Limb Reduction Defects Research Articles

Epidemiological association of cannabinoid- and drug- exposures and sociodemographic factors with limb reduction defects across USA 1989–2016: A geotemporospatial study

BackgroundReports of major limb defects after prenatal cannabis exposure (PCE) in animals and of human populations in Hawaii, Europe and Australia raise the question of whether the increasing use of cannabis in USA might be spatiotemporally associated with limb reduction rates (LRR) across USA. MethodsCongenital anomaly data was from the National Birth Defects Prevention Network, drug use data was taken from the National Survey of Drug Use and Health (NSDUH), cannabinoid concentration was estimated from Federal seizure data and ethnicity and income data were from the US Census bureau. Geotemporospatial analysis was conducted in R. Results436 LRR datapoints were obtained. LRR was significantly associated with cannabis use and tetrahydrocannabinol (THC) exposure and demonstrated prominent cannabis-use quintile effects. A sharp increase in LRR occurred from the fourth to fifth quintiles of cannabis exposure (mean ± S.E.M 3.78 ± 0.38 to 6.66 ± 0.56/10,000 live births, P = 5.22 × 10−9). In final lagged geospatial models adjusted for ethnicity and income interactive terms including cannabinoids were highly significant and robust to adjustment. States in which cannabis was not legalized had a lower LRR (4.28 v 5.01/10,000 live births, relative risk reduction = −0.15, (95%C.I. −0.25, −0.02), P = 0.021). Internationally 37–63% of cases are estimated to not be born alive. Their inclusion in these analyzes uniformly intensified the identified effects and the significance of the effect of the cannabis legalization paradigm rose from P = 0.0256 to P = 0.0146 to P = 0.0048 with silent factors of 0%, 36% and 63%, respectively. ConclusionTherefore a spatiotemporal and dose-dependent association between several cannabinoids including THC and cannabigerol and LRR is reported, is robust to adjustment, is consistent with pathophysiological and preclinical studies, accords with findings elsewhere, is markedly exacerbated in higher exposure quintiles, is exacerbated by cannabis legalization and evidences dose-related intergenerational sequaelae.

Maternal cigarette smoking before or during pregnancy increases the risk of birth congenital anomalies: a population-based retrospective cohort study of 12 million mother-infant pairs

BackgroundThe associations of maternal cigarette smoking with congenital anomalies in offspring have been inconsistent. This study aimed to clarify the associations of the timing and intensity of maternal cigarette smoking with 12 subtypes of birth congenital anomalies based on a nationwide large birth cohort in the USA.MethodsWe used nationwide birth certificate data from the US National Vital Statistics System during 2016–2019. Women reported the average daily number of cigarettes they consumed 3 months before pregnancy and in each subsequent trimester during pregnancy. Twelve subtypes of congenital anomalies were identified in medical records. Poisson regression analysis was used to estimate the risk ratios (RRs) with 95% confidence intervals (CIs) for 12 subtypes of congenital anomalies associated with the timing (i.e., before pregnancy, and during three different trimesters of pregnancy) and intensity (i.e., number of cigarettes consumed per day) of maternal cigarette smoking.ResultsAmong the 12,144,972 women included, 9.3% smoked before pregnancy and 7.0%, 6.0%, and 5.7% in the first, second, and third trimester, respectively. Maternal smoking before or during pregnancy significantly increased the risk of six subtypes of birth congenital anomalies (i.e., congenital diaphragmatic hernia, gastroschisis, limb reduction defect, cleft lip with or without cleft palate, cleft palate alone, and hypospadias), even as low as 1–5 cigarettes per day. The adjusted RRs (95% CIs) for overall birth congenital anomalies (defined as having any one of the congenital malformations above significantly associated with maternal cigarette smoking) among women who smoked 1–5, 6–10, and ≥ 11 cigarettes per day before pregnancy were 1.31 (1.22–1.41), 1.25 (1.17–1.33), and 1.35 (1.28–1.43), respectively. Corresponding values were 1.23 (1.14–1.33), 1.33 (1.24–1.42), 1.33 (1.23–1.43), respectively, for women who smoked cigarettes in the first trimester; 1.32 (1.21–1.44), 1.36 (1.26–1.47), and 1.38 (1.23–1.54), respectively, for women who smoked cigarettes in the second trimester; and 1.33 (1.22–1.44), 1.35 (1.24–1.47), and 1.35 (1.19–1.52), respectively, for women who smoked cigarettes in the third trimester. Compared with women who kept smoking before and throughout pregnancy, women who never smoked had significantly lower risk of congenital anomalies (RR 0.77, 95% CI 0.73–0.81), but women who smoked before pregnancy and quitted during each trimester of pregnancy had no reduced risk (all P > 0.05).ConclusionsMaternal smoking before or during pregnancy increased the risk of several birth congenital anomalies, even as low as 1–5 cigarettes per day. Maternal smokers who stopped smoking in the subsequent trimesters of pregnancy were still at an increased risk of birth congenital anomalies. Our findings highlighted that smoking cessation interventions should be implemented before pregnancy.

