Bruno Carbonne

Calcium channel blockers for inhibiting preterm labour

BACKGROUNDnPreterm birth is a major contributor to perinatal mortality and morbidity and affects approximately six to seven per cent of births in developed countries. Tocolytics are drugs used to suppress uterine contractions. The most widely tested tocolytics are betamimetics. Although they have been shown to delay delivery, betamimetics have not been shown to improve perinatal outcome, and they have a high frequency of unpleasant and even fatal maternal side effects. There is growing interest in calcium channel blockers as a potentially effective and well tolerated form of tocolysis.nnnOBJECTIVESnTo assess the effects on maternal, fetal and neonatal outcomes of calcium channel blockers, administered as a tocolytic agent, to women in preterm labour.nnnSEARCH STRATEGYnWe searched the Cochrane Pregnancy and Childbirth Groups specialised register of controlled trials (June 2002), the Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2002), MEDLINE (1965 to June 2002), EMBASE (1988 to June 2002), and Current Contents (1997 to June 2002). We also contacted recognised experts and cross referenced relevant material.nnnSELECTION CRITERIAnAll published and unpublished randomised trials in which calcium channel blockers were used for tocolysis for women in labour between 20 and 36 weeks gestation.nnnDATA COLLECTION AND ANALYSISnStandard methods of the Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group were used. Evaluation of methodological quality and trial data extraction were undertaken independently by three authors. Additional information was sought to enable assessment of methodology and conduct of intention-to-treat analyses. Meta-analysis was conducted assessing the effects of calcium channel blockers compared with any other tocolytic agent. Results are presented using relative risk for categorical data and weighted mean difference for continuous data.nnnMAIN RESULTSnTwelve randomised controlled trials involving 1029 women were included. When compared with any other tocolytic agent (mainly betamimetics), calcium channel blockers reduced the number of women giving birth within seven days of receiving treatment (relative risk (RR) 0.76; 95% confidence interval (CI) 0.60 to 0.97) and prior to 34 weeks gestation (RR 0.83; 95% CI 0.69 to 0.99). Calcium channel blockers also reduced the requirement for women to have treatment ceased for adverse drug reaction (RR 0.14; 95% CI 0.05 to 0.36), the frequency of neonatal respiratory distress syndrome (RR 0.63; 95% CI 0.46 to 0.88), necrotising enterocolitis (RR 0.21; 95% CI 0.05 to 0.96), intraventricular haemorrhage (RR 0.59 95% CI 0.36 to 0.98) and neonatal jaundice (RR 0.73; 95% CI 0.57 to 0.93).nnnREVIEWERS CONCLUSIONSnWhen tocolysis is indicated for women in preterm labour, calcium channel blockers are preferable to other tocolytic agents compared, mainly betamimetics. Further research should address the effects of different dosage regimens and formulations of calcium channel blockers on maternal and neonatal outcomes.

Tocolysis with nifedipine or beta-adrenergic agonists: a meta-analysis

Abstract Objective: To clarify the relative efficacy of nifedipine and beta-agonists for tocolysis. Data Sources: The literature was searched in the following databases: MEDLINE 1965–1998, Embase 1988–1998, Current Contents 1997–1998, and the Cochrane Database for 1998. We also sought unpublished trials and abstracts submitted to major international congresses. Search terms were: “tocolysis,” “nifedipine,” “calcium channel blocker,” “ritodrine,” “terbutaline,” and “salbutamol.” Methods of Study Selection: Randomized controlled trials comparing tocolysis with nifedipine and beta-adrenergic agonists during preterm labor were reviewed. In cases with postrandomization exclusions, authors were contacted to obtain intent-to-treat results and to avoid analytical bias. We identified 11 published and two unpublished randomized trials. Tabulation, Integration, and Results: Data were extracted by two reviewers and analyzed by a blinded biostatistician with RevMan 3.1 software from the Cochrane Collaboration. We analyzed nine relevant randomized controlled trials that included 679 patients. Meta-analysis showed that nifedipine was more effective than the beta-agonists in delaying delivery at least 48 hours [odds ratio (OR) 1.52, 95% confidence interval (CI) 1.03, 2.24], or over 34 weeks (OR 1.87, 95% CI 1.11, 3.15). The agents did not differ as to the incidence of deliveries after 37 weeks (OR 1.29, 95% CI 0.85, 1.96) or the neonatal mortality rate (OR 1.51, 95% CI 0.63, 3.65). Treatment with nifedipine was interrupted significantly less often because of side effects (OR 0.12, 95% CI 0.05, 0.29) and led to better neonatal outcomes (fewer infants with respiratory distress syndrome: OR 0.57, 95% CI 0.37, 0.89) or transferred to neonatal intensive care units (OR 0.65, 95% CI 0.43, 0.97). Conclusion: With respect to neonatal outcome, nifedipine appears to be more effective than beta-agonists for tocolysis and should be considered for use as a first-line tocolytic agent.

