Congenital Limb Reduction Defects Research Articles

Maternal Cigarette Smoking and Congenital Upper and Lower Limb Differences: A Systematic Review and Meta-Analysis.

Maternal smoking during pregnancy has been associated with adverse effects on foetal development, including congenital limb anomalies. This systematic review aimed to provide an updated assessment of the association between maternal smoking during pregnancy and the risk of congenital limb anomalies. A systematic search was conducted to identify relevant studies published up to February 2023. Studies reporting on the relationship between maternal smoking during pregnancy and congenital digital anomalies or congenital limb reduction defects were included. Two independent reviewers screened the studies, extracted data, and assessed the quality of the included studies. Meta-analyses were performed to estimate the pooled odds ratios with 95% confidence intervals using fixed and random-effects models. In total, 37 publications comprising 11 cohort and 26 case-control studies were included in the systematic review. The meta-analysis demonstrated a significant increased risk of congenital limb reduction defects (pooled OR: 1.27, 95% CI: 1.18-1.38) in infants born to mothers who smoked during pregnancy. Similarly, a significant relationship was observed for the development of polydactyly/syndactyly/adactyly when considered as a single group (pooled OR: 1.32, 95% CI: 1.25-1.40). Yet, in contrast, no significant association was observed when polydactyly (pooled OR: 1.06, 95% CI: 0.88-1.27) or syndactyly (pooled OR: 0.91, 95% CI: 0.77-1.08) were considered individually. This systematic review provides updated evidence of a significant relationship between maternal smoking during pregnancy and increased risk of congenital limb anomalies. These findings highlight the potential detrimental effects of smoking on foetal limb development and underscore the importance of smoking cessation interventions for pregnant women to mitigate these risks.

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.

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.

A transgenic, mesodermal specific, Dkk1 mouse model recapitulates a spectrum of human congenital limb reduction defects

Congenital limb reduction defects occurring in isolation of other developmental abnormalities continue to be an important medical problem in which little progress has been made. Herein we generated transgenic mice expressing Dkk1 in an appendicular mesodermal pattern. Prx1-Dkk1 mice recapitulate a full spectrum of human congenital limb reduction defects, without other developmental issues, and have normal life-spans. Importantly, a close examination of the inheritance pattern suggests that there is a significant degree of incomplete penetrance as progeny of phenotypically positive or phenotypically negative, but genotypically positive Prx1-Dkk1 mice, consistently give rise to both phenotypically positive mice and phenotypically normal-appearing mice. Thus, this heterogeneous phenotype is reproducible with each generation regardless of the phenotype of the parents. We further go on to identify that mesenchymal stem cells from Prx1-Dkk1 mice have limited proliferative ability, but normal differentiation potential, which may explain the mechanism for the limb reduction defects observed. We believe Prx1-Dkk1 mice may prove useful in the future to study the mechanisms underlying the development of congenital limb reduction defects.

Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

Cornelia de Lange syndrome (CdLS) is a rare multisystemic congenital anomaly disorder that is characterised by intellectual disability and growth retardation, congenital heart defects, intestinal anomalies, facial dysmorphism (including synophyris and high arched eyebrows) and limb reduction defects. Mutations in three cohesin-associated genes encoding a key regulator (NIPBL, chr 5p13.2) and one structural component of the cohesin ring (SMC1A, chr Xp11) occur in about 65% of CdLS patients. NIPBL is the major causative gene, and accounts for 40-60% of CdLS patients as shown by a number of mutational screening studies that indicate a wide mutational repertoire of mainly small deletions and point mutations. Only a few data are available concerning the occurrence of large NIPBL rearrangements or intragenic deletions or duplications involving whole exons. We used multiplex ligation-dependent probe amplification (MLPA) to study 132 CdLS patients negative to the standard mutation NIPBL test out of a cohort of 200 CdLS patients. A total of 7 out of 132 patients were found to carry NIPBL alterations, including two large gene deletions extending beyond the gene, four intragenic multi- or single-exon deletions and one single-exon duplication. These findings show that MLPA leads to a 5.3% increase in the detection of mutations when used in addition to the standard NIPBL scan, and contributes per se to the molecular diagnosis of 3.5% (7/200) of clinically diagnosed CdLS patients. It is recommended that MLPA be included in the CdLS diagnostic flow chart.

