruption, vascular disruption, and placental infarction. Review of recent epidemiologic studies (2005-2020) has confirmed an association between gestational hyperthermia and birth defects. There are strong associations between neural tube defects and maternal fever, and other studies have demonstrated associations between first trimester hyperthermia and an increased risk for cardiovascular defects, oral clefts, isolated congenital ear defects, cataracts, hypospadias, renal anomalies, possibly anorectal malformations, and congenital anomalies in general, suggesting that this association between maternal hyperthermia and birth defects in humans is causal. The first prospective evaluation of maternal fever was reported in 1998, and this study confirmed findings from previous case-control studies and case series regarding the magnitude and duration of elevated maternal body temperature in relation to an increased risk for neural tube defects as well as a specific pattern of malformation. The consistency of findings across these different study designs supports the causal nature of the relationship between maternal fever and specific birth defects. This review summarizes the recent human evidence documenting the gestational effects of maternal hyperthermia.

Pharmacological Approach to Managing Childhood-Onset Systemic Lupus Erythematosus During Conception, Pregnancy and Breastfeeding.

Pediatric patients often have poor pregnancy outcomes. Systemic lupus erythematosus predominantly impacts women in their second to fourth decade of life, with childhood-onset disease being particularly aggressive. Reproductive issues are an important clinical consideration for pediatric patients with systemic lupus erythematosus (SLE), as maintaining good disease control and planning a pregnancy are important for maternal and fetal outcomes. In this clinical review, we will consider the safety of medications in managing childhood-onset SLE during conception, pregnancy, and breastfeeding. The developing fetus is at highest risk for teratogenicity from maternal medications during the period of critical organogenesis, which occurs between the first 3-8weeks following conception. Medications known to be teratogenic, leading to a specific pattern of malformations, include mycophenolic acid, methotrexate, and cyclophosphamide. These should be discontinued prior to a planned pregnancy or as soon as pregnancy is suspected. Hydroxychloroquine is safe and should be continued throughout pregnancy and breastfeeding in those without contraindications to it. Azathioprine and calcineurin inhibitors are felt to be compatible with pregnancy in usual doses and may be used prior to and throughout pregnancy and lactation. Non-fluorinated corticosteroids including methylprednisolone and prednisone are inactivated by the placenta and can be used if needed for maternal indication during gestation. Addition of aspirin may be considered around the 12th week of gestation for prevention of pre-eclampsia. Illustrative cases are presented that demonstrate management of adolescents with childhood-onset SLE through conception, pregnancy, and breastfeeding.

Misoprostol exposure during the first trimester of pregnancy: Is the malformation risk varying depending on the indication?

ObjectiveTo report the prospective follow-up of pregnancies exposed to misoprostol during the first trimester and analyse the teratogenic risk depending on the indication for use. Study designProspective observational study of 265 women exposed to misoprostol during the first 12 weeks of pregnancy and followed until the delivery. Women were included if they or their physician had contacted a French pharmacovigilance centre before 22 weeks of gestation (WG) to obtain information on the risk of misoprostol exposure, and if there had been misoprostol exposure before 13 WG. Data were collected at the time of the first contact, and the pregnancy outcome was recorded at follow-up. Women were prospectively enrolled from January 1988 to December 2013. ResultsThe main indication for misoprostol was voluntary abortion (60.9%). Ten major malformations (5.5%) (95% CI 2.65–9.82%) were reported and five of them were consistent with the pattern of malformations attributed to misoprostol: Möbius sequence, hydrocephalus, terminal transverse limb reduction associated with a clubfoot, syndactyly, and complete posterior encephalocele. The rate of malformations was higher, but not significantly, in women exposed to misoprostol for voluntary abortion (7.9%) compared with women exposed to misoprostol for other or unknown indications (3.2%). ConclusionsOur results confirmed a specific pattern of malformations due to misoprostol use in early pregnancy, even with low dose of misoprostol. Despite the small number of cases, we observed a higher proportion of major malformations in fetuses born to women who continued their pregnancy after a failed voluntary abortion with misoprostol. Further studies should be conducted to evaluate other potential factors, such as combination treatment with mifepristone and the socio-environmental characteristics in this group of women.

Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study.

BackgroundPatients with multiple sclerosis (MS) or Crohn’s disease (CD) being treated with natalizumab (Tysabri®, Biogen) who are planning to become pregnant or discover they are pregnant after exposure to natalizumab are currently advised to balance the potential benefits and potential risks of exposure when considering treatment options. This study was undertaken to evaluate pregnancy outcomes of women with MS or CD who were exposed to natalizumab at any time within 3 months prior to conception or during pregnancy. A pregnancy registry was created to better understand the effect of natalizumab exposure on pregnancy outcomes.MethodsThe Tysabri Pregnancy Exposure Registry was a global, observational exposure registration and follow-up study. Evaluations included spontaneous abortions (<22 weeks gestational age), fetal losses (≥22 weeks gestational age), ectopic pregnancies, elective or therapeutic terminations, stillbirths, birth defects, and live births. Birth defects were reviewed and coded in accordance with the Metropolitan Atlanta Congenital Defects Program (MACDP) classification of birth defects.ResultsA total of 369 patients with MS and 7 patients with CD were enrolled prospectively, of whom 355 patients (99.4 %; 349 MS and 6 CD) had known pregnancy outcomes (including 8 twin sets). The spontaneous abortion rate was 9.0 % (n = 32; 95 % confidence interval [C. I.], 6.3–12.5 %). An independent advisory committee review determined the major birth defect rate to be 5.05 % (16 of 316 live births + 1 elective abortion; 95 % C. I., 2.9–8.1 %). The mean gestational age of the live-born infants was 38.3 weeks, and the mean birth weight was 3158.3 g.ConclusionsAlthough the overall rate of birth defects was higher than that observed by the MACDP, these registry outcomes showed no specific pattern of malformations that would suggest a drug effect, and the spontaneous abortion rate was consistent with that of the general population.Trial registrationClinicalTrials.gov NCT00472992 (11 May 2007).

Associated congenital anomalies among cases with Down syndrome

Down syndrome (DS) is the most common congenital anomaly widely studied for at least 150 years. However, the type and the frequency of congenital anomalies associated with DS are still controversial. Despite prenatal diagnosis and elective termination of pregnancy for fetal anomalies, in Europe, from 2008 to 2012 the live birth prevalence of DS per 10,000 was 10. 2. The objectives of this study were to examine the major congenital anomalies occurring in infants and fetuses with Down syndrome. The material for this study came from 402,532 consecutive pregnancies of known outcome registered by our registry of congenital anomalies between 1979 and 2008. Four hundred sixty seven (64%) out of the 728 cases with DS registered had at least one major associated congenital anomaly. The most common associated anomalies were cardiac anomalies, 323 cases (44%), followed by digestive system anomalies, 42 cases (6%), musculoskeletal system anomalies, 35 cases (5%), urinary system anomalies, 28 cases (4%), respiratory system anomalies, 13 cases (2%), and other system anomalies, 26 cases (3.6%). Among the cases with DS with congenital heart defects, the most common cardiac anomaly was atrioventricular septal defect (30%) followed by atrial septum defect (25%), ventricular septal defect (22%), patent ductus arteriosus (5%), coarctation of aorta (5%), and tetralogy of Fallot (3%). Among the cases with DS with a digestive system anomaly recorded, duodenal atresia (67%), Hirschsprung disease (14%), and tracheo-esophageal atresia (10%) were the most common. Fourteen (2%) of the cases with DS had an obstructive anomaly of the renal pelvis, including hydronephrosis. The other most common anomalies associated with cases with DS were syndactyly, club foot, polydactyly, limb reduction, cataract, hydrocephaly, cleft palate, hypospadias and diaphragmatic hernia. Many studies to assess the anomalies associated with DS have reported various results. There is no agreement in the literature as to which associated anomalies are most common in cases with DS with associated anomalies. In this study we observed a higher percentage of associated anomalies than in the other reported series as well as an increase in the incidence of duodenal atresia, urinary system anomalies, musculoskeletal system anomalies, and respiratory system anomalies, and a decrease in the incidence of anal atresia, annular pancreas, and limb reduction defects. In conclusion, we observed a high prevalence of total congenital anomalies and specific patterns of malformations associated with Down syndrome which emphasizes the need to evaluate carefully all cases with Down syndrome for possible associated major congenital anomalies.

