Transverse Limb Reduction Defects Research Articles

Population-based surveillance of congenital anomalies over 40 years (1981–2020): Results from the Paris Registry of Congenital Malformations (remaPAR)

IntroductionRegistries of congenital anomalies (CAs) play a key role in the epidemiological surveillance of CAs. The objective was to estimate the prevalence of CAs and proportions of prenatal diagnosis, terminations of pregnancy for fetal anomaly (TOPFA) and infant mortality in the Paris Registry of Congenital Malformations (remaPAR) over 40 years, from 1981 to 2020. Material and methodsremaPAR records all births (live births, stillbirths ≥22 weeks of gestation and TOPFA at any gestational age) with CAs detected prenatally until the early neonatal period. We estimated the prevalence of CAs and proportions of prenatal diagnosis, TOPFA and infant mortality, overall and for a selected group of CAs in 3-year intervals. ResultsThe prevalence of CAs remained stable during the study period: 2.9 % of total births and 2.1 % of live births. Genetic anomalies were the most frequent subgroup (about 23 %), followed by congenital heart defects (about 22 %) and limb defects (about 20 %). Among non-genetic anomalies, the prevalence per 10,000 births was the highest for hypospadias (about 18 %) and the lowest for bilateral renal agenesis (about 1 %). Prenatal diagnoses increased from about 17 % in the 1980s to approximately 70 % in the most recent period (2018–2020), whereas the proportion of early TOPFA <16 weeks of gestation increased from 0.4 % to 14 %. Infant mortality ranged from 0 % for transverse limb reduction defects to 86 % for hypoplastic left heart syndrome. ConclusionThe overall prevalence of CAs was fairly stable in Paris from 1981 to 2020. Prenatal diagnoses substantially increased, accompanied by much smaller increases in TOPFA.

Prevalence of vascular disruption anomalies and association with young maternal age: A EUROCAT study to compare the United Kingdom with other European countries.

Younger mothers are at a greater risk of having a pregnancy with gastroschisis and the risk is higher in the United Kingdom than other European countries. Gastroschisis is thought to be a vascular disruption anomaly and the aim of this study was to analyze the prevalence of other possible vascular disruption anomalies to determine whether both the younger maternal age and the UK associations also occur with these anomalies. All pregnancies with anomalies considered potentially due to vascular disruption from January 1, 2005 to December 31, 2017 from 26 European population-based congenital anomaly registries who were members of EUROCAT were analyzed. Multilevel models were used to allow for differences between registries when analyzing associations with maternal age, year of birth and whether the registry was in the United Kingdom. There were 5,220 cases with potential vascular disruption anomalies, excluding chromosomal and genetic conditions, with a prevalence of 8.85 per 10,000 births in the United Kingdom and 5.44 in the other European countries. The prevalence per 10,000 births of gastroschisis (4.45 vs. 1.56) and congenital constriction bands (0.83 vs. 0.42) was significantly higher in the United Kingdom, even after adjusting for maternal age. However, transverse limb reduction defects had a similar prevalence (2.16 vs. 2.14 per 10,000). The expected increased prevalence in younger mothers was observed for vascular disruption anomalies overall and for the individual anomalies: gastroschisis and congenital constriction bands. Vascular disruption anomalies that had an increased risk for younger mothers (such as gastroschisis) had a higher maternal age standardized prevalence in the United Kingdom, while vascular disruption anomalies with weaker associations with younger mothers (such as transverse limb reduction defects) did not have an increased prevalence in the United Kingdom, which may indicate a different etiology for these anomalies.

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.

Morphology of early intrauterine deaths with full trisomy 15.

