B. Carbonne

Pharmacokinetics of Tocolytic Agents

Tocolytic agents are drugs designed to inhibit contractions of myometrial smooth muscle cells. Such an effect has been demonstrated in vitro or in vivo for several pharmacological agents, including β-adrenergic agonists, calcium channel antagonists, oxytocin antagonists, NSAIDs and magnesium sulfate. However, the aim of tocolysis is not only to stop uterine contractions or to prevent preterm delivery, but to prevent perinatal morbidity and mortality associated with preterm birth. The achievement of this goal has not yet been clearly demonstrated for any of the drugs available, and the use of tocolytic agents may appear controversial. Therefore, it is important to avoid maternal and fetal toxicity when tocolytic agents are used.During pregnancy, all steps of drug pharmacokinetics are altered. Absorption of drugs administered orally is limited because of delayed stomach emptying and reduced intestinal motility. The volume of distribution of drugs is increased. The metabolic activity of the liver is increased, accelerating the metabolism of lipophilic drugs. Renal filtration is increased, leading to enhanced renal elimination of water-soluble drugs. These modifications are generally responsible for reduced plasma concentration and reduced half-life of most drugs. These specific modifications have to be taken into account when using a drug in pregnant women.The aim of this review is to provide the reader with pharmacological data about drugs currently used to treat preterm labour. Such data in pregnant women may affect the choice of optimal drug dosage and route of administration.

Fetal and neonatal ovarian cysts: is surgery indicated?

To evaluate the frequency of ovarian torsion in neonates with ovarian cysts (OCs) and to analyze the outcome after surgical treatment.

Risk factors for severe neonatal acidosis.

OBJECTIVE: Neonatal asphyxia may have severe consequences in term newborns. Our purpose was to identify possible risk factors of severe acidosis during pregnancy and labor. METHODS: In a case–control study from January 2003 to December 2008 in three university perinatal centers (two French and one Canadian hospitals), we analyzed 226 women with term pregnancies complicated by severe neonatal acidosis (umbilical artery pH less than 7.00). Cases were individually matched with controls with a normal acid-base status (pH 7.15 or greater) paired by parity. Groups were compared for differences in maternal, obstetric, and fetal characteristics. Univariable and logistic conditional regression were used to identify possible risk factors. RESULTS: Among 46,722 births after 22 weeks, 6,572 preterm births and 829 stillbirths or terminations of pregnancy were excluded. From the 39,321 live term births, 5.30% of pH values were unavailable. Severe acidosis complicated 0.63% of 37,235 term structurally normal pregnancies. By using multivariate conditional regression, maternal age 35 years or older (35.0% compared with 15.5%; odds ratio [OR] 5.58, 95% confidence interval [CI] 2.51–12.40), prior neonatal death (3.5% compared with 0%), prior cesarean delivery (24.7% compared with 6.6%; OR 4.08, 95% CI 1.71–9.72) even after excluding cases of uterine rupture, general anesthesia (8.4 compared with 0.9%; OR 8.04, 95% CI 1.26–50.60), thick meconium (6.4% compared with 2.8%; OR 5.81, 95% CI 1.72–19.66), uterine rupture (4.4% compared with 0%), and abnormal fetal heart rate (66.1% compared with 19.8%; OR 8.77, 95% CI 3.72–20.78) were independent risk factors of severe neonatal acidosis. CONCLUSION: Prior cesarean delivery, maternal age 35 years or older, prior neonatal death, general anesthesia, thick meconium, uterine rupture, and abnormal fetal heart rate are independent risk factors of severe neonatal acidosis. LEVEL OF EVIDENCE: II

Fetal growth restriction and intra-uterine growth restriction: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians

Small for gestational age (SGA) is defined by weight (in utero estimated fetal weight or birth weight) below the 10th percentile (professional consensus). Severe SGA is SGA below the third percentile (professional consensus). Fetal growth restriction (FGR) or intra-uterine growth restriction (IUGR) usually correspond with SGA associated with evidence indicating abnormal growth (with or without abnormal uterine and/or umbilical Doppler): arrest of growth or a shift in its rate measured longitudinally (at least two measurements, 3 weeks apart) (professional consensus). More rarely, they may correspond with inadequate growth, with weight near the 10th percentile without being SGA (LE2). Birthweight curves are not appropriate for the identification of SGA at early gestational ages because of the disorders associated with preterm delivery. In utero curves represent physiological growth more reliably (LE2). In diagnostic (or reference) ultrasound, the use of growth curves adjusted for maternal height and weight, parity and fetal sex is recommended (professional consensus). In screening, the use of adjusted curves must be assessed in pilot regions to determine the schedule for their subsequent introduction at national level. This choice is based on evidence of feasibility and the absence of any proven benefits for individualized curves for perinatal health in the general population (professional consensus). Children born with FGR or SGA have a higher risk of minor cognitive deficits, school problems and metabolic syndrome in adulthood. The role of preterm delivery in these complications is linked. The measurement of fundal height remains relevant to screening after 22 weeks of gestation (Grade C). The biometric ultrasound indicators recommended are: head circumference (HC), abdominal circumference (AC) and femur length (FL) (professional consensus). They allow calculation of estimated fetal weight (EFW), which, with AC, is the most relevant indicator for screening. Hadlocks EFW formula with three indicators (HC, AC and FL) should ideally be used (Grade B). The ultrasound report must specify the percentile of the EFW (Grade C). Verification of the date of conception is essential. It is based on the crown-rump length between 11 and 14 weeks of gestation (Grade A). The HC, AC and FL measurements must be related to the appropriate reference curves (professional consensus); those modelled from College Francais dEchographie Fetale data are recommended because they are multicentere French curves (professional consensus). Whether or not a work-up should be performed and its content depend on the context (gestational age, severity of biometric abnormalities, other ultrasound data, parents wishes, etc.) (professional consensus). Such a work-up only makes sense if it might modify pregnancy management and, in particular, if it has the potential to reduce perinatal and long-term morbidity and mortality (professional consensus). The use of umbilical artery Doppler velocimetry is associated with better newborn health status in populations at risk, especially in those with FGR (Grade A). This Doppler examination must be the first-line tool for surveillance of fetuses with SGA and FGR (professional consensus). A course of corticosteroids is recommended for women with an FGR fetus, and for whom delivery before 34 weeks of gestation is envisaged (Grade C). Magnesium sulphate should be prescribed for preterm deliveries before 32-33 weeks of gestation (Grade A). The same management should apply for preterm FGR deliveries (Grade C). In cases of FGR, fetal growth must be monitored at intervals of no less than 2 weeks, and ideally 3 weeks (professional consensus). Referral to a Level IIb or III maternity ward must be proposed in cases of EFW <1500g, potential birth before 32-34 weeks of gestation (absent or reversed umbilical end-diastolic flow, abnormal venous Doppler) or a fetal disease associated with any of these (professional consensus). Systematic caesarean deliveries for FGR are not recommended (Grade C). In cases of vaginal delivery, fetal heart rate must be monitored continuously during labour, and any delay before intervention must be faster than in low-risk situations (professional consensus). Regional anaesthesia is preferred in trials of vaginal delivery, as in planned caesareans. Morbidity and mortality are higher in SGA newborns than in normal-weight newborns of the same gestational age (LE3). The risk of neonatal mortality is two to four times higher in SGA newborns than in non-SGA preterm and full-term infants (LE2). Initial management of an SGA newborn includes combatting hypothermia by maintaining the heat chain (survival blanket), ventilation with a pressure-controlled insufflator, if necessary, and close monitoring of capillary blood glucose (professional consensus). Testing for antiphospholipids (anticardiolipin, circulating anticoagulant, anti-beta2-GP1) is recommended in women with previous severe FGR (below third percentile) that led to birth before 34 weeks of gestation (professional consensus). It is recommended that aspirin should be prescribed to women with a history of pre-eclampsia before 34 weeks of gestation, and/or FGR below the fifth percentile with a probable vascular origin (professional consensus). Aspirin must be taken in the evening or at least 8h after awakening (Grade B), before 16 weeks of gestation, at a dose of 100-160mg/day (Grade A).