Pregnancy Outcomes Following In Utero Exposure to Second-Generation Antipsychotics: A Systematic Review and Meta-Analysis.

Second-generation antipsychotics (SGAs) are increasingly used for a variety of mental illnesses; however, the data regarding the safety of these medications during pregnancy are inconclusive and contradictory. We examined the risk of adverse pregnancy outcomes associated with in utero exposure to SGAs by conducting a systematic review and meta-analysis. We searched the databases EMBASE and MEDLINE from January 1990 to December 2014. Eligible studies had to report pregnant women who took SGAs during pregnancy (first trimester exposure if analyzing congenital malformations), follow a healthy comparison group in a similar manner, and report data on pregnancy outcomes. There was no restriction on language, sample size, or publication date. The primary outcome analyzed was major congenital malformations, and secondary outcomes included miscarriages, stillbirths, preterm births, small or large for gestational age neonates, and differences in gestational ages and birth weights. A total of 12 studies met our inclusion criteria, totalling 1782 cases and 1,322,749 controls. The use of SGA during the first trimester of pregnancy was associated with a significant increased risk for major congenital malformations (odds ratio, 2.03; 95% confidence interval, 1.41-2.93); however, no specific pattern of malformations was found. An increased risk was also found for preterm births (odds ratio, 1.85; 95% CI, 1.20-2.86). The use of SGA during pregnancy was not found to be associated with an increased risk for secondary outcomes analyzed. The absence of a specific pattern of malformations makes it difficult to identify an explicit risk posed by SGAs, and therefore, further studies sufficiently controlling for confounding factors are needed to validate these findings.

No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study

There is increasing awareness of the potential impact of paternal exposures on pregnancy outcome. In particular this applies to MTX, which is used in low doses for the treatment of RA and other inflammatory diseases. MTX is associated with a specific pattern of malformations in fetuses of exposed women, but there is uncertainty concerning the risk of paternal low-dose MTX. The aim of this study was to investigate whether paternal low-dose MTX therapy around conception has an unfavourable effect on pregnancy outcome. We performed a prospective observational cohort study involving pregnancies fathered by men who were treated with low-dose MTX around conception. Pregnancies were identified through our Teratology Information Service. Pregnancy outcomes were compared with a cohort neither exposed to MTX nor to other teratogens. Outcomes evaluated were major birth defects, spontaneous abortion (SAB), elective termination of pregnancy, gestational age at delivery, and birth weight. A total of 113 pregnancies with paternal low-dose MTX treatment were compared with 412 non-exposed pregnancies. Neither the rate of major birth defects [odds ratio (OR) 1.02, 95% CI 0.05, 7.0) nor the risk of SAB (hazard ratio 1.19, 95% CI 0.65, 2.17) was increased. Gestational age at delivery and birth weights did not differ significantly between groups. The rate of electively terminated pregnancies was increased in the MTX-exposed patients compared with controls. Our study does not confirm an increased risk of adverse pregnancy outcome after paternal low-dose MTX therapy. The reassuring findings do not support the necessity of a 3-month MTX-free interval until conception. In the case of unavoidable paternal MTX therapy, it seems reasonable not to postpone family planning.