Prevalence of Single Umbilical Artery (Isolated and non-isolated) and Its Correlation with Birth Defects and Premature Death

Background: The single umbilical artery (SUA) is linked to congenital abnormalities in almost every organ system, however published findings have been inconsistent. Although It has been proposed that inherited and long-term environmental factors do play a role, there is a need for further investigations on the same. The goal is to look into the possibility of a link between a single umbilical artery (SUA) in the incidence of chromosomal anomalies in the second trimester of pregnancy and their collective occurrence.
 Methods: The exclusion of any one of the two umbilical artery and a present umbilical vein was considered as a single umbilical artery for the purpose of this research. A single umbilical artery was established by gross or histologic investigation of the placenta, neonatal evaluation, or autopsy. As a direct consequence, a newborn who did not have a single umbilical artery documented in these records was presumed to have an umbilical cord consisting of three vessels.
 Results: SUA was identified in 0.46 percent of our population (4241/918 933). SUA risk factors included pregestational diabetes in the mother, consistently high blood pressure, prior Cesarean delivery. Some other factors include smoking, epilepsy, and conception via assisted reproductive technology. SUA was associated with gastrointestinal atresia or stenosis in the neonate, esophageal and anorectal atresia or stenosis followed renal agenesis. SUA was linked to an elevated risk of congenital cardiac abnormalities by up to 7–8 times. There was a link between microcephaly, congenital hydrocephalus. There was a link established between other congenital brain and spinal cord anomalies as well. SUA displayed a lesser relationship with hernia associated with the diaphragm, limb reduction defect. It also showed a smaller relation to cleft lip or cleft palate. The risks of trisomy 13 and 21 were both increased, while the risk of trisomy 18 was maximum. Fetuses diagnosed with SUA, whether or not accompanied with a deformity, had two times the higher potential possibility of SUA in a future pregnancy.
 Conclusion: Single Umbilical Artery is closely linked to gastrointestinal atresia or stenosis, implying the same developmental processes. The higher likelihood of reappearance of Single Umbilical Artery implies that inheritable and/or long-term environmental variables play a role. SUA was shown to have high correlations with trisomies 13 and 18.

Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy.

The identification of thalidomide–Cereblon-induced SALL4 degradation has brought new understanding for thalidomide embryopathy (TE) differences across species. Some questions, however, regarding species variability, still remain. The aim of this study was to detect sequence divergences between species, affected or not by TE, and to evaluate the regulated gene co-expression in a murine model. Here, we performed a comparative analysis of proteins experimentally established as affected by thalidomide exposure, evaluating 14 species. The comparative analysis, regarding synteny, neighborhood, and protein conservation, was performed in 42 selected genes. Differential co-expression analysis was performed, using a publicly available assay, GSE61306, which evaluated mouse embryonic stem cells (mESC) exposed to thalidomide. The comparative analyses evidenced 20 genes in the upstream neighborhood of NOS3, which are different between the species who develop, or not, the classic TE phenotype. Considering protein sequence alignments, RECQL4, SALL4, CDH5, KDR, and NOS2 proteins had the biggest number of variants reported in unaffected species. In co-expression analysis, Crbn was a gene identified as a driver of the co-expression of other genes implicated in genetic, non-teratogenic, limb reduction defects (LRD), such as Tbx5, Esco2, Recql4, and Sall4; Crbn and Sall4 were shown to have a moderate co-expression correlation, which is affected after thalidomide exposure. Hence, even though the classic TE phenotype is not identified in mice, a deregulatory Crbn-induced mechanism is suggested in this animal. Functional studies are necessary, especially evaluating the genes responsible for LRD syndromes and their interaction with thalidomide–Cereblon.