The morphologic features of embryos with full trisomy 15 are described. A total of 1195 pregnancy losses were examined embryoscopically and cytogenetically. Of 1173 successfully karyotyped specimens, full trisomy 15 was diagnosed cytogenetically in 59 cases (5%). All 59 trisomy 15 embryos were diagnosed cytogenetically in the group of 962 embryonic miscarriages (6%). Trisomy 15 was not registered in 171 anembryonic or yolk sac miscarriages, and no case of full trisomy 15 was observed in 62 fetal miscarriages. Fifty-eight embryos with full trisomy 15 showed structural defects on embryoscopic examination. The most common defects were craniofacial anomalies (n=73), retarded development of the limbs (n=39), and abnormally short umbilical cords closely attaching the embryo to the chorionic plate (n=27). Seven embryos were classified as growth disorganized. Limb reduction defects with a prevalence of 5.6/10000 births, all affecting upper limb development (10 terminal transverse limb reduction defects and 3 embryos with split hand), were registered in 13 (22%) trisomy 15 embryos. Limb reduction defects and craniofacial abnormalities are a typical feature of trisomy 15. Gene dosage imbalances related to trisomy 15 might be the main molecular mechanism underlying the developmental defects observed in the present study and require further investigation.

Early Gestational Hypoxia and Adverse Developmental Outcomes.

Hypoxia is a normal and essential part of embryonic development. However, this state may leave the embryo vulnerable to damage when oxygen supply is disturbed. Embryofetal response to hypoxia is dependent on duration and depth of hypoxia, as well as developmental stage. Early postimplantation rat embryos were resilient to hypoxia, with many surviving up to 1.5 hr of uterine clamping, while most mid-gestation embryos were dead after 1 hour of clamping. Survivors were small and many had a range of defects, principally terminal transverse limb reduction defects. Similar patterns of malformations occurred when embryonic hypoxia was induced by maternal hypoxia, interruption of uteroplacental flow, or perfusion and embryonic bradycardia. There is good evidence that high altitude pregnancies are associated with smaller babies and increased risk of some malformations, but these results are complicated by increased risk of pre-eclampsia. Early onset pre-eclampsia itself is associated with small for dates and increased risk of atrio-ventricular septal defects. Limb defects have clearly been associated with chorionic villus sampling, cocaine, and misoprostol use. Similar defects are also observed with increased frequency among fetuses who are homozygous for thalassemia. Drugs that block the potassium current, whether as the prime site of action or as a side effect, are highly teratogenic in experimental animals. They induce embryonic bradycardia, hypoxia, hemorrhage, and blisters, leading to transverse limb defects as well as craniofacial and cardiovascular defects. While evidence linking these drugs to birth defects in humans is not compelling, the reason may methodological rather than biological. Birth Defects Research 109:1358-1376, 2017.© 2017 Wiley Periodicals, Inc.

Periventricular nodular heterotopia and transverse limb reduction defect in a woman with interstitial 11q24 deletion in the Jacobsen syndrome region

Jacobsen syndrome (JS) is a disorder of developmental delay, growth retardation, thrombocytopenia, dysmorphic features, and cardiac abnormalities, among other congenital anomalies. JS is caused by contiguous gene deletion in distal chromosome 11q, generally varying in size from 7 to 20 Mb. Periventricular nodular heterotopia (PVNH) is a neuronal migration disorder in which neurons are abnormally located in nodules along the edges of the lateral ventricles. PVNH can also be seen with other congenital anomalies, including a recurrent association with distal limb defects. Transverse limb defects have previously been reported in two patients with JS. We report on a patient with a 3.162 Mb interstitial deletion at chromosome region 11q24 overlapping the region commonly affected in JS. The patient had PVNH and a transverse limb reduction defect, with minimal typical findings of JS. This is the first report of PVNH associated with a microdeletion at chromosome 11q and may represent an expansion of the phenotypic spectrum associated with JS. This is the third report of transverse limb reduction defects in association with JS, supporting a widening of the skeletal phenotypic spectrum in JS to include more severe limb anomalies. ETS1 is proposed as a candidate gene for involvement in limb anomalies in JS.