The Role of the Pediatrician in Preventing Congenital Malformations

The Role of the Pediatrician in Preventing Congenital Malformations

Addressing environmentally caused human birth defects.

1. Robert L. Brent, MD, PhD, DSc* 1. 2. *Distinguished Professor of Pediatrics, Radiology, and Pathology, Anatomy, and Cell Biology; Louis and Bess Stein Professor of Pediatrics; Emeritus Chairman, Department of Pediatrics, Jefferson Medical College, Philadelphia, PA; Head, Laboratory of Clinical and Environmental Teratology, Research Department, Alfred I. DuPont Hospital for Children, Wilmington, DE. Objectives After completing this article, readers should be able to: 1. List the environmental drugs, chemicals, and physical agents that have been documented to result in congenital malformations and have reproductive effects. 2. List the requirements for a teratogenic exposure. 3. Describe the importance of dose when evaluating the risk of exposures. 4. Describe the most important advances in embryology, teratology, reproductive biology, genetics, and epidemiology in the past 50 years. When I was a medical student at the University of Rochester, I was fortunate to have James G. Wilson, an embryologist, as one of my teachers in the anatomy course. He was working on the effects of radiation on the embryo, which is how I became interested in congenital malformations. Many of the faculty members discouraged me from pursuing the study of the causes of birth defects as an academic goal, “Because we are never going to solve that problem.” In 1955, when I had completed medical school and graduate school, the scientific world did not even have the correct figure for the number of human chromosomes. Gregg had recently described the teratogenicity of rubella virus infection during pregnancy. The teratogenic risk of the folic acid antagonists was established, and there were experimental studies indicating that nutritional deficiencies could produce birth defects in animals. What have we learned and accomplished in the past 50 years? Thousands of previously unknown genetic diseases have been described, and many of their genes have been identified. The fields of prenatal intrauterine diagnoses, intervention, and treatment have been created. Metabolic and biochemical screening have become standard care for pregnant women and newborns. More than 50 teratogenic environmental drugs, chemicals, and physical agents have been described by using modern epidemiologic tools and the superb talents of clinical dysmorphologists. The basic science and clinical rules for evaluating teratogenic risks have …

Congenital limb reduction defects: clues from developmental biology, teratology and epidemiology

Congenital limb reduction defects: clues from developmental biology, teratology and epidemiology

The importance of rehabilitation on detection of congenital limb reduction defects by prenatal ultrasound screening.

Annals of the New York Academy of SciencesVolume 847, Issue 1 p. 245-248 The Importance of Rehabilitation on Detection of Congenital Limb Reduction Defects by Prenatal Ultrasound Screening A. K. DASGUPTA, A. K. DASGUPTA Disablement Services Centre, St. Mary's Hospital, Milton Road, Portsmouth PO3 6BR, England, United KingdomSearch for more papers by this author A. K. DASGUPTA, A. K. DASGUPTA Disablement Services Centre, St. Mary's Hospital, Milton Road, Portsmouth PO3 6BR, England, United KingdomSearch for more papers by this author First published: 07 February 2006 https://doi.org/10.1111/j.1749-6632.1998.tb08948.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume847, Issue1ULTRASOUND SCREENING FOR FETAL ANOMALIES: IS IT WORTH IT? - SCREENING REVISITED AFTER THE EUROFETUS DATAJune 1998Pages 245-248 RelatedInformation

Comparison of demographic and defect characteristics among different developmental stages of congenital limb reduction defects