Maternal Risk Factors Associated with Limb Reduction Defects: Data from the Polish Registry of Congenital Malformations (PRCM).

Data from the Polish Registry of Congenital Malformations (PRCM) suggest that the prevalence of limb reduction defects (LRDs) in some Polish regions is significantly higher in comparison to that reported in the European Surveillance of Congenital Anomalies (EUROCAT) registry, but specific risk factors are still unknown. The objectives of this study were two-fold: to detect risk factors linked to isolated LRDs among Polish natives and to search for geospatial clusters of isolated LRDs to identify high-risk areas across the country. Among the 2,939,001 births accounted for in the PRCM, we determined that there were 852 children with distinct LRDs. Our data demonstrate that lower birth weight, prematurity, and maternal smoking history are strongly associated with isolated LRDs. Furthermore, our investigation pointed to various additional risk factors for isolated LRDs, including paternal education, gestational hypertension, upper respiratory tract infections, and exposure to anti-inflammatory drugs in the first trimester of pregnancy. We did not recognize statistically significant spatial or spatiotemporal clusters over the area of Poland using Kulldorff’s scan. Our study strengthens the hypothesis that maternal factors have an integral role in the etiology of isolated LRDs.

Evidence for a cluster of rare birth defects in the Ain department (France).

REMERA (REgistre des Malformations En Rhône-Alpes) is a registry of congenital malformations that covers 58,000 births annually in Central-East France. In 2010, the registry raised an alarm to the health authorities (Santé publique France, SpF) about three cases of a unilateral isolated transverse upper limb reduction defect (UITULRD) in a small subarea; the general prevalence of this defect is one case in 10,000 births. In the following years, more infants were born with the same malformation in the same territory of the Ain department. Public health authorities, supported by an expert committee, rejected the existence of a cluster, but we aim here at providing evidence for this cluster. Geocoded data for all UITULRD cases (ICD-10 codes Q71.2 and Q71.3) were extracted from the REMERA database. We conducted a Kulldorff cluster analysis of these data, using the spatial SaTScanTM algorithm. The analysis found a cluster of eight cases of UITULRD among the 8,204 births occurring between 2009 and 2014 within a circle of 16.24 km radius centered on a village of the Ain department, whereas 0.82 cases were expected under a uniform probability of such a birth throughout the registry territory. This represents an almost 10fold excess over the expected number of cases (p=.0057). The arguments used to deny the cluster are disputed and we present the evidence supporting its reality. The controversy that has followed the alarm has compromised the search for the cause(s) of this excess of rare malformations.

A Broader Perspective on the Prenatal Diagnosis of Cornelia de Lange Syndrome: Review of the Literature and Case Presentation.

Cornelia de Lange syndrome (CDLS) is caused by pathogenic variants in genes which are structural or regulatory components of the cohesin complex. The classical Cornelia de Lange (CDLS) phenotype is characterized by distinctive facial features, growth retardation, upper limb reduction defects, hirsutism, and developmental delay. Non-classical phenotypes make this condition heterogeneous. Although CDLS is a heterogeneous clinical and genetic condition, clear diagnostic criteria have been described by specialist consensus. Many of these criteria refer to features that can be seen on prenatal ultrasound. The aim of this paper is twofold: to present the ultrasound findings in fetuses affected by CDLS syndrome; to discuss the recent advances and the limitations in the ultrasound and genetic prenatal diagnosis of CDLS. Our review aims to offer, apart from the data needed to understand the genetics and the prenatal presentation of the disease, a joint perspective of the two specialists involved in the prenatal management of this pathology: the fetal medicine specialist and the geneticist. To better illustrate the data presented, we also include a representative clinical case.

The Effects of Parent Ages on Birth Defects.

