Should prenatal chromosomal microarray analysis be offered for isolated fetal growth restriction? A French multicenter study.

BACKGROUND: Compared with standard karyotype, chromosomal microarray analysis improves the detection of genetic anomalies and is thus recommended in many prenatal indications. However, evidence is still lacking on the clinical utility of chromosomal microarray analysis in cases of isolated fetal growth restriction. OBJECTIVE: This study aimed to estimate the proportion of copy number variants detected by chromosomal microarray analysis and the incremental yield of chromosomal microarray analysis compared with karyotype in the detection of genetic abnormalities in fetuses with isolated fetal growth restriction. STUDY DESIGN: This retrospective study included all singleton fetuses diagnosed with fetal growth restriction and no structural ultrasound anomalies and referred to 13 French fetal medicine centers over 1 year in 2016. Fetal growth restriction was defined as an estimated fetal weight of

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.

Prenatal diagnosis of megacystis microcolon intestinal hypoperistalsis syndrome by biochemical analysis of fetal urine.

OBJECTIVES: The objective of the study is to determine a model of fetal urine biochemical markers to differentiate megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) from other megacystis. METHOD: This is a retrospective study of biochemical analysis of fetal urine in patients who presented prenatally with megacystis. We studied ß2-microglobulin, sodium, calcium, and phosphorus. Twenty-six patients subsequently diagnosed with MMIHS were compared with 2 control groups: one of end-stage renal failure (64 fetuses) and the second of "good" postnatal renal function (control group, 64 fetuses). RESULTS: Mean fetal urine ß2-microglobulin was significantly higher (P < .001) in end-stage renal failure (15.7 mg/L) than in MMIHS (2.2 mg/L) and the control group (3.2 mg/L). Fetal urine profiles differed significantly (P < .001) between MMIHS and the control group: median sodium 46.5 and 51 mmol/L, median calcium 1.12 and 0.73 mmol/L, and median phosphorus 0.03 and 0.15 mmol/L respectively. Fetal urinary ionic index [ratio: calcium / (phosphorus × sodium)] gave an area under the ROC curve of 0.86, at 54% sensitivity and 97% specificity, with correct classification in 84% of cases. We defined a nomogram to obtain a probability for MMIHS. CONCLUSION: Fetal urinalysis can be helpful in prenatal differentiation of MMIHS from posterior urethral valves with good postnatal renal function.

Management strategy in pregnancies with elevated second-trimester maternal serum alpha-fetoprotein based on a second assay.

OBJECTIVE: To assess maternal-fetal outcomes in pregnancies associated with persistently elevated second-trimester maternal serum alpha-fetoprotein. STUDY DESIGN: A retrospective cohort study in 658 patients with maternal serum alpha-fetoprotein ≥2.5 multiple of median, performed at routine Down syndrome screening. Maternal serum alpha-fetoprotein was assayed a second time in 341 of them. Outcomes were recorded in all cases. RESULTS: The group with unexplained maternal serum alpha-fetoprotein persistently ≥2.5 multiple of median was associated with more pregnancy complications 37 of 92 (40.2%) as fetal death, preeclampsia, intrauterine growth restriction, and congenital nephrotic syndrome, compared with the group with maternal serum alpha-fetoprotein that returned to a normal level 37 of 226 (16.4%) (P < .001). CONCLUSION: When maternal serum alpha-fetoprotein returns to a normal level on a second assay, the risk of adverse outcome significantly decreases, but these pregnancies are still at risk of complications and therefore need close surveillance. Repeat maternal serum alpha-fetoprotein assay allows identification of patients who should be offered amniocentesis to evaluate the risk of nephrotic syndrome and epidermolysis bullosa. Alpha-fetoprotein should be monitored in pregnancies associated with unexplained high maternal serum alpha-fetoprotein. A management strategy based on ultrasound examination, second maternal serum alpha-fetoprotein assay and amniocentesis is proposed to improve prenatal counseling and management of such pregnancies. However, a prospective study remains necessary to evaluate it.

[Sirenomelia as a part of VACTERL association: a study of three cases]. / Sirénomélie entrant dans le cadre d'une association VACTERL : à propos de trois cas.

