Idiopathic polyhydramnios and postnatal outcomes of children: The role of exome sequencing.

OBJECTIVES: The objective of our study was to evaluate the long-term outcome of children born from a pregnancy complicated by idiopathic polyhydramnios. The secondary objective was to investigate factors associated with adverse outcomes. METHODS: We conducted a retrospective study in two prenatal diagnosis centers between January 1, 2009 and December 31, 2020. Inclusion criteria were pregnancies with a diagnosis of idiopathic polyhydramnios, defined by a deepest pocket greater than 8 cm, no detectable abnormality at ultrasound and a negative amniotic fluid assessment including karyotype, chromosomal microarray, biochemical assays (electrolytes and digestive enzymes), and viruses (parvovirus B19 and cytomegalovirus). One-year outcomes of these children were collected. The primary endpoint was adverse postnatal outcome, defined by at least one of the following criteria: stillbirth, neonatal death, or serious and incurable condition diagnosed in the first year of life. RESULTS: Of the 245 women referred for isolated polyhydramnios, 73 were diagnosed with idiopathic polyhydramnios after prenatal investigations. The mean age at follow-up of children was 28 months (95% CI 20-36). An adverse outcome occurred in 25% of cases (18/73), with one stillbirth, two neonatal deaths, and 15 severe conditions diagnosed postnatally, including a rate of monogenic disorders of 8.2% (6/73). Pediatric follow-up was normal for 75% of the children (55/73), including a rate of 9% (5/55) of curable conditions. Repeated amnioreduction was independently associated with an adverse outcome. CONCLUSION: Pregnant women with polyhydramnios should be informed of the increased risk of 25% of perinatal mortality and serious conditions diagnosed after birth.

Management of short cervix in twin-to-twin transfusion syndrome: a role for pessary placement following fetoscopic laser surgery?

BACKGROUND: Preterm labor and delivery is a major concern for patients with twin-to-twin transfusion syndrome undergoing fetoscopic laser surgery. A preoperative short cervix is a risk factor for preterm labor. Pessary placement is a short-acting intervention that may be useful to reduce this adverse event. OBJECTIVE: This study aimed to investigate the relationship between pessary placement and preterm delivery in monochorionic twin pregnancies with twin-to-twin transfusion syndrome and a short cervix before fetoscopic laser surgery. STUDY DESIGN: This was a retrospective study in 2 centers, including all pregnancies affected by twin-to-twin transfusion syndrome that underwent fetoscopic laser surgery with the Solomon technique between 2013 and 2022 (center A) and 2014 and 2022 (center B) with a preoperative cervical length below 25 mm. This study explored the correlation between cervical length and fetoscopic laser surgery-to-delivery interval following active or expectant management and compared perinatal outcomes between patients managed expectantly and patients managed with pessary placement, using multivariate analysis to control for potential confounders. Patients with a cervical length below 5 mm were not included in the comparative analysis. RESULTS: Of 685 patients, 134 met the inclusion criteria. Moreover, 21 patients were treated with a cervical cerclage and excluded from the analysis, leaving 113 patients for the final analysis. There was a significant negative correlation between cervical length at fetoscopic laser surgery and the risk of early delivery (adjusted odds ratio, 0.66; 95% confidence interval, 0.49-0.81; P<.001). The use of a pessary correlated with fewer patients delivering before 28 weeks of gestation (adjusted odds ratio, 0.28; 95% confidence interval, 0.09-0.75), fewer double neonatal demise (adjusted odds ratio, 0.2; 95% confidence interval, 0.05-0.75). Posthoc subgroup analysis suggested that these improvements were essentially noticeable for cervical lengths between 5 and 18 mm, where pessary placement was associated with an increased fetoscopic laser surgery-to-delivery interval (+24 days; 95% confidence interval, 0.86-42; P=.042) and later gestational age at delivery (+3.3 weeks; 95% confidence interval, 0.86-42; P=.035). CONCLUSION: Patients with a moderately shortened cervix, between 5 and 18 mm, may benefit from pessary placement after fetoscopic surgery for twin-to-twin transfusion syndrome, resulting in a reduction of adverse neonatal outcomes, double neonatal demise, and severe preterm delivery.