This study investigates how the timing of the development of limb reduction defects (LRDs) is associated with selected demographic, medical variables and defect characteristics. The LRD cases (n = 281) were ascertained from the Congenital Malformations Registry of New York State among 1983-1987 births. Cases were classified according to five stages of gestation based on when their earliest LRD developed. A control group consisted of a systematic random sample (n = 327) of non-malformed livebirths. Demographic and LRD characteristics were abstracted from birth certificates and medical charts. Among LRDs, the defects that occurred in the earlier stages of gestation were found to be more complex problems, compared with those developing in the later stages. Middle or late stage LRDs tended to occur more often with syndactyly than early stage LRDs, and had significantly higher frequencies of non-white infants compared with controls. In addition, some perinatal complications, pre-term delivery and low birthweight were positively associated with any LRD. Our findings suggest that the timing of a disturbance in limb development is important in terms of LRD characteristics. Demographics did not vary consistently with the stage of LRD development. Further studies testing this classification technique are suggested.

Congenital limb reduction defects in twins.

The study relates to congenital limb reduction defects (CLRDs) in twins from a 10-year-period (1975-1984) and is based on cases from the Hungarian Congenital Abnormality Registry. In order to clarify the respective contributions of genetic and environmental factors to CLRDs and the role of causal factors in common with twinning, the occurrence of CLRDs in twins was studied. In eight multiple CLRD twin cases (i.e. those with additional non-limb malformations), one monozygous concordant and one semi-concordant twin pair was found, indicating that genetic factors play a limited role in pathogenesis. There is no correlation between twinning and isolated CLRDs. Frequency of CLRDs in general was no higher in twins than in all births, although there was a non-significantly higher twinning rate in multiple CLRD cases. Twins with CLRDs were more often male, especially in multiple cases. There may be a relationship between twinning and congenital abnormalities, but twinning is not a major factor contributing to CLRD cases.

UK to study congenital limb-reduction defects

UK to study congenital limb-reduction defects

Maternal Factors, Medications, and Drug Exposure in Congenital Limb Reduction Defects

Maternal Factors, Medications, and Drug Exposure in Congenital Limb Reduction Defects

Maternal factors, medications, and drug exposure in congenital limb reduction defects.

As part of an ongoing study on all limb reduction defects occurring among 1,213,913 consecutive live births in the province of British Columbia, Canada, during 1952-1984, cases with documented maternal drug exposure and chronic maternal diseases were analyzed separately. This population-based study was made possible through the existence of an ongoing Health Surveillance Registry, which documents all infants born with congenital, genetic, or chronically handicapping conditions in the province of British Columbia. Strict rules of confidentiality are obeyed. For this part of the analysis of limb reduction defects, cases with documented maternal illness, drug abuse, and exposure to environmental hazards early in pregnancy were analyzed as a separate group to identify specific, recurring patterns of anomalies. A total of 51 cases with possibly related maternal factors were identified. Among them were five cases with maternal epilepsy, four cases with documented maternal diabetes, and three cases with uterine anomalies. Three infants, all born in 1962, had documented thalidomide exposure. It is rarely possible to identify particular teratogenic factors or specific maternal factors as etiologically related to the pattern of limb reduction defects or a spectrum of congenital malformations. Exposure to environmental factors during pregnancy is not reliably registered and can thus only occasionally be ascertained in retrospective studies. This means that very large numbers of cases and cross-referencing to other family members are required to assess whether a potential teratogen is related to limb defects or not.

Isolated complex limb reduction abnormality diagnosed antenatally

Congenital limb reduction defects are rare lesions that are usually associated with other anomalies. Terminal defects are the commonest reduction defects. The aetiology seems to be multifactorial. We present a case of congenital terminal deficiency of the same side of the upper and lower limbs diagnosed by ultrasound scanning during the second trimester. The fetus had an absent right fibula and right foot, a hypoplastic right hand and left talipes equinovarus. The pregnancy was terminated. Micrognathia was the only associated anomaly found on postmortem examination. The cause of this isolated anomaly is unknown but, because of the very variable presentation of limb reduction defects, could possibly fit into the categories so far described in the literature.

