Publications

Abstract

Background: Prenatal care providers will play an important role in the acceptance of SARS-Cov-2 vaccination for pregnant women.

Objective: To determine the perceptions of French prenatal care providers: midwives, general practitioners (GPs) and obstetricians and gynaecologists (Ob-Gyn) regarding SARS-CoV-2 vaccination during pregnancy.

Study design: An anonymous online survey was sent to members of French professional societies representing prenatal practitioners. The participants were asked to answer questions on their characteristics and give their opinions of the SARS-CoV-2 vaccine for themselves and women who are pregnant or willing to become pregnant.

Results: Access to the survey was opened from January 11th, 2021, to March 1st, 2021. A total of 1,416 responses were collected from 749 Ob-Gyn, 598 midwives and 69 GPs. Most respondents (86.7% overall, 90.4% for Ob-GYN, 81.1% for GPs and 80.1% for midwives) agreed to receive the SARS-CoV-2 vaccine. Vaccination against SARS-CoV-2 would be offered to pregnant women by 49.4% 95%CI [48.1-50.8] of the participants. Midwives were less likely to recommend vaccination than GP and Ob-Gyn (37.5%, 50.7% and 58.8%, respectively). The multinomial logistic regression revealed that being an obstetrician, working in a group, usually offering a flu vaccine and wanting to be vaccinated against SARS-CoV-2 were positively associated with considering pregnant women for SARS-CoV-2 vaccination.

Conclusion: Most French prenatal healthcare providers are favourable towards vaccinating pregnant women, but a large minority express reservation. More evidence on safety and involvement by professional organisations will be important to encourage the access of pregnant women to vaccination against SARS-CoV-2.

Abstract

Objective: To compare mortality and rates of significant neurosensory impairment (sNSI) at 18-36 months’ corrected age in infants born extremely preterm across three international cohorts.

Design: Retrospective analysis of prospectively collected neonatal and follow-up data.

Setting: Three population-based observational cohort studies: the Australian and New Zealand Neonatal Network (ANZNN), the Canadian Neonatal and Follow-up Networks (CNN/CNFUN) and the French cohort Etude (Epidémiologique sur les Petits Ages Gestationnels: EPIPAGE-2).

Patients: Extremely preterm neonates of <28 weeks’ gestation in year 2011.

Main outcome measures: Primary outcome was composite of mortality or sNSI defined by cerebral palsy with no independent walking, disabling hearing loss and bilateral blindness.

Results: Overall, 3055 infants (ANZNN n=960, CNN/CNFUN n=1019, EPIPAGE-2 n=1076) were included in the study. Primary composite outcome rates were 21.3%, 20.6% and 28.4%; mortality rates were 18.7%, 17.4% and 26.3%; and rates of sNSI among survivors were 4.3%, 5.3% and 3.3% for ANZNN, CNN/CNFUN and EPIPAGE-2, respectively. Adjusted for gestational age and multiple births, EPIPAGE-2 had higher odds of composite outcome compared with ANZNN (OR 1.71, 95% CI 1.38 to 2.13) and CNN/CNFUN (OR 1.72, 95% CI 1.39 to 2.12). EPIPAGE-2 did have a trend of lower odds of sNDI but far short of compensating for the significant increase in mortality odds. These differences may be related to variations in perinatal approach and practices (and not to differences in infants’ baseline characteristics).

Conclusions: Composite outcome of mortality or sNSI for extremely preterm infants differed across high-income countries with similar baseline characteristics and access to healthcare.

Abstract

Aims: In 2018, 1.07 million pregnant women received antiretroviral drugs, raising whether this affects pregnancy outcomes. We assessed the adverse pregnancy outcomes associated with prenatal antiretroviral drug exposure, notified to the French ANRS pharmacovigilance system.

Methods: An exhaustive case report series has been performed using the ANRS pharmacovigilance database. All ANRS-sponsored HIV clinical research studies using antiretroviral drugs either in pregnant women or women of childbearing age were eligible from 2004 to 2019. We analysed the following pregnancy outcomes: abortion, ectopic pregnancy, stillbirth, prematurity (<37 weeks of gestational age), low birth weight (<2500 g) and congenital abnormalities. A logistic regression was performed to assess the odds ratio (OR) for each outcome separately (if occurrence >50) compared to the outcome observed when exposed to non-nucleoside-reverse-transcriptase-inhibitor (NNRTI)-based regimen as the reference.

Results: Among the 34 studies selected, 918 deliveries occurred, of whom 88% had pregnancy outcomes documented. Pregnant women were mainly exposed to PI (n = 387, 48.6%), NNRTI (n = 331, 41.5%) and INI-based combinations (n = 40, 5.0%, 18 on dolutegravir). Compared to NNRTI-based combinations, there was no significant association observed with exposure to other antiretroviral combination for spontaneous abortion, prematurity or low birth weight, except an increased risk of low birth weight in new-born exposed to exclusive nucleoside-reverse-transcriptase-inhibitor (NRTI) combinations (n = 4; OR 7.50 [1.49-37.83]).

Conclusions: Our study, mainly based on protease inhibitor (PI) and NNRTI-based regimens, is overall reassuring on the risk of adverse pregnancy outcomes, except for NRTI which should be interpreted cautiously (small number, indication bias). In this study, the number of integrase inhibitor (INI)-based combinations was too low to draw any conclusions.

Abstract

Background: Preterm prelabor rupture of membranes (PPROM) before 34 weeks of gestation complicates 1% of pregnancies and accounts for one-third of preterm births. International guidelines recommend expectant management, along with antenatal steroids before 34 weeks and antibiotics. Up-to-date evidence about the risks and benefits of administering tocolysis after PPROM, however, is lacking. In theory, reducing uterine contractility could delay delivery and reduce the risks of prematurity and its adverse short- and long-term consequences, but it might also prolong fetal exposure to inflammation, infection, and acute obstetric complications, potentially associated with neonatal death or long-term sequelae. The primary objective of this study is to assess whether short-term (48 h) tocolysis reduces perinatal mortality/morbidity in PPROM at 22 to 33 completed weeks of gestation.

Methods: A randomized, double-blind, placebo-controlled, superiority trial will be performed in 29 French maternity units. Women with PPROM between 22^0/7 and 33^6/7 weeks of gestation, a singleton pregnancy, and no condition contraindicating expectant management will be randomized to receive a 48-hour oral treatment by either nifedipine or placebo (1:1 ratio). The primary outcome will be the occurrence of perinatal mortality/morbidity, a composite outcome including fetal death, neonatal death, or severe neonatal morbidity before discharge. If we assume an alpha-risk of 0.05 and beta-risk of 0.20 (i.e., a statistical power of 80%), 702 women (351 per arm) are required to show a reduction of the primary endpoint from 35% (placebo group) to 25% (nifedipine group). We plan to increase the required number of subjects by 20%, to replace any patients who leave the study early. The total number of subjects required is thus 850. Data will be analyzed by the intention-to-treat principle.

Discussion: This trial will inform practices and policies worldwide. Optimized prenatal management to improve the prognosis of infants born preterm could benefit about 50,000 women in the European Union and 40,000 in the United States each year.

Trial registration: ClinicalTrials.gov identifier: NCT03976063 (registration date June 5, 2019).

Abstract

Objective: To evaluate the respiratory outcome in children with congenital heart disease (CHD), considering recent management procedures and the CHD pathophysiology.

Design and setting: Clinical and functional respiratory outcome were evaluated in 8-year-old children with isolated CHD followed up from birth in the prospective population-based EPICARD cohort.

Patients: Children were assigned to two groups, based on the pathophysiology of the CHD: CHDs with left-to-right shunt (n = 212) and CHDs with right outflow tract obstruction (n = 113).

Results: Current wheezing episodes were observed in 15% of the children with isolated CHD and left-to-right shunt, and 11% of the children with isolated CHD and right outflow tract obstruction (not significant). Total lung capacity (TLC) was the only respiratory function parameter that significantly differed between the two groups. It was lower in children with left-to-right shunt (88.72 ± 0.65% predicted) than in those with right outflow tract obstruction (91.84 ± 0.96, p = 0.006). In multivariate analysis, CHD with left-to-right shunt (coeff. [95% CI]: -3.17 [-5.45; -0.89]) and surgery before the age of 2 months (-6.52 [-10.90; -2.15]) were identified as independent factors associated with significantly lower TLC values.