Calcium channel blockers for inhibiting preterm labour; a systematic review of the evidence and a protocol for administration of nifedipine

Objective: To assess the effects on maternal, fetal and neonatal outcomes of nifedipine (and other calcium channel blockers) administered as a tocolytic agent to women in preterm labour.

Calcium channel blockers for inhibiting preterm labour and birth

BACKGROUNDnPreterm birth is a major contributor to perinatal mortality and morbidity, affecting around 9% of births in high-income countries and an estimated 13% of births in low- and middle-income countries. Tocolytics are drugs used to suppress uterine contractions for women in preterm labour. The most widely used tocolytic are the betamimetics, however, these are associated with a high frequency of unpleasant and sometimes severe maternal side effects. Calcium channel blockers (CCBs) (such as nifedipine) may have similar tocolytic efficacy with less side effects than betamimetics. Oxytocin receptor antagonists (ORAs) (e.g. atosiban) also have a low side-effect profile.nnnOBJECTIVESnTo assess the effects on maternal, fetal and neonatal outcomes of CCBs, administered as a tocolytic agent, to women in preterm labour.nnnSEARCH METHODSnWe searched the Cochrane Pregnancy and Childbirth Groups Trials Register (12 November 2013).nnnSELECTION CRITERIAnAll published and unpublished randomised trials in which CCBs were used for tocolysis for women in labour between 20 and 36 completed weeks gestation.nnnDATA COLLECTION AND ANALYSISnTwo review authors independently assessed trial eligibility, undertook quality assessment and data extraction. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for data measured on a continuous scale with the 95% confidence interval (CI). The number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH) were calculated for categorical outcomes that were statistically significantly different.nnnMAIN RESULTSnThis update includes 26 additional trials involving 2511 women, giving a total of 38 included trials (3550 women). Thirty-five trials used nifedipine as the CCB and three trials used nicardipine. Blinding of intervention and outcome assessment was undertaken in only one of the trials (a placebo controlled trial). However, objective outcomes defined according to timing of birth and perinatal mortality were considered to have low risk of detection bias.Two small trials comparing CCBs with placebo or no treatment showed a significant reduction in birth less than 48 hours after trial entry (RR 0.30, 95% CI 0.21 to 0.43) and an increase in maternal adverse effects (RR 49.89, 95% CI 3.13 to 795.02, one trial of 89 women). Due to substantial heterogeneity, outcome data for preterm birth (less than 37 weeks) were not combined; one placebo controlled trial showed no difference (RR 0.96, 95% CI 0.89 to 1.03) while the other (non-placebo controlled trial) reported a reduction (RR 0.44, 95% CI 0.31 to 0.62). No other outcomes were reported.Comparing CCBs (mainly nifedipine) with other tocolytics by type (including betamimetics, glyceryl trinitrate (GTN) patch, non-steriodal anti inflammatories (NSAID), magnesium sulphate and ORAs), no significant reductions were shown in primary outcome measures of birth within 48 hours of treatment or perinatal mortality.Comparing CCBs with betamimetics, there were fewer maternal adverse effects (average RR 0.36, 95% CI 0.24 to 0.53) and fewer maternal adverse effects requiring discontinuation of therapy (average RR 0.22, 95% CI 0.10 to 0.48). Calcium channel blockers resulted in an increase in the interval between trial entry and birth (average MD 4.38 days, 95% CI 0.25 to 8.52) and gestational age (MD 0.71 weeks, 95% CI 0.34 to 1.09), while decreasing preterm and very preterm birth (RR 0.89, 95% CI 0.80 to 0.98 and RR 0.78, 95% CI 0.66 to 0.93); respiratory distress syndrome (RR 0.64, 95% CI 0.48 to 0.86); necrotising enterocolitis (RR 0.21, 95% CI 0.05 to 0.96); intraventricular haemorrhage (RR 0.53, 95% CI 0.34 to 0.84); neonatal jaundice (RR 0.72, 95% CI 0.57 to 0.92); and admissions to neonatal intensive care unit (NICU) (average RR 0.74, 95% CI 0.63 to 0.87). No difference was shown in one trial of outcomes at nine to twelve years of age.Comparing CCBs with ORA, data from one study (which did blind the intervention) showed an increase in gestational age at birth (MD 1.20 completed weeks, 95% CI 0.25 to 2.15) and reductions in preterm birth (RR 0.64, 95% CI 0.47 to 0.89); admissions to the NICU (RR 0.59, 95% CI 0.41 to 0.85); and duration of stay in the NICU (MD -5.40 days,95% CI -10.84 to 0.04). Maternal adverse effects were increased in the CCB group (average RR 2.61, 95% CI 1.43 to 4.74).Comparing CCBs with magnesium sulphate, maternal adverse effects were reduced (average RR 0.52, 95% CI 0.40 to 0.68), as was duration of stay in the NICU (days) (MD -4.55, 95% CI -8.17 to -0.92). No differences were shown in the comparisons with GTN patch or NSAID, although numbers were small.No differences in outcomes were shown in trials comparing nicardipine with other tocolytics, although with limited data no strong conclusions can be drawn. No differences were evident in a small trial that compared higher- versus lower-dose nifedipine, though findings tended to favour a high dose on some measures of neonatal morbidity.nnnAUTHORS CONCLUSIONSnCalcium channel blockers (mainly nifedipine) for women in preterm labour have benefits over placebo or no treatment in terms of postponement of birth thus, theoretically, allowing time for administration of antenatal corticosteroids and transfer to higher level care. Calcium channel blockers were shown to have benefits over betamimetics with respect to prolongation of pregnancy, serious neonatal morbidity, and maternal adverse effects. Calcium channel blockers may also have some benefits over ORAs and magnesium sulphate, although ORAs results in fewer maternal adverse effects. However, it must be noted that no difference was shown in perinatal mortality, and data on longer-term outcomes were limited. Further, the lack of blinding of the intervention diminishes the strength of this body of evidence. Further well-designed tocolytic trials are required to determine short- and longer-term infant benefit of CCBs over placebo or no treatment and other tocolytics, particularly ORAs. Another important focus for future trials is identifying optimal dosage regimens of different types of CCBs (high versus low, particularly addressing speed of onset of uterine quiescence) and formulation (capsules versus tablets). All future trials on tocolytics for women in preterm labour should employ blinding of the intervention and outcome assessment, include measurement of longer-term effects into early childhood, and also costs.