From nuchal translucency to intracranial translucency: towards the early detection of spina bifida

It is now clear that the vast majority of major fetal abnormalities can be diagnosed prenatally by ultrasound, that most of these abnormalities can be detected in the first trimester of pregnancy and that women want firsttrimester rather than later diagnosis. It is also clear that effective diagnosis of fetal abnormalities often necessitates the identification of easily recognizable markers which direct the attention of the sonographer to the specific abnormality. Good examples of such markers are the scalloping of the frontal bones (the ‘lemon’ sign) and caudal displacement of the cerebellum (the ‘banana’ sign), observed in the second trimester in most fetuses with open spina bifida, and increased nuchal translucency thickness (NT) which identifies in the first trimester the majority of fetuses with major aneuploidies, lethal skeletal dysplasias and a high proportion of major cardiac defects. It is now widely accepted that increased NT at 11–13 weeks is the single most effective marker of trisomy 21 and all other major aneuploidies. First-trimester screening by a combination of maternal age, fetal NT, nasal bone, Doppler assessment of blood flow in the ductus venosus and across the tricuspid valve together with maternal serum free β-hCG and PAPP-A can identify more than 95% of all major aneuploidies for a screen-positive rate of less than 3%. A major remaining challenge in first-trimester ultrasonography has been the diagnosis of open spina bifida. This challenge, however, may now have been resolved by the realization that open spina bifida can be suspected by an easily detectable marker within the brain in the same mid-sagittal plane of the fetal face as for measurement of NT and assessment of the nasal bone. In normal fetuses the fourth cerebral ventricle presents as an intracranial translucency (IT) parallel to the NT, while in fetuses with open spina bifida there may be absence of the IT 1 .

The effect of hypoxia in development

There is increasing evidence that the oxygen supply to the human embryo in the first trimester is tightly controlled, suggesting that too much oxygen may interfere with development. The use of hypoxia probes in mammalian embryos during the organogenic period indicates that the embryo is normally in a state of partial hypoxia, and this may be essential to control cardiovascular development, perhaps under the control of hypoxia-inducible factor (HIF). A consequence of this state of partial hypoxia is that disturbances in the oxygen supply can more easily lead to a damaging degree of hypoxia. Experimental mammalian embryos show a surprising degree of resilience to hypoxia, with many organogenic stage embryos able to survive 30-60 min of anoxia. However, in some embryos this degree of hypoxia causes abnormal development, particularly transverse limb reduction defects. These abnormalities are preceded by hemorrhage/edema and tissue necrosis. Other parts of the embryo are also susceptible to this hypoxia-induced damage and include the genital tubercle, the developing nose, the tail, and the central nervous system. Other frequently observed defects in animal models of prenatal hypoxia include cleft lip, maxillary hypoplasia, and heart defects. Animal studies indicate that hypoxic episodes in the first trimester of human pregnancy could occur by temporary constriction of the uterine arteries. This could be a consequence of exposure to cocaine, misoprostol, or severe shock, and there is evidence that these exposures have resulted in hypoxia-related malformations in the human. Exposure to drugs that block the potassium current (IKr) can cause severe slowing and arrhythmia of the mammalian embryonic heart and consequently hypoxia in the embryo. These drugs are highly teratogenic in experimental animals. There is evidence that drugs with IKr blockade as a side effect, for example phenytoin, may cause birth defects in the human by causing periods of embryonic hypoxia. The strongest evidence of hypoxia causing birth defects in the human comes from studies of fetuses lacking hemoglobin (Hb) F. These fetuses are thought to be hypoxic from about the middle of the first trimester and show a range of birth defects, particularly transverse limb reduction defects.