Men and women, in the United States, are having children at considerably older ages. This changing demographic has been associated with multiple neonatal adverse birth outcomes that are currently considered to constitute a major public health crisis. The objective of this study was to evaluate the risk of parent age on birth defects and to provide results that can serve as a starting point for more specific mediation modeling. The modeling estimated the effects of parent age on birth defects controlling for confounding between maternal and paternal age and separated the mediating effect of chromosomal disorders, including Down syndrome. Data containing approximately 15,000,000 birth records were obtained from the United States Natality database for the years 2014 to 2018. A Bayesian modeling approach was used to estimate adjusted risks of parent ages both unadjusted and adjusted for the other parent's age and for the mediational effect of chromosomal disorders, including Down syndrome. Increasing maternal age was associated with increased risks for hypospadias and cyanotic congenital heart disease. Increasing maternal and paternal ages were associated with decreasing risks for gastroschisis. For limb reduction defect, cleft lip and all defects combined, the risk of maternal age was U-shaped with the lowest risks observed at approximately age 35y. Paternal age was not associated with an increase in the birth prevalence of birth defects. Advancing maternal age was associated with increased birth prevalence of hypospadias and cyanotic congenital heart disease and associated with a lower birth prevalence for gastroschisis. Both older and younger maternal ages were related to limb reduction defect and cleft lip. Advancing paternal age was not associated with an increased birth prevalence of birth defects but was associated with a decreased birth prevalence of gastroschisis.

Etiological diagnosis in limb reduction defects and the number of affected limbs: A population-based study in the Northern Netherlands.

Limb reduction defects (LRDs) that affect multiple limbs are considered to be more often heritable, but only few studies have substantiated this. We aimed to investigate if an etiological diagnosis (genetic disorder or clinically recognizable disorder) is more likely to be made when multiple limbs are affected compared to when only one limb is affected. We used data from EUROCAT Northern Netherlands and included 391 fetuses and children with LRDs born in 1981–2017. Cases were classified as having a transverse, longitudinal (preaxial/postaxial/central/mixed), intercalary, or complex LRD of one or more limbs and as having an isolated LRD or multiple congenital anomalies (MCA). We calculated the probability of obtaining an etiological diagnosis in cases with multiple affected limbs versus one affected limb using relative risk (RR) scores and Fisher's exact test. We showed that an etiological diagnosis was made three times more often when an LRD occurred in multiple limbs compared to when it occurred in one limb (RR 2.9, 95% CI 2.2–3.8, p < 0.001). No genetic disorders were found in isolated cases with only one affected limb, whereas a genetic disorder was identified in 16% of MCA cases with one affected limb. A clinically recognizable disorder was found in 47% of MCA cases with one affected limb. Genetic counseling rates were similar. We conclude that reduction defects of multiple limbs are indeed more often heritable. Genetic testing seems less useful in isolated cases with one affected limb, but is warranted in MCA cases with one affected limb.

Associations between cumulative environmental quality and ten selected birth defects in Texas.

Causes of most birth defects are largely unknown. Genetics, maternal factors (e.g., age, smoking) and environmental exposures have all been linked to some birth defects, including neural tube, oral cleft, limb reduction, and gastroschisis; however, the contribution of cumulative exposures across several environmental domains in association with these defects is not well understood. The Environmental Quality Index (EQI) and its domains (air, water, land, sociodemographic, built) were used to estimate county-level cumulative environmental exposures from 2006-2010 and matched to birth defects identified from Texas Birth Defects Registry and live birth records from births in years 2007-2010 (N = 1,610,709). Poisson regression models estimated prevalence ratios (PR) and 95% confidence intervals (CI) for associations between 10 birth defects and the EQI. We observed some positive associations between worst environmental quality and neural tube, anencephaly, spina bifida, oral cleft, cleft palate, cleft lip with and without cleft palate, and gastroschisis [PR range: 1.12-1.55], but near null associations with limb reduction defects. Among domain specific results, we observed the strongest positive associations with the sociodemographic domain across birth defects but varied positive associations among the air and water domains, and negative or null associations with the land and built domains. Overall, few exposure-response patterns were evident. Our results highlight the complexities of cumulative, simultaneous environmental exposures in the prevalence rates of 10 selected birth defects. We were able to explore the impact of overall and domain specific environmental quality on birth defects and identify potential domain specific drivers of these associations.