Phenotypic spectrum of fetal Smith–Lemli–Opitz syndrome

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation syndrome caused by dehydrocholesterol reductase deficiency. The diagnosis is confirmed by high 7- and secondarily 8-dehydrocholesterol levels in plasma and tissues and/or by detection of biallelic mutations in the DHCR7 gene. The phenotypic spectrum of SLOS is broad, ranging from a mild phenotype combining subtle physical anomalies with behavioral and learning problems, to a perinatally lethal multiple malformations syndrome. The fetal phenotype of SLOS has been poorly described in the literature. We report a series of 10 fetuses with molecularly proven SLOS. Even in young fetuses, the facial dysmorphism appears characteristic. Genital abnormalities are rare in 46,XX subjects. Gonadal differentiation appears histologically normal and in agreement with the chromosomal sex, contrary to what has been previously stated. We observed some previously unreported anomalies: ulnar hypoplasia, vertebral segmentation anomalies, congenital pulmonary adenomatoid malformation, fused lungs, gastroschisis, holomyelia and hypothalamic hamartoma. This latter malformation proves that SLOS phenotypically overlaps with Pallister-Hall syndrome which remains clinically a major differential diagnosis of SLOS.

Prenatal diagnosis of anoxic cerebral lesions caused by profound fetal anemia secondary to maternal red blood cell alloimmunization.

BACKGROUND: The long-term neurological prognosis of severe fetal anemia is usually considered favorable, especially when fetal hydrops regresses after successful in utero transfusion. CASES: We report two cases of prenatally diagnosed fetal cerebral anoxic lesions associated with severe fetal anemia despite appropriate and successful treatment by in utero transfusion. The two pregnancies were terminated. CONCLUSION: Profound fetal anemia may cause anoxic lesions of the fetal brain that may be diagnosed prenatally. If new onset ventriculomegaly is observed on ultrasonography after in utero transfusion for severe fetal anemia, anoxic lesions could be suspected.

Cause of Preterm Birth as a Prognostic Factor for Mortality.