Sonographic diagnosis of limb reduction defects in a fetus with haemoglobin Bart's disease at 12 weeks of gestation

Limb reduction defect is a rare event but is found in eight per cent of fetuses affected by haemoglobin Bart's disease. We present a case of haemoglobin Bart's disease with terminal transverse limb reduction defects of all four limbs diagnosed by abdominal ultrasound examination at 12 weeks of gestation. The pregnancy was terminated by suction curettage. Just prior to the procedure, transabdominal needle embryoscopy was performed and this confirmed the sonographic diagnosis. The present case demonstrates the need and feasibility of a detailed anatomic survey of a fetus affected by haemoglobin Bart's disease at 12 weeks. This is particularly relevant if the patient is considering the option of intra-uterine therapy. Copyright © 1999 John Wiley & Sons, Ltd.

Sonographic diagnosis of limb reduction defects in a fetus with haemoglobin Bart's disease at 12 weeks of gestation

Limb reduction defect is a rare event but is found in eight per cent of fetuses affected by haemoglobin Bart's disease. We present a case of haemoglobin Bart's disease with terminal transverse limb reduction defects of all four limbs diagnosed by abdominal ultrasound examination at 12 weeks of gestation. The pregnancy was terminated by suction curettage. Just prior to the procedure, transabdominal needle embryoscopy was performed and this confirmed the sonographic diagnosis. The present case demonstrates the need and feasibility of a detailed anatomic survey of a fetus affected by haemoglobin Bart's disease at 12 weeks. This is particularly relevant if the patient is considering the option of intra-uterine therapy.

First 10 000 chorionic villus samplings performed on singleton pregnancies by a single operator

Chorionic villus sampling (CVS) was performed in 10,000 consecutive singleton pregnancies by a single principal operator, working in two institutions. The procedure was performed between 8 and 32 gestational weeks: transabdominal (TA) sampling was carried out in 8479 cases and transcervical (TC) in 1521. Patients were referred for chromosomal risk in 89.1 per cent of cases, Mendelian disorders in 10.5 per cent, and DNA investigations for paternity or infectious agents in 0.4 per cent of cases. The sampling success rate for both TA and TC techniques by the second insertion was 99.8 and 99.2 per cent, respectively. TA sampling succeeded in a higher number of cases at the first insertion (98 per cent vs. 86.8 per cent) and was associated with smaller samples (< 10 mg) in fewer cases (3.2 per cent vs. 4.9 per cent). Cytogenetic analysis was highly successful (99.4 per cent) and accurate; however, in one case a de novo structural rearrangement of chromosome I was not recognized. Mosaicism or rare trisomies were reported in 1.30 per cent of cases. Five diagnostic errors in DNA investigation (0.51 per cent) ended with the birth of affected fetuses. Fetal loss through 28 weeks' gestation in the pregnancies intended to continue was 2.58 per cent; the rate increased with maternal age (1.22 per cent at less than 30 years to 3.8 per cent at 40 years or more), while gestational age affected the abortion rate only at 8 weeks (odds ratio=2.22, P<0.05). Rates of premature delivery, low birth weight, and perinatal mortality did not differ from the Italian standards. By comparison with the Italian Birth Defects Registry data, no differences were found for the major malformations, including transverse limb reduction defects (TLRDs) (4.34 vs. 3.28 x 10,000). Total malformations and TLRDs did not show any pattern relation to either maternal age or gestational age.

Limb reduction defects in fetuses with homozygous α-thalassaemia-1

Limb reduction defect is a rare event. Its exact pathogenesis is unknown. We retrospectively reviewed the outcome of 130 fetuses affected by homozygous α-thalassaemia-1 and found that 11 of them (8 per cent; 95 per cent confidence interval: 4–13 per cent) had terminal transverse limb reduction defects. Chromosome study was available in ten fetuses with limb defects and the results were normal. We postulate that the strong association between homozygous α-thalassaemia-1 and limb reduction is related to the hypoxic insult in early gestation. This may be the final common pathway in the pathogenesis of other forms of limb reduction defects. © 1997 John Wiley & Sons, Ltd.