Antidepressant Use in Pregnant and Postpartum Women

Women in their reproductive years are at risk of experiencing depressive and anxiety disorders. As such, it is likely that pregnant women will undergo treatment with antidepressants. We review the risk of adverse birth outcomes and neonatal complications subsequent to antidepressant use in pregnancy. An inconsistent literature shows that antidepressant exposure is associated with shortened gestations and diminished fetal growth; these effects are small. Transitory neonatal signs are seen in some neonates after exposure to antidepressants in utero. No specific pattern of malformations has been consistently associated with antidepressants, with the possible exception of paroxetine and cardiac malformations. There is inconclusive evidence of a link between antidepressants in late pregnancy and persistent pulmonary hypertension in the newborn. Extensive study finds that antidepressants cannot be considered major teratogens. It is likely that confounding factors contribute to a number of the adverse effects found to be associated with antidepressant use in pregnancy.

English

INTRODUCTION: Congenital anomalies of gastrointestinal tract occur from oesophagus upto anorectum as a result of abnormal embryogenesis. Specific patterns of malformations of gastrointestinal tract include stenosis and atresia, duplications, abnormal rotation and fixation, abdominal defects and others associated with persistence of embryonic structures (e.g. Meckel's diverticulum), or abnormalities in its cellular components (e.g. nerves in Hirschsprung's disease). These disorders primarily result in symptoms of intestinal obstruction, effects on surrounding structures or of associated anomalies. Early diagnosis is therefore very vital. AIM: To study the clinical presentation, radiological features, gross and histopathology of congenital anomalies of G.I.T. MATERIAL AND METHODS: Surgical specimens collected were sent to the department of pathology for gross and histopathological confirmation of diagnosis. The specimens were processed routinely and H & E stained slides studied. RESULTS: Out of 2996 specimens, 286 were found to be of congenital anomalies of G.I.T. With a sex ratio of 3:1Hirschsprung's disease was commonest 50.34%, Omphalomesenteric duct remnants 16.78%, followed by intestinal atresia 10.13% CONCLUSION: Congenital anomalies of gastrointestinal tract are a cause of significant mortality and Morbidity in paediatric age group. Though radiodiagnosis is the preliminary diagnostic modality, gross and histopathological examinations are essential to confirm the diagnosis.

Sella turcica morphology and the pituitary gland—a new contribution to craniofacial diagnostics based on histology and neuroradiology

The present review summarizes two decades of published and unpublished studies on normal and pathological development of sella turcica and pituitary gland in humans. The pathological conditions are studied in known genotype deviations, syndromes, and other malformations. The studies include histological analyses of human prenatal material and profile radiographic analyses of human postnatal material, supplemented in a few cases with neuroradiology. Prenatal and postnatal results are compared. Similarities between prenatal and postnatal deviations in sella turcica morphology were demonstrated. Malformations in the pituitary gland were observed in several cases. For diagnostic purposes, the review distinguishes between deviations in the anterior wall and in the posterior wall of the sella turcica. Deviations in the anterior wall seem to be associated with deviations specifically in the frontonasal developmental field, while deviations in the posterior wall are often connected with malformations in the posterior structures, e.g. the cerebellum. In normal cases, minor variations in morphology are observed. In each pathological case, a specific malformation pattern was observed in sella turcica morphology, varying from mild to severe phenotype. The malformation in the sella turcica/pituitary gland can be associated with a malformation within a developmental field that forms the craniofacial region (frontonasal, maxillary, palatal, and mandibular fields), sometimes also involving the brain stem, thymus, thyroid, and heart (velocardiofacial syndrome). Pathological sella turcica morphology can also be associated with malformations in the cerebellum and larynx (Cri-du-Chat syndrome). This review demonstrates the value of combining profile radiographic diagnostics with neuroradiological diagnostics in cases with malformed sella turcicae.

Multiple sclerosis and pregnancy: therapeutic considerations

For women with multiple sclerosis (MS) who become pregnant, the risks and benefits of ongoing therapy for the health of both the mother and the fetus must be carefully considered. Based on a literature review and our MS center's standard practices, we provide guidance to aid clinical decision making in the absence of clear evidence-based clinical practice guidelines. Women seeking to achieve pregnancy should generally discontinue disease-modifying therapy use prior to attempting conception. For example, the immunosuppressant mitoxantrone is teratogenic and should be prescribed only with the assurance of effective contraception. Conception should be discouraged for patients on fingolimod, because of the limited information available on human pregnancy outcomes. Current evidence, including data from pregnancy registries for glatiramer acetate (GA), interferon beta-1a (IFNβ-1a), and natalizumab, has not shown specific patterns of malformations suggesting teratogenicity. Pregnancy registry data have not been published for IFNβ-1b. During breastfeeding, intravenous immunoglobulin and corticosteroids are generally safe and may be associated with a reduction in postpartum relapses; however, a washout period is recommended between corticosteroid administration and the resumption of breastfeeding. Clinical data on the use of IFNβ, GA, and natalizumab during lactation are limited. Mitoxantrone is contraindicated during breastfeeding, and fingolimod should be avoided in nursing mothers, because of a lack of data.

Immunosuppressive Drugs and Pregnancy: Mycophenolate Mofetil Embryopathy

Mycophenolate mofetil (MMF) and its active metabolite mycophenolic acid (MPA) are both very effective immunosuppressive agents widely used for the prevention of organ rejection following transplantation and in the therapy of autoimmune diseases. In experimental studies performed in pregnant animals, MMF exhibited teratogenicity, which later was confirmed in humans, as documented in the United States National Transplantation Pregnancy Registry (NTPR). In 2008, a specific pattern of malformations associated with in utero exposure to MMF was suggested. Subsequently, numerous reports in the scientific literature of newborns having similar patterns of malformations born to mothers who had undergone transplantation and were receiving immunosuppressive therapy provided supporting evidence for the existence of a specific MMF embryopathy. The most consistent characteristics of the MMF embryopathy phenotype include cleft lip and palate, microtia and aural atresia, and ocular anomalies (hypertelorism, arching eyebrows). Perinatal clinicians should be aware of the potential teratogenicity of MMF. Importantly, effective contraception measures should be recommended to fertile women who have received transplants before they become pregnant. Given the cumulative effect of MMF, contraceptive measures should be continued for at least 6 months after discontinuing MMF therapy.

Extending the phenotype of monosomy 1p36 syndrome and mapping of a critical region for obesity and hyperphagia

Rearrangements of 1p36 are the most frequently detected abnormalities in diagnostic testing for chromosomal cryptic imbalances and include variably sized simple terminal deletions, derivative chromosomes, interstitial deletions, and complex rearrangements. These rearrangements result in the specific pattern of malformation and neurodevelopmental disabilities that characterizes monosomy 1p36 syndrome. Thus far, no individual gene within this region has been conclusively determined to be causative of any component of the phenotype. Nor is it known if the rearrangements convey phenotypes via a haploinsufficiency mechanism or through a position effect. We have used multiplex ligation-dependent probe amplification to screen for deletions of 1p36 in a group of 154 hyperphagic and overweight/obese, PWS negative individuals, and in a separate group of 83 patients initially sent to investigate a variety of other conditions. The strategy allowed the identification and delineation of rearrangements in nine subjects with a wide spectrum of clinical presentations. Our work reinforces the association of monosomy 1p36 and obesity and hyperphagia, and further suggests that these features may be associated with non-classical manifestations of this disorder in addition to a submicroscopic deletion of approximately 2-3 Mb in size. Multiplex ligation probe amplification using the monosomy 1p36 syndrome-specific kit coupled to the subtelomeric kit is an effective approach to identify and delineate rearrangements at 1p36.

Associated malformations in patients with esophageal atresia

Esophageal atresia is a common type of congenital malformation. The etiology of esophageal atresia is unclear and its pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with esophageal atresia, we conducted this study in a geographically well-defined population, evaluating the birth prevalence of esophageal atresia and associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 99 patients with esophageal atresia, 46 (46.5%) had associated malformations. These included patients with chromosomal abnormalities (8 patients, 8%); non-chromosomal recognized syndromes (4 patients), including one each CHARGE syndrome, Fanconi anemia, Fryns syndrome, and Opitz G/BBB syndrome; associations including VACTERL (10 patients), and one schisis; one oculo-auriculo-vertebral spectrum; one malformation complex, a sirenomelia, and non-syndromic multiple congenital anomalies (MCA) (21 patients, 21%). Malformations of the cardiovascular system (24%), urogenital system (21%), digestive system (21%), musculoskeletal system (14%), and central nervous system (7%) were the most common other congenital malformations occurring in patients with esophageal atresia and non-syndromic MCA. We observed a high prevalence of total malformations and specific patterns of malformations associated with esophageal atresia which emphasizes the need to evaluate all patients with esophageal atresia for possible associated malformations. The malformations associated with esophageal atresia could be classified into a recognizable malformation syndrome or pattern in 25 out of 46 patients (54%).

Review of published studies of kidney, liver, and gastrointestinal birth defects in fetal alcohol spectrum disorders

Review of published studies of birth defects of the renal, liver, and gastrointestinal organ systems in subjects with fetal alcohol spectrum disorders (FASD). We searched PubMed (http://www.pubmed.gov) using the following terms: fetal alcohol syndrome and: gastrointestinal tract, kidney, liver, and congenital abnormalities for all years and English only citations. We located 12 studies of FASD and defects of or functional impairments for the liver, 12 of renal abnormalities, and only two with gastrointestinal defects. We did not identify specific patterns of malformations or functional deficits for any of the three organ systems. The existing literature suggests a series of nonspecific outcomes in FASD. Fetal alcohol spectrum disorder includes a diagnostic category of alcohol-related birth defects which is clinically difficult to apply. This study adds to the existing literature on birth defects in FASD which is still very limited. The categorical diagnosis of alcohol-related birth defects requires additional research to determine if a specific pattern of organ specific abnormalities or functional deficits emerges in subjects with FASD.

Omphalocele and gastroschisis and associated malformations

The etiology of gastroschisis and omphalocele is unclear and their pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with omphalocele and gastroschisis, we assessed these associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 86 patients with omphalocele, 64 (74.4%) had associated malformations. These included patients with chromosomal abnormalities (25, 29.0%); non-chromosomal syndromes including Beckwith-Wiedemann syndrome, Goltz syndrome, Marshall-Smith syndrome, Meckel-Gruber syndrome, Oto-palato-digital type II syndrome, CHARGE syndrome, and fetal valproate syndrome; malformation sequences, including ectopia cordis, body stalk anomaly, exstrophy of bladder, exstrophy of cloaca, and OEIS (Omphalocele, Exstrophy of bladder, Imperforate anus, Spinal defect); malformation complexes including Pentalogy of Cantrell, and non-syndromic multiple congenital anomalies (MCA) (26, 30.2%). Malformations of the musculoskeletal system (31, 23.5%), urogenital system (27, 20.4%), cardiovascular system (20, 15.1%), and central nervous system (12, 9.1%) were the most common other congenital malformations in patients with omphalocele and non-syndromic MCA. Of the 60 patients with gastroschisis, 10 (16.6%) had associated malformations. In contrast to omphalocele, gastroschisis was rarely associated with a complex pattern of malformation, that is, one each (1.7%) with a chromosomal abnormality (trisomy 21), sequence (amyoplasia congenita), unspecified dwarfism, and 7 (11.7%) with MCA. We observed a striking difference in the prevalence of total malformations (74.4% vs. 16.6%, P < 0.001) and specific patterns of malformations associated with omphalocele and gastroschisis which emphasizes the need to evaluate all patients with omphalocele and gastroschisis for possible associated malformations. Malformation surveillance programs should be aware that the malformations associated with omphalocele can be often classified into a recognizable malformation syndrome or pattern (44.2%).