Major birth defects in the Brazilian side of the triple border: a population-based cross-sectional study

BackgroundMajor birth defects increase the risk of fetal death and pediatric hospitalization, which also impact on healthcare costs. Sociodemographic factors can drastically affect reproductive health and be used to discriminate the exposure to hidden risk factors. Foz do Iguassu is a Brazilian city located in the triple-border region of Brazil / Paraguay / Argentina with high rates of birth defects. However no study aimed to verify factors associated with this incidence or preventive care is reported. The current work investigated the prevalence of major birth defects and its association with maternal sociodemographic factors in Foz do Iguassu.MethodsIn this population-based cross-sectional study we used data of all live births occurred in Foz do Iguassu from 2012 to 2017. The associated sociodemographic variables such as maternal age, maternal education, maternal race, country of residence, maternal parity and onset of prenatal care were analyzed. Each major birth defect was described according to absolute and relative frequencies, Kruskal-Wallis and logistic regression models were used to evaluate variables associated with selected birth defects.ResultsThe most prevalent major birth defects were Cleft Lip and/or Palate (9.5/10,000), gastroschisis (6.93/10,000), spina bifida (5.53/10,000), hydrocephalus (5.53/10,000), hypospadias (4.55/10,000), Down syndrome (4.23/10,000), anencephaly (2.93/10,000), anorectal atresia / stenosis (1.95/10,000), undetermined sex (1.95/10,000), esophageal atresia / stenosis with or without fistula (1.63/10,000) and limb reduction defects (1.30/10,000). Maternal age was associated with gastroschisis and Down syndrome. Only maternal education up to 7 years was statistically associated with major birth defects considering all other sociodemographic variables.ConclusionCleft Lip and/or Palate and Gastroschisis prevalence were higher than those found in the literature. This findings may suggest a distinct epidemiological behavior regarding major birth defects in the region. The work opens new perspectives for birth defects risk factors in the triple-border.

A Case report of Congenital Unilateral Upper and Lower Limb Reduction

Background: Congenital limb reduction defect is a rare condition that is detectable in prenatal ultrasound. The purpose of this study was to report a rare case of congenital unilateral upper and lower limb reduction, which was not detected in prenatal ultrasound. Case report: A primiparous woman was admitted to undergo a cesarean section due to breech presentation. The results of routine blood tests and first-trimester screening were normal. Anomaly ultrasound scan indicated the possibility of midface hypoplasia; however, three-dimensional ultrasound ruled out this condition. Other ultrasound evaluations in the following weeks of pregnancy were indicative of the normal health condition of the fetus. The outcome of the cesarean section was a girl with obvious unilateral shortening of the left limbs. Other associated anomalies included saddle nose, hepatomegaly, ichthyosis, and low-set ears. Conclusion: Congenital limb reduction defect can be detected at an early stage through an anomaly ultrasound scan in the second trimester of pregnancy. It is recommended to allocate sufficient time for an anomaly ultrasound scan, observe all parts of the four fetal limbs, and perform fetal examination in all three coronal, longitudinal, and axial planes.

Congenital limb reduction defects in 1.6 million births in Argentina.

The objectives of this study were to describe the birth prevalence of limb reduction defects (LRD) in Argentina, their clinical features, and to review the literature on this topic. The data source was the National Network of Congenital Anomalies of Argentina, a surveillance system that has been operative since 2009. Data were collected from November 1, 2009 to December 31, 2016. 1,663,610 births and 702 affected patients were registered during this period. The prevalence of LRD was 4.22/10,000 births (CI 95%: 3.93-4.54). In 15,094 stillbirths, prevalence was 30.80/10,000 (CI 95%: 22.31-40.65). Perinatal mortality (stillbirths plus early neonatal deaths) was 24.6%, mostly explained by postnatal deaths. LRD were classified according to different variables, including Gold's anatomic classification. Then, 41.0% of patients had transverse terminal defects and 50.2% had longitudinal defects. We found multiple and syndromic clinical presentation to be associated with both preaxial LRD and lethality. The prevalence of LRD was lower and perinatal mortality was higher in our study compared to that of previously published studies. Because there is heterogeneity in the inclusion and exclusion criteria among publications, a greater effort should be made in order to include similar populations and to use a unified anatomic classification and nomenclature.

Antenatal Diagnosis of Bilateral Proximal Femoral Focal Deficiency (PFFD)