Limb reduction defects in fetuses with homozygous α-thalassaemia-1

Limb reduction defect is a rare event. Its exact pathogenesis is unknown. We retrospectively reviewed the outcome of 130 fetuses affected by homozygous alpha-thalassaemia-1 and found that 11 of them (8 per cent; 95 per cent confidence interval: 4-13 per cent) had terminal transverse limb reduction defects. Chromosome study was available in ten fetuses with limb defects and the results were normal. We postulate that the strong association between homozygous alpha-thalassaemia-1 and limb reduction is related to the hypoxic insult in early gestation. This may be the final common pathway in the pathogenesis of other forms of limb reduction defects.

MATERNOEMBRYONIC TRANSFUSION AND CONGENITAL MALFORMATIONS

There is an increasing number of reports relating chorionic villus sampling (CVS) to transverse limb reduction defects or the oromandibular limb hypogenesis complex. In addition, a correlation has been established between the severity of the defect and the gestational age when CVS is performed. Several hypotheses have been proposed for the increased incidence of congenital malformations after CVS including vascular disruption. Recently, it has been suggested that maternoembryonic transfusion can occur after CVS and that this can lead to a local antibody-mediated reaction, followed by local pathogenetic cell degeneration, i.e., apoptotic cell death, due to vascular disruption. This increased apoptotic cell death will ultimately result in congenital malformations. This paper describes an experimental model that can explain the pathogenesis of congenital malformations after CVS. The model designed uses a whole rat embryo culture technique and intracardiac injection of antisera, mimicking transplacental transfusion after CVS. Injection of antibodies directed against blood group antigens is capable of inducing increased apoptotic cell death. Immunological staining gives evidence of involvement of antibody-mediated reactions in the occurrence of apoptotic cell death. The dorsal aortae in 10-day-old rat embryos of 10-somite stages of development consist of a continuous endothelial cell layer. The effect of intracardiac injection of antisera on the dorsal aortae is only transient. Smaller vessels such as the pharyngeal arch arteries or arteries of the limbs still have fenestrated endothelium and are therefore more vulnerable to the pathogenetic effect of the reaction after transplacental transfusion causing vascular disruption. Development of the vascular pattern and differentiation of the vascular wall reduce the risk of severe malformations later on in pregnancy, although the risk of malformations remains throughout pregnancy. Thus, intracardiac injection of antisera simulating maternoembryonic transfusion such as after CVS can lead to an antibody-mediated reaction with vascular disruption early in pregnancy inducing apoptotic cell death. Increased cell death may ultimately result in congenital malformations, such as transverse limb defects or the oromandibular limb hypogenesis complex.

The utilization rate and pregnancy outcome of multifetal pregnancy reduction in the Nordic countries.

To review the utilization rate and pregnancy outcome of multifetal pregnancy reductions (MFR) in the Nordic countries during the period January 1986-June 1992. All centers offering assisted conception in Denmark, Finland, Norway and Sweden were retrospectively surveyed by means of a questionnaire with regard to the number and methods used for MFR, pregnancy loss and the outcomes of the pregnancies. The response rate was 100%. During the period studied, 185 births of triplets or higher multiples occurred in Sweden, 120 in Finland and 102 in Denmark. MFR was performed in 42 women (Sweden 26, Finland 10, Denmark 6) but not in Norway at all. This gives an estimated average utilization rate of 1/7 multiple births of three or more in Sweden, 1/17 in Denmark and 1/12 in Finland. The most frequently used method was intracardiac or intrathoracic injection of a potassium chloride solution in gestational weeks 9-12. One pregnancy was reduced from seven to four fetuses, two from five to three, 10 from five to two, one from four to three, 17 from four to two, one from four to one, five from three to two, four from three to one and one from two to one. Nine (21%) pregnancies terminated in a spontaneous abortion within one week (n = 2) to several weeks (n = 7) after the procedure. Of the remaining 33 (79%) pregnancies which continued to delivery, two fetuses died in utero in the second trimester, three infants died perinatally and one child had transverse limb reduction defects. A successful pregnancy defined by the discharge home of at least one infant occurred in 79% of the cases. This study gives national estimates on the utilization rate of MFR. Although MFR is performed more frequently in Sweden than in Denmark and Finland, the overall figures remain low in the Nordic countries. The incidence of pregnancy loss in this study is somewhat higher than in several larger reported series, probably reflecting the learning curve of the procedure. It seems reasonable that MFR should be performed in only a few centers in the Nordic countries.