Selective vs complete fetoscopic coagulation of vascular equator: a matched comparative study.

BACKGROUND: Complete coagulation of the vascular equator (as in the Solomon technique) has been suggested to reduce postoperative complications such as twin anemia polycythemia syndrome and the recurrence of twin-twin transfusion syndrome following fetoscopic laser coagulation of chorionic vessels for twin-twin transfusion syndrome. OBJECTIVE: We aimed to evaluate the benefit of this technique on perinatal outcomes compared with selective ablation of anastomoses. STUDY DESIGN: We conducted a monocentric retrospective study comparing selective laser coagulation of anastomoses to the Solomon technique from January 2006 to August 2020. To adjust for potential confounders, the cases operated by selective surgery were matched to the cases operated with the Solomon technique according to the gestational age at laser therapy, placental localization, and Quintero stage using propensity score matching. RESULTS: With a total of 994 cases, 399 matched pairs were included in the analysis. Compared with selective ablation, the Solomon technique was associated with significantly improved survival: the overall twin survival at delivery and discharge was 72% vs 79% (P=.003) and 69% vs 75% (P=.006), respectively; the double twin survival rate at discharge was 55% vs 65% (P=.02), respectively, and the rate of intrauterine death dropped from 18% to 12% (P=.003), respectively. The Solomon technique significantly reduced the rate of twin anemia polycythemia syndrome (10% vs 4%; P=.02), leading to fewer secondary rescue procedures (13% vs 7.3%; P=.01). However, the Solomon technique was associated with an increased risk of preterm rupture of membranes, especially at early gestational ages (3.8% vs 11%; P<.001 for preterm rupture of membranes <24 weeks). Among the survivors at delivery, both the groups had similar gestational ages at birth. Both neonatal mortality and severe neurologic morbidity were similar in both the groups. However, an increased risk of bronchopulmonary dysplasia was found in the Solomon group (4.5% vs 12%; P<.001). CONCLUSION: Although the risk of preterm premature rupture of membranes has increased, the introduction of the Solomon technique has significantly improved perinatal outcomes in pregnancies affected with twin-twin transfusion syndrome.

Effect of gestational age at laser therapy on perinatal outcome in monochorionic diamniotic pregnancies affected by twin-to-twin transfusion syndrome.

OBJECTIVE: To evaluate the effect of gestational age at laser therapy for twin-to-twin transfusion syndrome (TTTS) on perinatal outcome. DESIGN AND SETTINGS: Single retrospective observational cohort. POPULATION: All consecutive pregnancies affected by TTTS and referred to our department between January 2013 and August 2020. METHODS: Gestational age was modelled both as a categorical and as a continuous variable. Log-binomial regression was used to estimate the odds ratios (crude and adjusted for placental location, Quintero stage and cervical length) as well as the adjusted predicted probability of survival and fetal loss according to gestational age at laser therapy. MAIN OUTCOMES: Fetal and neonatal survival, preterm prelabour rupture of membranes (PPROM). RESULTS: Of the 503 pregnancies referred for TTTS, 431 were treated by laser therapy. Gestational age at laser therapy was positively and significantly associated with the overall survival at birth and at discharge (adjusted odds ratio [aOR] 1.12, 95% CI 1.05-1.19), as with a reduction in double fetal loss (aOR 0.81, 95% CI 0.71-0.92). Conversely, the rate of PPROM before 24 weeks was significantly higher in early cases (32% of PPROM <24 weeks when laser therapy was performed before 17 weeks versus 1.5% after 22 weeks, p < 0.001, aOR 0.60, 95% CI 0.48-0.72). Among the survivors, preterm birth before 28 weeks was significantly related to the gestational age at laser (OR 0.91, 95% CI 0.84-0.99), resulting in a significant impact on neonatal morbidity (OR 0.91, 95% CI 0.85-0.97). CONCLUSION: Our results suggest a significant and independent impact of the gestational age at laser surgery on perinatal survival, PPROM and neonatal morbidity.