AbstractProximal femoral focal deficiency (PFFD) is a rare skeletal dysplasia, characterized by hypoplasia of the subtrochanteric femur with variable degrees of shortening of the femoral shaft. There are numerous gene e.g. TBX4, FGF, FGFR, TP63 and HOX responsible for limb formation, type and its shape. Normal limb development is three dimensional; proximodistal axis regulated by AER; anteroposterior axis (preaxial/postaxial) governed by SHH with ZPA and dorsoventral axis controlled by LMX1B. Primigravida with diamniotic dichorionic twins in first trimester was found to have absent right femur, fibula and left femural bone with hypoplastic right foot in one foetus. Right tibia, both left tibia and fibula and left foot were visualized normally. Bilateral humerus, radius and ulna along with digits were visualized with no evidence of oligodactyly. Twin II had no major limb reduction defect. Both nasal bones, hard palate were visualized; nuchal translucency was within normal range for the foetus of 13 weeks 3 days of duration; suggestive of bilateral PFFD; Aitken type 4 in Twin I. We are the first to describe bilateral PFFD in the first trimester of pregnancy. Nuchal scan provides a window of opportunity to the foetal medicine specialists to screen the foetus for major congenital anomalies and to proceed with further investigation or with selective reduction as in this case so as to optimize the pregnancy outcome. Identification of PFFD at 13 weeks with foetal reduction helped in minimizing the risk to the surviving foetus.

Challenges in handling congenital anomalies clusters: a recent mediatic example in France

Abstract Issue In 2018 in France, reports of aggregated cases of isolated transverse limb reduction defects, a rare congenital anomaly (1.7 for 10,000 total births) generated a large mediatic interest with environmental factors overtly pointed out. Our aim is to describe the investigations carried out and to share the challenges we met. Description of the response Over a period of 5 years (2010-2015), 3 aggregates were signaled by health professionals in 3 different areas in France. Investigations included case ascertainment, epidemiological analyses, and search for a common exposure. Standardized Incidence Ratios were computed using the 6 French registries’s data as reference. In one area, the local registry performed a concurrent analysis using satscan. Parents filled a questionnaire addressing environmental and occupational exposures. Environmental databases were consulted as well as animal health surveillance data. Results Fourteen cases met the case definition. The excess of cases was ascertained in two aggregates located in a two small towns in the western part of France and comprising respectively 3 children born in 2007-2008 (SIR: 87.8 CI95%:[17-256]) and 4 children born in 2011-2013 (79.8 [2.5-204.2]). The third signal included 7 cases born between 2009 and 2014 residing in 7 towns located above the Alps and did not yield a significant excess when related to expected cases in the administrative subdivision (0.94 [0.38-1.95]). The concurrent analysis found a significant excess, generating a lengthy debate. None of the investigations identified a common cause or notable exposure. Delayed feedback and negative conclusions led to incomprehension among families. Lessons Informing stakeholders timely is crucial but communicating effectively about methods used and negative results can be challenging. Key messages Congenital anomalies clusters are sensitive topics. Cluster investigations involve a scientific and a societal component that must both be taken into account in organizing the public health response.

Comparative evaluation of the prevalence of congenital malformations de novo in newborns from radiation-contaminated territories of the Bryansk region (1999-2014)

On the basis of official statistics for 1999-2014 there was performed the comparative evaluation of the prevalence of congenital malformations de novo: polydactyly, reduction limb defects and multiple congenital malformations in newborns of radiation-contaminated areas of the Bryansk area residing in areas with the various density of radioactive contamination by long lived radionuclides cesium-137 (from 10.0 to 2523.4 kBq/m) and strontium-90 (from 0.7 to 42.5 kBq/m). The findings showed no statistically significant differences in the prevalence of polydactyly, reduction limb defects and multiple congenital malformations in newborns in the South-Western areas compared to medium regional values, although the maximum value of the amount of congenital malformations de novo is found in most radiation-contaminated areas.

Effects of pre-gestational diabetes mellitus and gestational diabetes mellitus on macrosomia and birth defects in Upstate New York

AimsTo evaluate the effects of pre-gestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM) on macrosomia and birth defects. MethodsExisting birth registry data from the Perinatal Data System in Upstate New York was analysed. 650,914 women with a singleton term pregnancy (≥37 weeks) aged 18–55 years from 2004 to 2016 were included. ResultsThe prevalence of macrosomia in infants born to women with PGDM and GDM were 26.0% and 16.4%, respectively, higher than that in the controls (11.2%). Compared with the controls (0.8%), the PGDM and GDM groups had higher prevalence of any birth defect (1.8% and 1.0%). The PGDM group had the highest prevalence of cyanotic heart disease (0.6%). Moreover, the PGDM group had higher prevalence of cleft lip and palate, cleft palate alone, hypospadias and limb reduction defect compared to the GDM and control groups (p < 0.05). However, these birth defects in the GDM group were similar to those in the controls. Both the PGDM and GDM groups had significantly elevated odds of macrosomia, cyanotic heart disease and any birth defect than controls. The PGDM group had higher odds of cleft lip and palate, cleft palate alone, hypospadias and limb reduction defect. ConclusionsUsing the Perinatal Data System database, PGDM and GDM, especially PGDM, was associated with higher prevalence of macrosomia, cyanotic heart disease and any birth defect in singleton term pregnancy in Upstate New York. PGDM, not GDM had higher prevalence of cleft lip and palate, cleft palate alone, hypospadias and limb reduction defect.