Conclusion: Lower TLC remains a long-term complication in CHD, particularly in cases with left-to-right shunt and in patients requiring early repair. These findings suggest that an increase in pulmonary blood flow may directly impair lung development.

Abstract

Intrauterine growth restriction (IUGR) increases the risk of bronchopulmonary dysplasia (BPD), one of the major complications of prematurity. Antenatal low-protein diet (LPD) exposure in rats induces IUGR and mimics BPD-related alveolarization disorders. Peroxisome proliferator-activated receptor-γ (PPARγ) plays a key role in normal lung development and was found deregulated following LPD exposure. The objective of this article was to investigate the effects of nebulized curcumin, a natural PPARγ agonist, to prevent IUGR-related abnormal lung development. We studied rat pups antenatally exposed to an LPD or control diet (CTL) and treated with nebulized curcumin (50 mg/kg) or vehicle from postnatal (P) days 1 to 5. The primary readouts were lung morphometric analyses at P21. Immunohistochemistry (P21) and microarrays (P6 and P11) were compared within animals exposed to LPD versus controls, with and without curcumin treatment. Quantitative morphometric analyses revealed that LPD induced abnormal alveolarization as evidenced by a significant increase in mean linear intercept (MLI) observed in P21 LPD-exposed animals. Early curcumin treatment prevented this effect, and two-way ANOVA analysis demonstrated significant interaction between diet and curcumin both for MLI [F_(1,39) = 12.67, P = 0.001] and radial alveolar count at P21 [F_(1,40) = 6.065, P = 0.0182]. Immunohistochemistry for fatty acid binding protein 4 (FABP4), a major regulator of PPARγ pathway, showed a decreased FABP4⁺ alveolar cell density in LPD-exposed animals treated by curcumin. Transcriptomic analysis showed that early curcumin significantly prevented the activation of profibrotic pathways observed at P11 in LPD-exposed animals. Nebulized curcumin appears to be a promising strategy to prevent alveolarization disorders in IUGR rat pups, targeting pathways involved in lung development.

Background

To examine disparities by maternal place of birth in the opportunity to make an informed choice about Down syndrome screening, in France, where the national guidelines recommend that physicians offer it to all pregnant women.

Methods

We used population-based data from the nationally representative French Perinatal Surveys in 2010 and 2016 (N=24,644 women) to analyze the opportunity for an informed choice for prenatal screening, measured by a composite indicator.

Results

Among the 24 644 women in the study, 20 612 (83.6%) were born in France, 861 (3.5%) elsewhere in Europe, 1550 (6.3%) in North Africa, and 960 (3.9%) in sub-Saharan Africa. The probability of screening was lower for women born outside France. After adjustment for survey year, maternal age, parity, education level, and the maternity unit’s level of perinatal care, women born outside France had the opportunity to make an informed choice less often than women born in France. This association remained essentially the same even after excluding women without adequate prenatal care.

Conclusions

Women born outside France, including those with adequate prenatal care, had less opportunity than women born in France to make an informed choice about prenatal screening for Down syndrome.

Abstract

Purpose: Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf-Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood.

Methods: We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro.

Results: The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants.

Conclusion: NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch-Steindl syndrome after the delineators of this phenotype.

Abstract

Background: Despite several years of school-based MDA implementation, STH infections remain an important public health problem in Benin, with a country-wide prevalence of 20% in 2015. The DeWorm3 study is designed to assess the feasibility of using community-based MDA with albendazole to interrupt the transmission of STH, through a series of cluster-randomized trials in Benin, India and Malawi. We used the pre-treatment baseline survey data to describe and analyze the factors associated with STH infection in Comé, the study site of the DeWorm3 project in Benin. These data will improve understanding of the challenges that need to be addressed in order to eliminate STH as a public health problem in Benin.