Comparison of crown-rump length discordance and abnormal cord insertions as first-trimester predictors of poor outcome in monochorionic diamniotic twin pregnancies.

OBJECTIVES: This is a retrospective study to determine the predictive value and comparison of first trimester (1) crown-rump length discordance and (2) abnormal cord insertion as screening tests for poor outcome in monochorionic diamniotic twin pregnancies. RESULTS: Retrospective data were collected over last 10 years from a single center (2009-2018). A total of 261 patients were a part of this study. CRL discordance or abnormal cord insertions are not accurate predictors of twin-to-twin transfusion syndrome, which corresponds to previously published data on the same subject. Both CRL discordance and abnormal cord insertions are strongly associated with selective fetal growth restriction (sFGR) as defined according to conventional criteria or the newer consensus criteria. A combination of these two markers substantially improves the screening rates, with a positive likelihood ratio of 10.33 for sFGR. However, this combination fails to distinguish the type 1 sFGR cases from the type 2/3, which typically have poorer outcomes. CONCLUSION: CRL discordance and abnormal cord insertions are strongly associated with the development sFGR in monochorionic pregnancies. A combination of these two markers shows promising potential as a screening test to identify pregnancies at a high risk for development of sFGR. Earlier diagnosis can help plan timely fetal intervention and improve the overall outcomes of these pregnancies. These markers need to be validated in larger studies before being adopted for screening of monochorionic pregnancies.

Spontaneous twin anemia polycythemia sequence: diagnosis, management, and outcome in an international cohort of 249 cases.

BACKGROUND: Twin anemia polycythemia sequence is a chronic form of unbalanced fetofetal transfusion through minuscule placental anastomoses in monochorionic twins, leading to anemia in the donor and polycythemia in the recipient. Owing to the low incidence of twin anemia polycythemia sequence, data on diagnosis, management, and outcome are limited. OBJECTIVE: This study aimed to investigate the diagnosis, management, and outcome in a large international cohort of spontaneous twin anemia polycythemia sequence. STUDY DESIGN: Data from the international twin anemia polycythemia sequence registry, retrospectively collected between 2014 and 2019, were used for this study. A total of 17 fetal therapy centers contributed to the data collection. The primary outcomes were perinatal mortality and severe neonatal morbidity. Secondary outcomes included a risk factor analysis for perinatal mortality and severe neonatal morbidity. RESULTS: A total of 249 cases of spontaneous twin anemia polycythemia sequence were included in this study, 219 (88%) of which were diagnosed antenatally and 30 (12%) postnatally. Twin anemia polycythemia sequence was diagnosed antenatally at a median gestational age of 23.7 weeks (interquartile range, 9.7-28.8; range, 15.1-35.3). Antenatal management included laser surgery in 39% (86 of 219), expectant management in 23% (51 of 219), delivery in 16% (34 of 219), intrauterine transfusion (with partial exchange transfusion) in 12% (26 of 219), selective feticide in 8% (18 of 219), and termination of pregnancy in 1% (3 of 219) of cases. Perinatal mortality rate was 15% (72 of 493) for the total group, 22% (54 of 243) for donors, and 7% (18 of 242) for recipients (P<.001). Severe neonatal morbidity occurred in 33% (141 of 432) of twins with twin anemia polycythemia sequence and was similar for donors (32%; 63 of 196) and recipients (33%; 75 of 228) (P=.628). Independent risk factors for spontaneous perinatal mortality were donor status (odds ratio, 3.8; 95% confidence interval, 1.9-7.5; P<.001), antenatal twin anemia polycythemia sequence stage (odds ratio, 6.3; 95% confidence interval, 1.4-27.8; P=.016 [stage 2]; odds ratio, 9.6; 95% confidence interval, 2.1-45.5; P=.005 [stage 3]; odds ratio, 20.9; 95% confidence interval, 3.0-146.4; P=.002 [stage 4]), and gestational age at birth (odds ratio, 0.8; 95% confidence interval, 0.7-0.9; P=.001). Independent risk factors for severe neonatal morbidity were antenatal twin anemia polycythemia sequence stage 4 (odds ratio, 7.9; 95% confidence interval, 1.4-43.3; P=.018) and gestational age at birth (odds ratio, 1.7; 95% confidence interval, 1.5-2.1, P<.001). CONCLUSION: Spontaneous twin anemia polycythemia sequence can develop at any time in pregnancy from the beginning of the second trimester to the end of the third trimester. Management for twin anemia polycythemia sequence varies considerably, with laser surgery being the most frequent intervention. Perinatal mortality and severe neonatal morbidity were high, the former especially so in the donor twins.