Atosiban for Preterm Labour

Oxytocin antagonists are synthetic analogues that have the nonapeptide structure of oxytocin. They act by competing with oxytocin for receptors in the myometrium. Animal experiments and pilot clinical studies have examined several agents and, of these, atosiban has been the object of extensive clinical trials. In a large placebo-controlled trial with >500 patients, atosiban reduced the number of premature deliveries over 7 days compared with placebo with no more adverse effects than placebo. In large multicentre studies comparing atosiban with β-adre-noceptor agonists, the efficacy of the two medications was similar for pregnancy prolongation for 48 hours and for 7 days. The adverse effects, particularly cardiovascular, were considerably more frequent in the patients receiving β-adrenoceptor agonists, who had to stop treatment significantly more often than the atosiban recipients. No fetal adverse effects were seen with atosiban and, in particular, no effect on baseline fetal heart rate, unlike with the β-adrenoceptor agonists. Neonatal outcome did not differ significantly according to the treatment. The usefulness of maintenance treatment after the initial 48 hours has not been confirmed.Thus, the effectiveness of oxytocin antagonists appears to be similar to β-adrenoceptor agonists and the former are not accompanied by measurable adverse effects. Oxytocin antagonists were designed specifically as tocolytics and have been validated by the European Drug Agency. They may be the treatment of choice for preterm labour, particularly in patients at risk of cardiovascular complications (e.g. multiple pregnancy, heart disease, etc.).

Management of Very Early Fetal Anemia Resulting From Red-Cell Alloimmunization Before 20 Weeks of Gestation

OBJECTIVE: To evaluate the results of management of very early fetal anemia (before 20 weeks of gestation) in cases of red-cell alloimmunization. METHODS: Retrospective study of the outcome of all in utero transfusions performed before 20 weeks of gestation and all pregnancies requiring an in utero transfusion before 20 weeks in our reference center from January 1990 through August 2011 in cases with severe alloimmunization. RESULTS: Twenty-five in utero transfusions were performed in 18 pregnancies in 16 patients during the study period. A vascular access was performed successfully in 22 of the 24 cases in which it was attempted. An intraperitoneal transfusion was necessary in two cases. Two in utero deaths attributable to the intravascular procedure occurred during attempts before 18 weeks of gestation and another, not associated with a transfusion, at 29 weeks. The overall survival rate was 83.3% (compared with 88.0% when the first in utero transfusion took place before 22 weeks). The risk of fetal loss for each transfusion was 8.0% before 20 weeks and 6.3% before 22 weeks. An intraperitoneal transfusion at 17 2/7 weeks allowed one fetus to survive until the first intravascular in utero transfusion could take place at 18 2/7 weeks. CONCLUSION: Fetal anemia before 20 weeks remains at high risk of lethal complications compared with later gestational ages. Technical difficulties in a vascular access are mainly encountered before 18 weeks of gestation. At an earlier gestational age, intraperitoneal transfusion may gain the days necessary to perform an intravascular transfusion more safely. LEVEL OF EVIDENCE: III

Le point sur le suivi des allo-immunisations érythrocytaires

Anti-RhD allo-immunisation has become rare since anti-D prophylaxis was introduced in the seventies; however, it remains the first cause of fetal anemia. It may cause severe fetal complications such as fetal hydrops, cerebral anoxic lesions and fetal death. In the neonatal period, severe jaundices and anemias requiring transfusion or exsanguino-transfusion are still common in case of severe allo-immunisation. Neonatal death and sequellae due to bilirubin encephalopathy have not fully disappeared. Follow-up of pregnancies with maternal allo-immunisation requires identification of the antibody (anti-RhD, anti-Kell and anti-c are the most frequently responsible for fetal complications), dosage and titration. In RhD allo-immunization, feto-maternal incompatibility may be confirmed by non-invasive RHD genotyping of the fetus in maternal blood. In cases at risk for fetal anemia, weekly Doppler assessment of middle cerebral artery peak systolic velocity (MCA-PSV) allows identification of fetal anemia before the occurrence of fetal hydrops. The reference treatment of fetal anemia is in utero fetal transfusion. The risk of fetal loss due to in utero transfusion (IUT) is 3% per procedure. The cumulated risk of fetal loss can thus exceed 10% in case of early occurrence of fetal anemia requiring up to five or six IUTs in a single pregnancy.

Foetal scalp blood sampling during labour for pH and lactate measurements

Second-line methods of foetal monitoring have been developed in an attempt to reduce unnecessary interventions due to continuous cardiotocography (CTG), and to better identify foetuses that are at risk of intrapartum asphyxia. Very few studies directly compared CTG with foetal scalp blood (FBS) and CTG only. Only one randomised controlled trial (RCT) was published in the 1970s and had limited power to assess neonatal outcome. Direct and indirect comparisons conclude that FBS could reduce the number of caesarean deliveries associated with the use of continuous CTG. The main drawbacks of FBS are its invasive and discontinuous nature and the need for a sufficient volume of foetal blood for analysis, especially for pH measurement, resulting in failure rates reaching 10%. FBS for lactate measurement became popular with the design of test-strip devices, requiring <0.5xa0mL of foetal blood. RCTs showed similar outcomes with the use of FBS for lactates compared with pH in terms of obstetrical interventions and neonatal outcomes. In conclusion, there is some evidence that FBS reduces the need for operative deliveries. However, the evidence is limited with regard to actual standards, and large RCTs, directly comparing CTG only with CTG with FBS, are still needed.