Methods: Between March and April 2018, the prevalence of STH (hookworm spp., Ascaris and Trichuris trichiura) was assessed by Kato-Katz in stool samples collected from 6,153 residents in the community of Comé, Benin using a stratified random sampling procedure. A standardized survey questionnaire was used to collect information from individual households concerning factors potentially associated with the presence and intensity of STH infections in pre-school (PSAC, aged 1-4), school-aged children (SAC, aged 5-14) and adults (aged 15 and above). Multilevel mixed-effects models were used to assess associations between these factors and STH infection.

Results: The overall prevalence of STH infection was 5.3%; 3.2% hookworm spp., 2.1% Ascaris lumbricoides and 0.1% Trichuris. Hookworm spp. were more prevalent in adults than in SAC (4.4% versus 2.0%, respectively; p = 0.0001) and PSAC (4.4% versus 1.0%, respectively; p<0.0001), whilst Ascaris lumbricoides was more prevalent in SAC than in adults (3.0% versus 1.7%, respectively; p = 0.004). Being PSAC (adjusted Odds Ratio (aOR) = 0.2, p< 0.001; adjusted Infection Intensity Ratio (aIIR) = 0.1, p<0.001) or SAC (aOR = 0.5, p = 0.008; aIIR = 0.3, p = 0.01), being a female (aOR = 0.6, p = 0.004; aIIR = 0.3, p = 0.001), and having received deworming treatment the previous year (aOR = 0.4, p< 0.002; aIIR = 0.2, p<0.001) were associated with a lower prevalence and intensity of hookworm infection. Lower income (lowest quintile: aOR = 5.0, p<0.001, 2nd quintile aOR = 3.6, p = 0.001 and 3rd quintile aOR = 2.5, p = 0.02), being a farmer (aOR = 1.8, p = 0.02), medium population density (aOR = 2.6, p = 0.01), and open defecation (aOR = 0.5, p = 0.04) were associated with a higher prevalence of hookworm infection. Lower education-no education, primary or secondary school- (aIIR = 40.1, p = 0.01; aIIR = 30.9, p = 0.02; aIIR = 19.3, p = 0.04, respectively), farming (aIIR = 3.9, p = 0.002), natural flooring (aIIR = 0.2, p = 0.06), peri-urban settings (aIIR = 6.2, 95%CI 1.82-20.90, p = 0.003), and unimproved water source more than 30 minutes from the household (aIIR = 13.5, p = 0.02) were associated with a higher intensity of hookworm infection. Improved and unshared toilet was associated with lower intensity of hookworm infections (aIIR = 0.2, p = 0.01). SAC had a higher odds of Ascaris lumbricoides infection than adults (aOR = 2.0, p = 0.01) and females had a lower odds of infection (aOR = 0.5, p = 0.02).

Conclusion: Hookworm spp. are the most prevalent STH in Comé, with a persistent reservoir in adults that is not addressed by current control measures based on school MDA. Expanding MDA to target adults and PSAC is necessary to substantially impact population prevalence, particularly for hookworm.

Abstract

In preterm infants, a high risk of hemodynamically significant patent ductus arteriosus (PDA) exists and its persistence is associated with an increased risk of severe morbidity. Current pharmacological options include ibuprofen or indomethacin. However, treatment by indomethacin or ibuprofen of a large PDA was shown to reduce early pulmonary hemorrhage and later medical treatment but had no effect on neonatal death or morbidity. Early prophylactic treatment of ductus arteriosus by paracetamol seems to be an attractive opportunity to reduce life-threatening morbidity. However, there are currently no data regarding the pharmacokinetics (PK) and pharmacodynamics of paracetamol in preterm neonates in this potential new indication. In this study, we aimed to develop a population PK model for paracetamol and investigate the relationship between paracetamol exposure levels and time to contraction of the ductus. Data were modeled using Monolix software. A one-compartment model adequately described the paracetamol concentration-time course. A Weibull model adequately described the time to contraction of the ductus. Our results suggest that the dosage used in this study (i.e., first day 42.5 mg/kg, then 30 mg/kg/day) allows for reaching the maximum inhibition response from paracetamol regarding the time to close the ductus. However, this study pointed out a lower effect of paracetamol on extremely preterm neonates (below 27 weeks). Therefore, a dose-finding study focusing specifically on extremely preterm neonates with treatment efficacy and toxicity is strongly needed.