Twin-twin transfusion syndrome - What we have learned from clinical trials.

Monochorionic twin pregnancies are at increased risk for adverse outcome compared to dichorionic twin pregnancies and singletons. Monochorionic-specific complications include twin-twin transfusion syndrome (TTTS), twin anemia-polycythemia sequence, single intrauterine fetal demise and its consequences on the co-twin, and selective intrauterine growth restriction. Whereas the natural history of monochorionic-specific complications carries a high risk of fetal death or severe neurologic disability, a framework now exists, based on well-designed clinical trials, for optimal treatment of these entities. Fetoscopic selective laser coagulation of anastomotic vessels on the chorionic plate has been clearly demonstrated to improve survival and neurologic outcomes for Quintero stage ≥2 TTTS. However, many challenges remain unsolved, the most important of which is preterm premature rupture of membranes. Further improvement in the outcomes of monochorionic pregnancies will require improvements in the rate of premature delivery, and improved diagnosis and treatment strategies for early and late onset TTTS.

Prenatal diagnosis of isochromosome 20q in a fetus with vertebral anomaly and rocker-bottom feet.

OBJECTIVE: Isochromosome of the long arm of chromosome 20 (i(20q)) is a rare structural abnormality in prenatal diagnosis. Thirty prenatal cases of mosaic i(20q) have been reported, among which only four are associated with fetal malformations. We describe a new prenatal case of i(20q) with fetal malformations. MATERIALS AND METHODS: We also observed a discrepancy between uncultured and cultured amniotic fluid cells by using conventional cytogenetic, fluorescence in situ hybridization and array-SNP analysis. RESULTS: The short arm deletion of chromosome 20 arising from the isochromosome encompassed two candidate genes PAX1 and JAG1 involved in cranio-facial and vertebral development. CONCLUSION: The data would allow establishing a phenotype-genotype correlation. Thus, we proposed to define a recognizable syndrome combining cranio-facial dysmorphism, vertebral bodies' anomalies, feet and cerebral malformations.

Pseudofeeders on fetal magnetic resonance imaging predict outcome in vein of Galen malformations.

OBJECTIVE: Although vein of Galen aneurysmal malformations (VGAM) can be diagnosed in the fetus, the challenge is predicting the occurrence of its 2 major complications: cardiopulmonary failure and encephalomalacia. This study attempts to determine which fetal brain magnetic resonance imaging (MRI) features might be used to predict the development of these complications at birth. METHODS: The cohort was extracted from a prospectively assembled database of VGAM cases managed at a single referral center from 2000 to 2014. Of 251 patients with VGAM, 83 cases were diagnosed prenatally. A total of 58 patient charts having at least 1 fetal MRI were reviewed. Patterns of brain parenchyma, hydrocephalus, and so-called middle cerebral artery (MCA) "pseudofeeders" were correlated with cardiac failure, pulmonary hypertension, and encephalomalacia at birth. RESULTS: The median gestational age at fetal MRI was 32.3 weeks of pregnancy (±2.3). Nine fetuses (16%) had encephalomalacia. Thirty-one fetuses (53%) had MCA pseudofeeders. Twenty-six fetuses (45%) had prenatal hydrocephalus. Prenatal MCA pseudofeeders were a risk factor for encephalomalacia at birth (p = 0.001). MCA pseudofeeders and hydrocephalus were risk factors for both severe cardiac failure (p = 0.01 and p = 0.04, respectively) and severe pulmonary hypertension (p = 0.014 and p = 0.05, respectively) at birth. INTERPRETATION: MCA pseudofeeders are the result of impaired cerebral blood flow, and are thus a risk factor for further brain melting at birth. Their presence can be used for informing parents and as an aid in management decisions. Ann Neurol 2017;81:278-286.