Congenital hypoplasia of the abdominal wall muscles following fetal ascites due to parvovirus B19 infection

Maternofetal parvovirus B19 infection may be a cause of fetal hydrops through fetal anemia or myocarditis and heart failure1,2. We report a case of fetal hydrops with subsequent postnatal muscular hypoplasia and major persistent abdominal distension. A 25-year-old woman, gravida 2 para 1, was referred at 22 weeks’ gestation for fetal hydrops detected at routine ultrasound scan. Findings included abundant fetal ascites and moderate pericardial effusion. Abdominal circumference was 203 mm (99th centile). Middle cerebral artery peak systolic velocity, at 56 cm/s, was > 1.5 multiples of the median. Serology testing was positive for parvovirus B19 immunoglobulin-M. Fetal anemia was confirmed by blood sampling (hemoglobin 4.4 g/dL) and an in-utero transfusion restored hemoglobin to 14 g/dL. Parvovirus infection was confirmed by polymerase chain reaction. Paracentesis was performed at 25 weeks’ gestation for persistent abundant ascites. Labor was induced at 41 + 6 weeks and a female infant weighing 3710 g was delivered vaginally with a 5-min Apgar score of 10. The neonate’s abdomen was enlarged but without significant ascites. Subsequent follow-up showed hypoplasia of the anterior and lateral abdominal wall muscles visible during crying as two lateral subumbilical oval projections (Figure 1). Distension continued at 1 and 2 years. Computed tomography showed hypoplasia, mainly of the internal oblique and transverse muscles of the abdomen (Figure 2). The rectus abdominis muscle was affected to a lesser degree. According to embryological studies, diastasis recti abdominis would result from disruptive phenomena before the fusion of myotomes during the eighth week, while muscular hypoplasia should result from later

Utilisation de la nifédipine et de la nicardipine dans le traitement de la menace d’accouchement prématurée : données observationnelles en population

OBJECTIVEnFor the first line tocolysis, calcium channel blockers (CCB)--oral nifedipine (Adalate®) or intravenous nicardipine (Loxen®)--are frequently used in France. No study compared nifedipine and nicardipine in management of threatened preterm delivery. From data of a French observational study, we compared factors associated with the use of nifedipine and nicardipine. Efficacy and tolerance of the two treatments were also compared.nnnMETHODSnIt was a secondary analysis of EVAPRIMA study, a practice survey describing management of threatened preterm delivery in 107 French maternity units. Only women who received calcium channel blockers in their first line tocolytic therapy were included. We studied obstetrical factors associated with the choice of nifedipine or nicardipine. We also analyzed factors associated with a delivery within seven days following admission using univariate and multivariate analysis. Adverse secondary effects were compared between women who received nifedipine or nicardipine.nnnRESULTSnThree hundred and four women received calcium channel blockers for their first line tocolytic therapy, in 73 maternity units: 93 (30.6%) women received oral nifedipine and 211 (69.4%) intravenous nicardipine. The same CCB was always prescribed in 69 maternity units. Admission after in utero transfer was less frequent among women who received nifedipine (6.5% versus 17.1%, P=0.01). Premature rupture of the membranes was also less frequent among women who received nifedipine (4.3% versus 13.7%, P=0.02), in comparison with women who received nicardipine. Median duration between admission for threatened preterm labor and delivery was longer when nifedipine was used (44 days versus 36 days, P=0.04). After adjustment on obstetrical factors, the risk to have a delivery within 7 days following admission was not significantly different between nifedipine and nicardipine groups (adjusted OR=0.5 [0.2-1.2]). Among women who received nifedipine only two cases (2.1%) of adverse event were reported with only one case needing a switch of treatment. Thirteen (6.2%) cases of adverse event were reported among women who received nicardipine (P=0.16); in three cases it motivated a switch. However, due to bias and limits inherent in such studies, our results should be interpreted cautiously.nnnCONCLUSIONnNicardipine is the first choice for French obstetricians in management of severe threatened preterm delivery. However, intravenous nicardipine does not increase gestational duration in comparison with oral nifedipine.