Congenital Microgastria and Limb Reduction Defects

In 1842 Robert1 reported the case of a girl with microgastria; hypoplastic left forearm, hand, and wrist; and asplenia. Since that time, six additional patients with a similar pattern of malformation have been described.2-7 The purposes of this report are to describe three additional cases of the microgastria-limb reduction complex which illustrate the clinical variability of this condition, to discuss overlap of this disorder with other malformation syndromes and associations, and to present evidence that suggests that the microgastria-limb reduction complex represents a developmental field defect. CLINICAL REPORTS Patient 1 Patient 1 was evaluated at age 1 month for bilateral absent thumbs.

Evaluation of congenital limb reduction defects in upstate New York.

Limb reduction defects (LRD), reported to the Congenital Malformations Registry in upstate New York between 1983-1987, were investigated in terms of LRD classification, parental demographics, and LRD characteristics. After excluding LRD with chromosome abnormalities, we followed guidelines developed by the European Congenital Anomaly Surveillance Consortium (EUROCAT) to classify 271 LRD into six groups based on similar patterns of embryological failure. The descriptive analysis indicated a prevalence of 0.45 per 1,000 births (stable over 5 years) for LRD diagnosed during the first 2 years of life. Among 271 LRD cases, 95 were classified as terminal transverse (35.1%), 71 as split limbs (26.2%), 36 as preaxial (13.3%), 32 as postaxial (11.8%), 26 as intercalary (9.6%), and 11 as multiple types (4.1%). In cases with multiple limb involvement (28.4%), two thirds had the same type of LRD in each limb. The multiple types and preaxial groups showed the most distinctive characteristics: they had the highest frequency of suspected syndromes, other birth defects, and syndactyly compared to the other LRD. There were no significant differences in the distribution of demographic variables among different LRD types. Consideration of the incidence and characteristics of LRD by classifying them into these distinct subgroups may be useful for evaluating possible mechanisms of malformation.

Fetal Vascular Disruption With Prenatal Exposure to Cocaine or Methamphetamine

To the Editor.— Hoyme et al1 have described seven children from four states with congenital limb reduction defects associated with prenatal exposure to cocaine. I am concerned that digit and limb reduction following cocaine or methamphetamine exposure in utero may be much more common than the nine existing case reports1,2 indicate and that a Ross Laboratories patient education brochure is correct in stating, "cocaine can make a baby have missing fingers."3 We began recognizing cocaine-exposed infants in 1986.

Fetal Vascular Disruption With Prenatal Exposure to Cocaine or Methamphetamine

In Reply.— Dr Bays has pointed out that congenital limb reduction defects associated with prenatal exposure to cocaine may be quite common. I would agree that such limb and digital disruptions are occasional accompaniments of fetal exposure to maternal cocaine abuse. However, the exact magnitude of individual fetal risk for prenatal vascular disruption associated with such exposure remains to be delineated. One must take the percentage of cocaine-exposed children in this report as the minimal number of exposed because many of the medical records did not record prenatal drug exposure.

Prenatal Cocaine Exposure and Fetal Vascular Disruption

The question of the potential teratogenicity of cocaine has been raised by the increasing frequency of its abuse in the United States. In previous studies, an increased incidence has been documented of spontaneous abortion, placental abruption, prematurity, intrauterine growth retardation, and neurologic deficits in the infants of women who abused cocaine. More recently, it has been suggested in studies that fetal vascular disruption accompanying maternal cocaine abuse may lead to cavitary central nervous system lesions and genitourinary anomalies. In this article, 10 children born of women who abused cocaine are described, 9 of whom have congenital limb reduction defects and/or intestinal atresia or infarction. The spectrum of anomalies associated with embryonic and fetal vascular disruption accompanying maternal cocaine abuse is thus enlarged. The specific risk for congenital anomalies accompanying maternal cocaine abuse during an individual pregnancy is unknown. However, data from these patients and the available literature suggest that counseling pregnant women concerning cocaine use should incorporate warnings about the possibility of associated embryonic or fetal vascular disruption.