Sirenomelia, characterized by a fusion of lower limb buds, is rare. Moreover, the coexistence of this malformation with a VACTERL sequence is exceptional. We report, here, three new observations associating these two diseases on fetuses from 14 to 26 weeks gestation. With these three new cases associating sirenomelia and VACTERL, observed in our unit and examined in light of data from the medical literature, we discuss the embryologic origin of such malformations and the nosologic frontiers between these two diseases.

Use of low-molecular-weight heparin from the first trimester of pregnancy: a retrospective study of 111 consecutive pregnancies.

BACKGROUND: During the first trimester of pregnancy, unfractionated heparin is the standard anticoagulant treatment for pregnant women at high risk of thrombosis. OBJECTIVE: To observe maternal and fetal tolerance for low-molecular-weight heparin begun in the first trimester of pregnancy. METHODS: Observational study conducted from 1 January 1997 to 31 May 2001. All patients began treatment before the 15th week of pregnancy. The outcome measures were the incidence and causality of adverse events in mother and fetus. RESULTS: The study included 97 patients (and 111 pregnancies) at very high risk for thrombosis. Seven fetal losses (6.3%) were observed: three early spontaneous abortions, three late spontaneous abortions and one medically indicated abortion. Twenty-five (22.5%) bleeding events occurred during pregnancy, seven (6.3%) of which required medical intervention: five curettages for first trimester spontaneous abortions, one late abortion at 21 weeks and one placental abruption at 25 weeks. Of nine (8.1%) primary postpartum hemorrhages involving a blood loss > or = 500 mL, three involved losses of 1000 mL or more and one required embolization of the uterine arteries. Five patients had thrombocytopenia, but none was treatment-related. Local cutaneous reactions occurred in 33 (29.7%) patients. Six (5.4%) maternal thromboembolic complications occurred during pregnancy or postpartum. At birth, two children had non-chromosomal congenital malformations (pyelectasia, cleft lip and palate). No fetal or neonatal complication was attributed to the treatment. CONCLUSION: The use of low-molecular-weight heparin (LMWH) for patients requiring anticoagulant treatment from the first trimester appears safe for mother and fetus.

Prenatal diagnosis of ring chromosome 6 in a fetus with cerebellar hypoplasia and partial agenesis of corpus callosum: case report and review of the literature.

Ring chromosome 6 (RC6) is a rare constitutional abnormality, with variable material loss, leading to a variable clinical phenotype: minimal physical anomalies and mild psychomotor retardation to severe physical and mental defects. Among the 22 published cases, only five have been prenatally detected. We describe here a RC6 prenatally diagnosed. Ultrasound follow-up showed growth retardation and cerebellar hypoplasia. Magnetic resonance imaging (MRI) confirmed this, but showed a partial corpus callosum agenesis, leading to amniocentesis and revealing the chromosomal abnormality. Imaging features were correlated with autopsy findings.

French multicentric survey of outcome of pregnancy in women with pregestational diabetes.

OBJECTIVE: To evaluate perinatal outcome in pregnancies in women with type 1 and type 2 diabetes and the influence of preconception care 10 years after the St. Vincent's declaration. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted in 12 perinatal centers in France in 2000-2001. The main investigated outcomes were perinatal mortality, major congenital malformations, and preterm delivery. RESULTS: Among 435 single pregnancies, 289 (66.4%) were from women with type 1 and 146 (33.6%) from women with type 2 diabetes. Perinatal mortality rate was 4.4% (0.7% national rate), severe congenital malformations rate was 4.1% (2.2% national rate), and preterm delivery rate was 38.2% (4.7% national rate). Preconception care was provided in 48.5% women with type 1 diabetes and in 24.0% women with type 2 diabetes. Women whose first trimester HbA(1c) was >8% had higher rates of perinatal mortality (9.2 vs. 2.5%; odds ratio 3.9; 95% CI 1.5-9.7; P < 0.005), major congenital malformations (8.3 vs. 2.5%; 3.5; 1.3-8.9; P < 0.01), and preterm delivery (57.6 vs. 24.8%; 1.4; 1.1-1.7; P < 0.005) than those with first trimester HbA(1c) <8%. These results are similar to those reported in France in 1986-1988. CONCLUSIONS: Pregnancies in women with diabetes are still poorly planned and complicated by higher rates of perinatal mortality and major congenital malformations. Despite knowledge of the importance of intensified glycemic control before pregnancy, reaching the St. Vincent's target needs further implementation in France.