Transcervical chorionic villus sampling beyond 12 weeks of gestation

The aim of this study was to evaluate the feasibility of transcervical chorionic villus sampling (CVS) after 12 completed weeks of pregnancy. The transcervical route for CVS, using thin biopsy forceps, was accomplished in 335 procedures in the study group, between 12 + 1 and 15 + 0 weeks. Cases were subdivided into two subgroups, the late (13 + 0 to 15 + 0 weeks) and intermediate (12 + 1 and 12 + 6 weeks) subgroups, and the results were compared with a previous series of 1202 early (8 + 0-12 + 0 weeks) transcervical CVS. A successful diagnosis was made in 97.3% of the cases. No differences were found in diagnostic success between the study subgroups, in comparison to the early transcervical CVS series. However, success rates in the study group increased from 90% in the first 60 procedures to 98.9% in the remaining cases (p < 0.001). Amniocentesis was eventually performed in nine cases (2.7%). All cases were rescanned 2 weeks after the procedure, and fetal demise was detected in five cases (1.5%). The spontaneous fetal loss rate up to 28 weeks was 3.1% (2.7% for intermediate and 4.0% for late subgroups). No cases of transverse limb reduction defects were observed. The results of our study suggest that the transcervical route for CVS beyond the 12th week of pregnancy has a satisfactory diagnostic success rate, and an acceptable pregnancy loss rate.

Transverse limb reduction defects after chorion villus sampling: a retrospective cohort study. GIDEF--Gruppo Italiano Diagnosi Embrio-Fetali.

A retrospective cohort study was performed in five Italian obstetrical centres from 1984 to 1991 in order to verify the association between chorionic villus sampling (CVS) and transverse limb reduction defects (TLRDs). TLRD rates by period of gestation at CVS were calculated, and the study's results were compared with data from the general population. Of the 3430 pregnancies for which CVS was performed, 2759 had a known outcome. The overall rate for TLRDs was 1 in 1143 CVS pregnancies, four times higher than that of the general population in Italy (1 in 4458). The rate of TLRDs was 2.9/1000 for CVS performed at 9 weeks' gestation and 1.0/1000 for CVS at 10 weeks' gestation. A scalp defect was detected in a pregnancy in which CVS was performed at 10 weeks. A high proportion of pregnancies lost to follow-up and the poor quality of the data may have affected the results. Nevertheless, our results suggest an association between CVS carried out at less than 10 weeks' gestation and TLRDs which is consistent with the findings of other studies. CVS should not be prepared at less than 10 weeks' gestation until additional evidence is obtained.

Vascular pathogenesis of transverse limb reduction defects

Evaluation of four patients with unilateral transverse limb reduction defects indicates that some instances of this structural defect may be the result of an in utero vascular accident. Three of the four patients had microscopic evidence of fetal vascular occlusive disease on multiple sections of the placenta, suggesting that occlusion of the brachial artery was secondary to embolization from the placental vascular thrombi. The fourth, a 116 mm crown-rump long fetus, had a massive thrombus occluding the brachial artery, which was felt secondary to hypovolemia and hypoperfusion associated with fetal blood loss during placental abruption. Recognition of the disruptive vascular pathogenesis of some cases of unilateral transverse limb reduction defects explains their negligible recurrence risk. In such cases attention should be focused on careful gross and, microscopic evaluation of the placenta.