The performance of an intermediate 16th-week ultrasound scan for the follow-up of euploid fetuses with increased nuchal translucency.

OBJECTIVE: The objective of the study is to assess the utility of an intermediate ultrasound scan at 16(+0) to 18(+6) weeks of gestation in euploid fetuses with increased nuchal translucency ≥ 3.5 mm. METHODS: Three hundred eighty-nine fetuses with nuchal translucency (NT) ≥ 3.5 mm were identified in two prenatal centers between January 2008 and December 2012. Pregnancy work-up included karyotyping, monthly detailed ultrasound scan starting with a 16th-week scan, a cardioechography, and a genetic counseling. Abnormal findings and pregnancy outcomes were analyzed retrospectively. RESULTS: Of the 389 fetuses included, 52% had normal karyotype. Among euploid fetuses, 51 (30.7%) structural defects were identified overall. First-trimester scan was useful to identify 16 of the major defects (31.3%), and the 16th-week scan was useful to identify an additional 21 of them (41.2%), whereas the 22nd-week pregnancy scan discovered an additional 14 (27.4%). Structural defects discovered with the 16th-week scan were cardiac defects (n = 7), polymalformative syndromes (n = 3), left diaphragmatic hernias (n = 3), limbs abnormalities (n = 2), genitourinary (n = 2), microretrognathism (n = 2), hydrops (n = 1), and exomphalos (n = 1). If the intermediate scan was normal, the chances of a favorable outcome were as high as 85% and were close to 100% after 20 weeks, irrespective of initial NT. CONCLUSION: The intermediate ultrasound was useful in fetuses with increased NT pregnancy work-up.

Non-invasive prenatal testing for fetal sex determination: is ultrasound still relevant?

Early prenatal diagnosis of fetal sex is necessary to optimize pregnancy management in families known to be at risk of some heritable disorders. The demonstration of cell-free fetal DNA (cffDNA) in the mother's blood has made it possible to identify Y chromosome sequences in maternal blood and to determine fetal sex noninvasively, during the first trimester. This procedure can significantly reduce the number of invasive procedures for women with fetuses at risk of sex-linked diseases and optimize the management of these pregnancies. Fetal sex can be diagnosed by ultrasound with the same sensitivity and specificity, but later in pregnancy. We performed a review of the published literature evaluating the use of cffDNA and ultrasound for prenatal determination of fetal sex during the first trimester of pregnancy. We present the feasibility of the two methods and their impact on clinical practice. We applied a sensitive search of multiple bibliographic databases including Pubmed (MEDLINE), EMBASE, the Cochrane Library and Web of science between 1998 and 2013. Sixteen reports of the determination of fetal sex in maternal blood and 13 reports of the determination by ultrasound met our inclusion criteria. We found a sensitivity and specificity of nearly 100% from 8 weeks of gestation for cffDNA and from 13 weeks of gestation for ultrasound respectively. Based on this review, we conclude that fetal sex can be determined with a high level of accuracy by analyzing cffDNA and at an earlier gestation than ultrasound. Ten years after the first feasibility study, the French National Authority for Health (HAS) released a technological assessment report on the determination of fetal sex in maternal blood, which has resulted in validating this test for reimbursement by the national health insurance fund for the following indications: X-linked recessive disease and congenital adrenal hyperplasia.