OBJECTIVE: To investigate the association of the cause of preterm birth on in-hospital mortality of preterm neonates born from 24 to 34 weeks of gestation. METHODS: LEtude épidémiologique sur les petits âges gestationnels (EPIPAGE)-2 is a prospective, nationwide, population-based cohort of very preterm births. After dividing causes of preterm birth into six mutually exclusive groups, we analyzed the association of each cause with in-hospital deaths of preterm neonates born alive with adjustment for organizational, maternal, and obstetric factors. RESULTS: The analysis included 3,138 singleton live births from 24 to 34 weeks of gestation with a newborn in-hospital mortality rate of 5.0% (95% confidence interval 4.5–5.7). Preterm labor was the most frequent cause of preterm birth (n=1,293 [43.5%]) followed by preterm premature rupture of membranes (n=765 [23.9%]), hypertensive disorders without suspected fetal growth restriction (n=397 [12.7%]), hypertensive disorders with suspected fetal growth restriction (n=408 [10.9%]), placental abruption after an uncomplicated pregnancy (n=92 [3.0%]), and suspected fetal growth restriction without hypertensive disorders (n=183 [5.9%]). Neonates born because of suspected fetal growth restriction with or without hypertensive disorders (adjusted odds ratio [OR] 3.0 [1.9–4.7] and adjusted OR 2.3 [1.1–4.6], respectively) had higher adjusted risks of in-hospital death than those born after preterm labor. Risks of in-hospital mortality for preterm births caused by preterm premature rupture of membranes (adjusted OR 1.3 [0.9–1.9]), hypertensive disorders without fetal growth restriction (adjusted OR 0.7 [0.4–1.4]), or placental abruption (adjusted OR 1.6 [0.7–3.7]) were similar to those born after preterm labor. CONCLUSION: Among neonates born alive before 34 weeks of gestation, only those born because of suspected fetal growth restriction have a higher mortality risk than those born after preterm labor.

Ultrasound markers for the detection of women at risk of developing pre-eclampsia

Abstract Pre-eclampsia (PE) is a consequence of an abnormal placental invasion. Uterine artery Doppler (Ut-AD) is directly related to trophoblastic invasion of the spiral arteries, which occurs before 18 weeks’ gestation. A correct interpretation of Ut-AD indices and waveform patterns requires a rigorous and standardized methodology, in particular for the definition of notches. To date, aspirin is the only treatment associated with a decreased incidence of PE, and early identification of women at risk is crucial to optimize its use. The diagnostic performance of Ut-AD as a screening test should take into account the characteristics of the population studied. In women at high-risk of PE (i.e., women with a previous history of PE), results vary from a detection rate of 63%, with 25% false-positive results for all forms of PE, to 91% detection with 5% false-positive for early PE if repeated measurements, combined with maternal characteristics, are performed. Multicenter randomized clinical trials failed to demonstrate a benefit from administering aspirin in low-risk women with abnormal Ut-AD. In unselected populations, the use of Ut-AD, alone or integrated into algorithms including maternal characteristics, cannot be recommended for clinical practice at any gestational age. Combination with biological markers is a new field of research that could improve the performance of Ut-AD.

Predictive value of pulse oximetry and fetal scalp blood pH in the case of meconium-stained amniotic fluid

OBJECTIVEnTo compare the predictive value of intrapartum fetal pulse oximetry to that of fetal scalp blood pH for an abnormal neonatal outcome in the case of thick meconium.nnnSTUDY DESIGNnA prospective multicenter observational study was performed from June 1994 to November 1995. Fetal oxygen saturation was monitored using a Nellcor N-400 fetal pulse oximeter in case of abnormal FHR. The last readings of fetal oxygen saturation and fetal scalp blood pH before birth were used to assess the ability of both techniques to predict an abnormal neonatal status.nnnRESULTSnAt a 30% cutoff, the negative predictive value of fetal oxygen saturation was not altered in case of meconium when compared to clear amniotic fluid (79 and 83%, respectively). Fetal scalp blood pH at a 7.20 threshold had a poor negative predictive value in case of meconium when compared to clear amniotic fluid (56% versus 88%, respectively). The receiver operator characteristic curve showed similar performance of fetal scalp blood pH and pulse oximetry in cases with clear amniotic fluid. In cases with meconium, the performance of fetal scalp blood pH was poor, whereas that of pulse oximetry remained unchanged. In three cases with meconium below the vocal cords, a drop in fetal oxygen saturation was observed during labor whereas fetal scalp blood pH remained within normal values.nnnCONCLUSIONnThe predictive value of fetal scalp blood pH is poor in case of meconium, whereas the predictive value of pulse oximetry seems to be unchanged in this situation.

Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome

BackgroundLaminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase.MethodsWe analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied.ResultsTwo normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p.Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a second trimester-abortion in the other. WRN-mutated fibroblasts showed oxidative stress, increased lamin B1 expression, nuclear dysmorphies and premature senescence.ConclusionsWe show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Increased expression of lamin B1 with altered lamina architecture observed in WRN-mutated fibroblasts could contribute to premature cellular senescence. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes.