Lionel Carbillon

Pregnancy, vascular tone, and maternal hemodynamics: a crucial adaptation.

The adaptation of vascular tone in early pregnancy precedes and probably triggers blood volume and cardiac output increase. Because the endothelium is known to regulate vascular smooth muscle action, the role of nitric oxide (NO) in the setting up of adequate uteroplacental and renal blood flow during normal pregnancy was investigated. The persistence of abnormally high uteroplacental resistance is a strong predisposing factor for intrauterine growth retardation and preeclampsia and can be screened by second trimester Doppler assessment of the uterine arteries. Current hypotheses suggested by experimental and clinical data concerning preeclampsia confirm the crucial role played by the endothelium and vascular tone adaptation. The analysis of these data leads to consider apart early-onset preeclampsia affecting pregnancies with growth retarded fetuses and associated with high vascular resistance. Lastly, NO donors seem to significantly decrease the impedance in the uteroplacental circulation and to improve fetoplacental hemodynamics assessed by Doppler measurements, and their therapeutic use in some forms of preeclampsia might be promising. Target Audience Obstetricians & Gynecologists, Family Physicians Learning Objectives After completion of this article, the reader will be able to summarize the events that regulate vascular tone in pregnancy, specifically the role of nitric oxide and other vasoactive prostaglandins in the regulation of vascular tone and to describe the various hypotheses concerning the mechanism and the mediators responsible for initiating endothelial damage in the various disorders of vascular tone in pregnancy.

European registry of babies born to mothers with antiphospholipid syndrome

Objectives This study aimed to describe the long-term outcome and immunological status of children born to mothers with antiphospholipid syndrome, to determine the factors responsible for childhood abnormalities, and to correlate the childs immunological profile with their mothers. Methods A prospective follow-up of a European multicentre cohort was conducted. The follow-up consisted of clinical examination, growth data, neurodevelopmental milestones and antiphospholipid antibodies (APL) screening. Children were examined at 3, 9, 24 months and 5 years. Results 134 children were analysed (female sex in 65 cases, birth weight 3000±500 g, height 48±3 cm). Sixteen per cent had a preterm birth (<37 weeks; n=22), and 14% weighted less than 2500 g at birth (n=19). Neonatal complications were noted in 18 cases (13%), with five infections (4%). During the 5-year follow-up, no thrombosis or systemic lupus erythematosus (SLE) was noted. Four children displayed behavioural abnormalities, which consisted of autism, hyperactive behaviour, feeding disorder with language delay and axial hypotony with psychomotor delay. At birth lupus anticoagulant was present in four (4%), anticardiolipin antibodies (ACL) IgG in 18 (16%), anti-β2 glycoprotein-I (anti-β2GPI) IgG/M in 16 (15%) and three (3%), respectively. ACL IgG and anti-β2GPI disappeared at 6 months in nine (17%) and nine (18%), whereas APL persisted in 10% of children. ACL and anti-β2GPI IgG were correlated with the same mothers antibodies before 6 months of age (p<0.05). Conclusion Despite the presence of APL in children, thrombosis or SLE were not observed. The presence of neurodevelopmental abnormalities seems to be more important in these children, and could justify long-term follow-up.

The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study.

In European multicenter study, we aimed to describe the real-life hydroxychloroquine use in APS patients during pregnancy and determine its benefit in refractory obstetrical APS. We analyzed the outcome of pregnancies treated by hydroxychloroquine in patients with APS or asymptomatic antiphospholipid (aPL) antibodies carriers. Thirty patients with APS with 35 pregnancies treated by hydroxychloroquine were analyzed. Comparing the outcome of pregnancies treated by the addition of hydroxychloroquine to previous pregnancies under the conventional treatment, pregnancy losses decreased from 81% to 19% (p<0.05), without differences in the associated treatments. The univariate analysis showed that the previous intrauterine deaths and higher hydroxychloroquine amount (400mg per day) were the factors associated with pregnancy outcome. Considering 14 patients with previous refractory obstetrical APS (n=5 with obstetrical and thrombotic primary APS and n=9 with purely obstetrical APS), all with previous pregnancy losses under treatment (aspirin with LMWH in 11 cases and LMWH in 3 cases), the addition of hydroxychloroquine resulted in live born babies in 11/14 (78%) cases (p<0.05). Our study shows the benefit of hydroxychloroquine addition in patients with refractory obstetrical APS and raises the need of prospective studies to confirm our preliminary study.

Universal rather than selective screening for gestational diabetes mellitus may improve fetal outcomes

AIM The benefit of treating gestational diabetes mellitus (GDM) has recently been shown. The aim of this study was to compare offspring and maternal health benefits from selective or universal screening for GDM. METHODS The incidence of outcomes was compared in three series of pregnant women: 1) the 159 consecutive women with GDM out of the 1909 women who delivered between October 2000 and September 2001: during this period screening for GDM was based on risk factors (risk factor-GDM); 2) the 265 consecutive women with GDM out of the 2111 women who delivered during the year 2002: during this period screening for GDM was universal (universal-GDM); 3) 1255 women with no GDM during year 2002 (controls). RESULTS After adjustment for age, pregravid body mass index, parity, and ethnicity, the risk of large for gestational age (Odds ratio 2.19[95% confidence interval 1.36-3.54], P < 10(-3)), delivery before 37 weeks of gestation (OR 2.44 [95CI 1.32-4.51], P = 0.004), jaundice (OR 3.31[95CI 1.58-6.93], P = 0.002), hospitalization in the department of pediatrics (OR 2.35 [95CI 1.53-3.61], P < 10(-3)) was higher in the GDM-risk factor group than in the control group, whereas it was similar in the universal-GDM group and the control group. Compared with the control group, the risk of anticipated delivery and hospital stay > 4 days after delivery was increased in the GDM-risk factor group (OR 2.69[1.88-3.84], P < 10(-3); and OR 2.6 [1.82-3.71], P < 10(-3) respectively) and the universal-GDM group (OR 1.54 [1.15-2.07] P = 0.004; and OR 1.49 [1.13-1.97], P = 0.005 respectively). CONCLUSION This observational study suggests that universal rather than selective screening for GDM may improve outcomes. Universal screening might reduce delay of diagnosis and care.

Prospective Evaluation of Uterine Artery Flow Velocity Waveforms at 12–14 and 22–24 Weeks of Gestation in Relation to Pregnancy Outcome and Birth Weight

Objective: Uterine artery flow velocity was prospectively assessed using Doppler ultrasound at 12–14 and 22–24 weeks of gestation in the prediction of subsequent complications related to uteroplacental insufficiency: preeclampsia, pregnancy-induced hypertension, fetal growth restriction, fetal death and placental abruption, and to elucidate its relationship with birth weight. Methods: Uterine artery Doppler assessment was obtained during routine ultrasound screening in 263 unselected women. Flow velocity waveforms were coded according to the number of notches present at each scanning, respectively: none (0, 0), uni-/bilateral notches that disappeared (1, 0) or (2, 0), uni-/bilateral notches that persisted unilaterally (1, 1) or (2, 1), and persistent bilateral notches (2, 2). Results: Complete outcome data was obtained for 243 (92.4%) women. Of these women, 55 (22.6%) and 84 (34.6%) women had uni- and bilateral notches, respectively, at 12–14 weeks’ gestation; 14 (5.8%) and 21 (8.6%) patients had uni- and bilateral notches, respectively, at 22–24 weeks’ gestation. Analysis of complication rates for the four groups showed that they increased with notch persistence (5.7, 13.5, 57.1 and 76.2%), while the corresponding mean birth weight declined (3,273, 3,180, 2,698 and 2,418 g). Conclusion: The absence or early disappearance of uterine artery notches is associated with fewer complications related to uteroplacental insufficiency and normal birth weight, whereas their late and partial disappearance or bilateral persistence tends to compromise the prognosis.

The Role of Integrins in Human Embryo Implantation

Integrins are adhesion molecules present in endometrial, decidual, and extravillous cytotrophoblast (EVCT) cells. They participate in cell-cell adhesion as well as in adhesion between cells and components of the extracellular matrix, and they play an important role in the endometrial phenotype change that occurs during the secretory phase, the first stage of implantation. At the beginning of pregnancy, the change in integrin expression is synchronized with the trophoblast attachment (embryo-endometrium interactions with integrins αvβ3, α4β1, α6β1, and α7β1) and the embryo’s invasion of the decidua (integrins α6β4→α5β1→α1β1→α4β1 switch from proliferative to endovascular EVCT). Several diseases, including preeclampsia, intrauterine growth retardation caused by vascular problems and defective luteal phases, may be explained by anomalies in integrin patterns.

First-Trimester Diagnosis of Sirenomelia

We report a case of sirenomelia diagnosed at 13 gestational weeks. This rare malformation sequence is characterized by fusion and rotation of the lower limbs to various degrees and anorectal atresia, usually associated with absence of bladder and agenesis or dysgenesis of the kidneys. Diagnosis is commonly made later in the second trimester of pregnancy with oligohydramnios as the alerting sign. Survival is extremely rare, and only possible in the absence of bilateral renal agenesis. In view of the dismal prognosis, early diagnosis allows for earlier and less traumatic therapeutic abortion.

Obstetrical APS : Is there a place for hydroxychloroquine to improve the pregnancy outcome?

The use of the conventional APS treatment (the combination of low-dose aspirin and LMWH) dramatically improved the obstetrical prognosis in primary obstetrical APS (OAPS). The persistence of adverse pregnancy outcome raises the need to find other drugs to improve obstetrical outcome. Hydroxychloroquine is widely used in patients with various autoimmune diseases, particularly SLE. Antimalarials have many anti-inflammatory, anti-aggregant and immune-regulatory properties: they inhibit phospholipase activity, stabilize lysosomal membranes, block the production of several pro-inflammatory cytokines and, in addition, impair complement-dependent antigen-antibody reactions. There is ample evidence of protective effects of hydroxychloroquine in OAPS similar to the situation in SLE arising from in vitro studies of pathophysiological working mechanism of hydroxychloroquine. However, the clinical data on the use of hydroxychloroquine in primary APS are lacking and prospective studies are necessary.

Autism spectrum disorders in babies born to mothers with antiphospholipid syndrome

OBJECTIVES To evaluate the outcomes of babies born to mothers with primary antiphospholipid syndrome and to compare to the outcomes of babies of mothers with systemic lupus erythematosus. METHODS A retrospective study from 2003 to 2010 assessing the clinical characteristics and psychomotor development, as well as the immunological data, of children born to mothers with antiphospholipid syndrome (APS) (group 1) and systemic lupus erythematosus (group 2). RESULTS Group 1 consisted of 36 children born to mothers (n = 26) with a primary APS. Autism spectrum disorders occurred in 3 children from group 1 and all of them had persistent anti-β2GP1 IgG antibodies. Group 2 consisted of 12 children born to mothers (n = 9) with lupus erythematosus. Three children experienced cutaneous neonatal lupus, but there were no neurodevelopmental disorders. Comparing children of groups 1 and 2, no significant difference was found with regard to the parameters at birth or during follow-up. The children in group 2 had antinuclear antibodies more frequently (p < 0.05). CONCLUSION Autism spectrum disorders could be observed in babies born to mothers with antiphospholipid syndrome, but there is no risk of thrombosis. KEY MESSAGES Neonatal lupus is well-known complication in children born to mothers with systemic lupus erythematosus, but there is no risk of thrombosis in APS-exposed children. In children of APS mothers the rate of prematurity and small-for-gestational age weight remain high even in treated pregnancy. The presence of several cases of autism spectrum disorders in APS-exposed children could be related to mothers antibodies exposition, but need to be confirmed.

First trimester uterine artery Doppler for the prediction of preeclampsia and foetal growth restriction.

Feasibility and reproducibility of uterine artery Doppler (UAD) at 11–14 gestational weeks was recently confirmed. Normal range values were established for resistance and pulsatility indexes. A body of evidence supports that the risk of developing preeclampsia or foetal growth restriction is highest when UAD impedance (evaluated by sus-mentioned indexes or uterine artery notch persistence) remains bilaterally high from first to second trimester, whereas the risk is lowest when UAD impedance is low from 11 to 14 gestational weeks. In unselected women, the sensitivity of 11–14 weeks-UAD is high but the positive predictive value is low, and data do not support its introduction as the sole predictive test. In models using maternal history and 11–14 weeks-UAD, the negative predictive value is high while abnormal UAD may identify a high proportion of women that will develop early-onset preeclampsia. Algorithms combining biochemical markers could still improve this prediction rate at higher cost and complexity.