Epidemiology of limb reduction defects as registered in the Medical Birth Registry of Norway, 1970-2016: Population based study.

BackgroundFollowing the Thalidomide disaster, the Medical Birth Registry of Norway (MBRN) was established in 1967, with epidemiological surveillance of congenital anomalies as one main aim. Limb reduction defects (LRD) constitute a rare and heterogeneous anomaly group, where correct registration and classification is important for surveillance and research. We aimed at reviewing and recoding LRD cases in the MBRN using the same classification system for all years, and evaluate time trends, characteristics and risk factors, 1970–2016.MethodsAfter reviewing and recoding LRD cases using International Classification of Diseases (ICD), 10th version, for all years, time trends, association with major anomalies, risk factors and infant outcomes were calculated. Generalized linear models for the binomial family with log link gave relative risks (RR) with 95% confidence intervals (CI). Classification of LRD as suggested by European surveillance of congenital anomalies (EUROCAT) was attempted.ResultsOverall LRD prevalence, 1970–2016, was 4.4 per 10 000, slightly increasing during 1970–1981, followed by relatively stable rates. There were more defects in upper than lower limbs. Defects in hands/fingers were most common, but unspecific descriptions prevented classification of LRD according to EUROCAT. A majority of cases had associated anomalies, the most common being other limb defects, followed by cardiac defects and anomalies in the nervous and digestive systems. From 1999, 26% of LRD cases were terminated, more than 90% of these had associated major anomalies. Stillbirth, neonatal and infant mortality were higher among infants with LRD, also related to associated anomalies. Pre-gestational diabetes was associated with a more than three times increased risk of offspring total LRD, while no association with maternal epilepsy was found. Taking folate/multivitamin supplements before and/or during pregnancy was associated with lower risk of offspring LRD (adjusted RR 0.7; 95% CI 0.6–0.9), while daily smoking did not significantly increase the risk.ConclusionThe MBRN now has information on LRD coded by ICD-10 from 1970, but information is not specific enough to use other recommended classification systems. Collecting radiographic descriptions and/or more details from hospital records would improve the quality of the registry data. Taking folate supplements before/during pregnancy may reduce the risk of offspring LRD.

Folic acid supplementation and risk for congenital limb reduction defects in China.

Folic acid (FA) supplementation prevents neural tube defects, but there are mixed results for its ability to prevent limb reduction defects. We examined whether a preventive effect of FA supplementation exists for congenital limb reduction defects in a large population in China. Data from a large population-based cohort study in China were used to evaluate the effects of FA supplementation on birth defects. All births at 20 complete gestational weeks, including live births, stillbirths and pregnancy terminations, and all structural congenital anomalies, regardless of gestational week, were recorded. A total of 247 831 singleton live births delivered at gestational ages of 20-42 weeks to women from northern and southern China with full information on FA intake were included. Limb reduction defects were classified by subtype and maternal FA supplementation. The prevalence of limb reduction defects was 2.7 per 10 000 births among women who took FA compared with 9.7 per 10 000 births among those who did not take FA in northern China; the prevalence was 4.5 and 3.8 per 10 000 births, respectively, in southern China. In both unadjusted and adjusted analyses, the estimated relative risk for upper limb reduction defects [odds ratio (OR) = 0.17, 95% confidence interval (CI): 0.04, 0.63] and total limb reduction defects (OR = 0.24, 95% CI: 0.08, 0.70) in northern China, but not for lower limb reduction defects ,was significantly decreased in association with FA supplementation in northern China. There was no association between FA supplementation and either an increased or decreased risk for limb reduction defects in southern China. FA supplementation successfully reduces the prevalence of limb reduction defects in northern China, whose population has low folate concentrations.

Duplication of 10q24 locus: broadening the clinical and radiological spectrum.

Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.