A contemporary description of French newborns' growth using the Efemeris cohort.

BACKGROUND: Overweight and obesity in childhood are a major concern in developed countries. Reference growth curves are used in current practice to identify children at risk, especially at risk of overweight or obesity. National reference growth curves were published 35 years ago from children born in the 1950s to study growth from birth to adulthood. Additionally, more recent national curves exist to study birth weight and height according to gestational age. The primary objective was to describe anthropometric measurements of French children born in the 2000s and to compare them with the French references. The secondary objective was to describe overweight indicators during infancy. METHODS: A total of 77,315 singletons live-born from 1 July 2004 to 31 December 2013 recorded in the Efemeris (a French cohort of women and their children) were included. The z-score means based on the French references for weight, height, and body mass index (BMI) at birth, 9 months, and 24 months were calculated. RESULTS: At birth, the weight and height of the cohort did not deviate from the recent French references taking into account gestational age. At 9 and 24 months, the cohort was between 0.12 and 0.39 standard deviations (SD) heavier and between 0.70 and 0.97 SD taller than the old French reference population. Between 0 and 2 years, 28.6% of the children underwent a rapid weight gain (change in SD scores>0.67). The prevalence of overweight at 2 years was between 5 and 6% using the International obesity task force (IOTF) references. CONCLUSION: The distributions of the height, weight, and BMI during early childhood differ from those of children in the national growth references. Contemporary children at 2 years are taller and heavier than children born in the 1950s. Approximately one in 20 children is overweight at 2 years.

Medication exposure and spontaneous abortion: a case-control study using a French medical database.

PURPOSE OF INVESTIGATION: Few studies have been conducted to investigate drug effects on spontaneous abortion risk. The objective of the present study was to evaluate the potential association between first trimester drug exposure and spontaneous abortion occurrence. MATERIALS AND METHODS: The authors performed a nested case-control study using data from TERAPPEL, a French medical database. Cases were the women who had a spontaneous abortion (before the 22nd week of amenorrhea) and controls were women who gave birth to a child. Analyzed variables were: maternal age, obstetric history, tobacco, and alcohol and drug consumption during the first trimester of pregnancy. For comparison of drug exposures between cases and controls, the authors calculated odds ratios (ORs) by means of multivariate logistic regressions adjusted on age and on other drug exposures. RESULTS: The study included 838 cases and 4,508 controls that were identified in the database. In adjusted analyses, cases were more exposed than controls to "non-selective monoamine reuptake inhibitors" [OR=2.2 (CI 95% 1.5-3.3)], "antiprotozoals" [OR = 1.6 (CI 95% 1.1 - 2.5)] and "centrally acting antiobesity products" [OR = 3.4 (CI 95% 1.9 - 6.2)]. Conversely, controls were more exposed than cases to H1 antihistamines [OR = 0.6 (CI 95% 0.4 - 0.9)]. CONCLUSION: This exploratory study highlights some potential associations between first trimester drug exposure and risk of spontaneous abortion. Further studies have to be carried out to investigate these findings.

[Down syndrome maternal serum screening: results' comments recommended by accredited biologists]. / Dépistage de la trisomie 21 par les marqueurs sériques maternels : justification des commentaires appliqués par les biologistes.

Down syndrome maternal serum screening is largely used in France. The aim of this article is to specify and to explain the different comments applied on the reports in order to optimize the management of the patient. These comments represent the consensus of the study group of the biologist accredited for Down syndrome maternal serum screening.

Safety of oseltamivir during pregnancy: a comparative study using the EFEMERIS database.

OBJECTIVE: To compare pregnancy outcome between women exposed and unexposed to oseltamivir during pregnancy. DESIGN: A comparative observational cohort study of women exposed to oseltamivir during pregnancy. SETTING: A French prescription database (EFEMERIS) that includes data for pregnant women was used. EFEMERIS records prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes in Haute-Garonne, South West France. POPULATION: Women who delivered from 1 July 2004 to 31 December 2010. METHODS: The study compared exposed and unexposed pregnant women. Two women unexposed to oseltamivir were individually matched, by maternal age, month, and year of delivery, with one women exposed to oseltamivir. Multivariable conditional logistic regression and multivariable Cox proportional hazards regression were used to evaluate associations between each outcome and exposure to oseltamivir during pregnancy. MAIN OUTCOME MEASURES: Pregnancy loss for any cause, preterm delivery, low birthweight, neonatal pathology, and congenital malformation. RESULTS: A cohort of 337 (0.58% of women included in EFEMERIS) women exposed to oseltamivir were compared with 674 unexposed women. The risk for pregnancy loss (HR 1.52; 95% CI 0.80-2.91), for preterm birth (adjusted OR 0.64; 95% CI 0.31-1.27), and for neonatal pathology (adjusted OR 0.62; 95% CI 0.23-1.54) did not differ between exposed and unexposed groups. When exposure during organogenesis was considered, one case of congenital anomaly (2.0%) among 49 exposed women and one case (1.0%) among 99 unexposed women were observed (crude OR 2.00; 95% CI 0.13-32.00). CONCLUSIONS: There was no significant association between adverse pregnancy outcomes and exposure to oseltamivir during pregnancy.

Pandemic A/H1N1 influenza vaccination during pregnancy: a comparative study using the EFEMERIS database.

OBJECTIVE: To evaluate the risk of adverse pregnancy outcomes following A/H1N1 vaccination in pregnant women. METHODS: This observational cohort study compared vaccinated and non-vaccinated pregnant women in EFEMERIS, a French prescription database including pregnant women. Women who ended their pregnancy in South Western France between October 21, 2009 and November 30, 2010 (the period of the French vaccination campaign) were included. Two non-vaccinated women were individually matched to each vaccinated woman by month and year of pregnancy onset. Conditional logistic regression and Cox proportional hazards regression were used to evaluate associations between each outcome (all-cause pregnancy loss, preterm delivery, small for gestational age (SGA) and neonatal pathology) and A/H1N1 vaccination during pregnancy. RESULTS: 1645 women of the 12,120 (13.6%) in the database who were administered A/H1N1 vaccine during pregnancy were compared to 3290 non-vaccinated women. Most were vaccinated in December 2009 (61%) with a non-adjuvanted vaccine (93%). The risks of pregnancy loss (adjusted HR=0.56; 95% CI=0.31-1.01), of preterm birth (adjusted HR=0.82; 95% CI=0.64-1.06), and of neonatal pathology (adjusted OR=0.70; 95% CI=0.49-1.02) did not differ between the vaccinated and the non-vaccinated groups. The rate of SGA was lower in the vaccinated group than in the non-vaccinated group (0.5% vs. 1.4%; adjusted OR=0.36; 95% CI=0.17-0.78). CONCLUSION: There was no significant association between adverse pregnancy outcomes and vaccination with a non-adjuvanted A/H1N1 vaccine during pregnancy.

Non-adjuvanted 2009 influenza A (H1N1)v vaccine in pregnant women: the results of a French prospective descriptive study.

UNLABELLED: In 2009, during the influenza A (H1N1)v pandemic, the French Health authorities recommended influenza immunisation for pregnant women because of the higher risk of serious influenza outcomes in that population. Thus, the non-adjuvanted inactivated influenza vaccine Panenza(®) was administered to French women from the second trimester of pregnancy. Several studies suggest that inactivated seasonal influenza vaccines are safe during pregnancy but there are few data about the effects of new A (H1N1)vaccines (new antigen) on pregnant women. OBJECTIVE: The aim of the present prospective study was to describe pregnancy outcomes among women vaccinated with non-adjuvanted influenza vaccines in South Western France. METHODS: the study ran from November 2009 to February 2010 and included, on a voluntary basis, pregnant women who were vaccinated against A (H1N1) influenza in vaccination clinics or maternity wards. RESULTS: 569 pregnant women were monitored until delivery. Compared with the general population, the risks of maternal conditions, malformations and neonatal conditions were not statistically different. CONCLUSION: This study does not reveal any sign of safety concerns regarding the effects of the vaccine on pregnancy outcomes.

[Drugs in pregnancy: study in the EFEMERIS database (2004 to 2008)]. / Médicaments et grossesse: étude dans la base de données EFEMERIS 2004-2008.

OBJECTIVES: To analyze the evolution of drug prescriptions during pregnancy from 2004 to 2008 in Haute-Garonne (France) and the impact of recommendations concerning drugs in pregnancy sent by French health authorities (AFSSAPS) and French college of gynaecologists and obstetricians to health professionals during the period. PATIENTS AND METHODS: This descriptive study of reimbursed drug prescriptions during pregnancy concerns women included in the EFEMERIS database who have given birth from July 1st, 2004 to June 30th, 2008. The health insurance service records of Haute-Garonne were used. RESULTS: Taking into account 2 subsequent delistings of drugs for reimbursement during the period, we observed a significant increase of reimbursed drug prescriptions dispensed to pregnant women (8.7 different substances for women who have given birth in 2004 and 9.4 in 2008). Vitamins, immunserums, immunoglobulins and homeopathy prescriptions have especially increased. Paracetamol, iron, folic acid and phloroglucinol were the most prescribed drugs during all the periods. DISCUSSION AND CONCLUSION: Since 2004, EFEMERIS represents a monitoring centre for the prescription of reimbursed drugs to pregnant women. This analysis allowed to exhibit trends in prescription patterns. Most of the alerts or recommendations had a positive but limited impact.

[First epidemiologic data about phloroglucinol exposure during first trimester of pregnancy]. / Premières données épidémiologiques sur le phloroglucinol et exposition au cours du premier trimestre de grossesse.

OBJECTIVE: Phloroglucinol is used to prevent gastric, intestine or urogenital spasms. In France, many pregnant women are exposed to phloroglucinol for which no data are available about its use in pregnancy. The present study, using EFEMERIS database, investigates potential teratogenic risk of phloroglucinol in pregnancy. MATERIALS AND METHODS: EFEMERIS is a database including prescribed and delivered drugs during pregnancy (data from Caisse Primaire d'Assurance Maladie of Haute-Garonne) and outcomes (data from Maternal and Infant Protection Service and from Antenatal diagnostic Centre). Women delivered from July 1st 2004 to June 30th 2008 in Haute-Garonne and registered in the French Health Insurance Service were included into EFEMERIS database. We compared pregnancy outcomes and newborn health between women exposed to phloroglucinol during organogenesis and non-exposed women. Malformations were classified according to Eurocat classification. RESULTS: Five thousand one hundred and thirty-two newborns (12.7%) exposed during organogenesis to phloroglucinol were compared to 35,223 controls (non exposed newborns). The mean number of different drugs prescribed during the first trimester of pregnancy per woman was higher in women exposed to phloroglucinol than in non-exposed women (6.4 ± 4.3 versus 2.4 ± 3.3, P < 10(-4)). Among newborns, 126 (2.5%) had a malformation versus 804 (2.3%) in control newborns (OR=1.1, [0.9-1.3]). The present study was powered to find a 1.3 fold increase in the overall rate of major anomalies. DISCUSSION AND CONCLUSION: This first epidemiologic study about phloroglucinol in pregnancy does not support evidence of a teratogenic risk for phloroglucinol in humans.

Prescription of drugs during pregnancy: a study using EFEMERIS, the new French database.

BACKGROUND: Because of the limited data concerning drug risks in pregnancy, health professionals are often deprived of relevant and sufficient information related to prescribing or dispensing during pregnancy. However, previous studies have emphasised the widespread French prescription of several drugs (sometimes "typically French") which have not been assessed in pregnant women. OBJECTIVES: The aim of the present study was to create the first French database of drugs prescribed and dispensed during pregnancy and the outcome of these pregnancies. METHODS: This feasibility study concerns pregnant women who gave birth to a baby between 1 July 2004 to 30 June 2005 in Haute-Garonne and who are registered in the French Health Insurance Service. Data sources include (1) the French Health Insurance Database (drugs prescribed during pregnancy), (2) the Mother and Child Protection Centre Database (newborn health at birth and 9 months after) and (3) the Antenatal Diagnostic Centre Database (medical pregnancy interruptions). RESULTS: The database is composed of 10,174 "mother-outcome" pairs. The prevalence rate of congenital anomalies was 2.2%. Pregnant women were prescribed 11.3 +/- 8.2 different drugs. Among the 20 most frequently prescribed drugs, around half of them have not been evaluated in pregnant women. CONCLUSIONS: The first results of this study show that implementation of a French database on prescription of drugs and pregnancy outcomes is feasible. Compared with several databases available in other countries, EFEMERIS provides exact data on period of exposure to drugs, pregnancy terminations, and follow up of the baby 9 months after birth. Recording these data would make it possible to assess the risk of malformations due to a greater number of drugs and would contribute to international drug evaluation studies.

[Screening for Down syndrome using first-trimester combined screening followed by second trimester ultrasound examination in an unselected population]. / Dépistage de la trisomie 21 par le test combiné du premier trimestre suivi par l'échographie du second trimestre en population générale.

BACKGROUND: Recent studies have reported the efficacy of first trimester combined screening for Down Syndrome based on maternal age, serum markers (human chorionic gonadotropin, pregnancy-associated plasma protein A), and ultrasound measurement of fetal nuchal translucency. However, those do not incorporate the value of the widely accepted routine 20-22 week anomaly scan. STUDY DESIGN: We carried out a multi-centre, interventional study in the unselected population of a single health authority in order to assess the performance of first trimester combined screening, followed by routine second trimester ultrasound examination and/or screening by maternal serum markers (free beta-hCG and alpha-fetoprotein measurement or total hCG, alpha-fetoprotein and unconjugated estriol measurement) when incidentally performed. Detection and screen positive rates were estimated using a correction method for non verified issues. A cost analysis was also performed. RESULTS: During the study period, 14,934 women were included. Fifty-one cases of Down Syndrome were observed, giving a prevalence of 3.4 per 1000 pregnancies. Of these, 46 were diagnosed through first (N=41) or second (N=5) trimester screening. Among the 5 screen-negative Down syndrome cases, all were diagnosed postnatally after an uneventful pregnancy. Detection and screen positive rates of first trimester combined screening were 79.6% and 2.7%, respectively. These features reached 89.7 and 4.2%, respectively when combined with second trimester ultrasound screening. The average cost of the full screening procedure was 108 euro (120 $) per woman and the cost per diagnosed Down syndrome pregnancy was 7,118 euro (7,909 $). CONCLUSION: Our findings suggest that one pragmatic interventional two-step approach using first-trimester combined screening followed by second trimester detailed ultrasound examination is a suitable and acceptable option for Down syndrome screening in pregnancy.

[Myocardial infarction in a young female smoker taking oral contraception]. / Infarctus du myocarde chez une jeune femme fumeuse sous contraception orale.

A 33 year old woman suffered a lateral myocardial infarction for the first time, and was treated by pre-hospital thrombolysis and secondary angioplasty on the diagonal artery. Fifteen days before the cardiac event she had undergone a left ovarian cyst excision and left salpingectomy for an ectopic pregnancy. She was a moderate smoker and had been taking a second-generation biphasic minidose oral contraceptive (ethinyl-estradiol 30-40mg and levonorgestrel 150-200 mg) for about ten years. Fifteen days before the myocardial infarction and due to the ectopic pregnancy she had changed to a combined monophasic minidose oral contraceptive pill containing ethinylestradiol (30 mg) and drospirenone (3 mg). The eventual outcome was favourable, with no complications. In this article we discuss the possible implications of the various factors (oral contraceptive, tobacco use, and surgical intervention) in this young woman with a myocardial infarction.

Nonsteroidal anti-inflammatory drug-induced liver injury: a case-control study in primary care.

Several nonsteroidal anti-inflammatory drugs (NSAIDs) have been withdrawn from the market because of hepatic adverse drug reactions (ADRs). Moreover, some cases of liver diseases have been reported in patients taking NSAIDs (arylcarboxylic NSAIDs, piroxicam, sulindac, nimesulide, etc.). Pharmacoepidemiological studies have shown a risk of hepatic ADRs with NSAIDs used in association with other hepatotoxic drugs. In contrast, other studies performed in hospitalized patients did not found any association. The aim of this study was to assess the hepatic risk associated with the use of NSAID in the setting of primary care. The study design was a case-control study where cases and controls were all recruited among patients seen in the context of medical community care. Eighty-eight cases and 178 controls were included between January 1998 and December 2000. Cases used more drugs than controls in the 15 days before index day (2.9 +/- 2.2 vs. 1.8 +/- 1.8 different consumed drugs; P < 10(-4)). After adjustment, we found a significant association between liver injury and NSAID exposure in women [odds ratio (OR) = 6.49 (1.67-25.16)] but not in men [OR = 1.06 (0.36-3.12)]. A total of 22 cases were exposed to NSAIDs. Of them, seven patients were exposed to salicylates, five to diclofenac, four to ibuprofen, four to ketoprofen, two to niflumic acid, one to flurbiprofen and one to meloxicam (two patients were simultaneously exposed to two different NSAIDs: salicylate + niflumic acid and salicylate + diclofenac). These patients suffered from hepatocellular (53.3%), cholestatic (20%) or mixed (26.7%) injury. In 18 cases, liver enzymes returned to normal values after discontinuation of drug. No case had a fatal outcome. This study shows the existence of a significant association between liver disturbances and NSAID use in women.

Buprenorphine in pregnant opioid-dependent women: first results of a prospective study.

AIM: To report results on the prospective follow-up of 34 pregnant women exposed to buprenorphine maintenance for opiate dependence. DESIGN AND SETTING: Prospective multicentre study: all pregnant women receiving buprenorphine as maintenance therapy were included as early as possible during their pregnancy. PARTICIPANTS: The pregnant women were recruited from opiate maintenance therapy centres, general practitioner-networks involved in addiction, maternity hospitals and centres for drug information during pregnancy. MEASUREMENTS: Women: drugs and medications consumed, medical and obstetrical events; offspring: withdrawal syndrome, malformation, neonatal disease. FINDINGS: The buprenorphine-exposed pregnancies resulted in 31 live births, one stillbirth, one spontaneous abortion and one voluntary termination. A neonatal withdrawal syndrome was observed in 13 cases (41.9%) and eight of these babies required opiate treatment. Two neonates had a malformation: a premature ductus arteriosus stricture and a tragus appendix. CONCLUSION: Taken together with other prospective studies, no alarming results were observed concerning pregnancy outcomes. However, further data from the comparative prospective study are required to determine whether buprenorphine can be considered as a good alternative to methadone treatment in pregnant women.

Comparison of progesterone concentration determination by 12 non-isotopic immunoassays and gas chromatography/mass spectrometry in 99 human serum samples.

A single serum progesterone determination may be highly predictive for early pregnancy and in vitro fertilisation and embryo-transfer outcomes. We therefore compared 12 direct non-isotopic progesterone immunoassays with gas-chromatography/mass spectrometry (GC/MS). For each assay, data from the analysis of 99 individual sera were compared with data obtained by GC/MS, using regression and bias plot analyses and the ratio method. We observed a larger difference in concentration between high and low values and a broader distribution of results for immunoassays than for GC/MS. All immunoassays displayed bias in the calibration process and a lack of specificity and/or sensitivity, to various degrees. We tried to identify the parameters of the assay procedure that might contribute to these discrepancies. None of the criteria investigated (antibodies, control and preparation of calibrators, blocking agents and choice of tracer) had a significant effect when studied alone.

A new type of acquired C1 inhibitor deficiency associated with systemic lupus erythematosus.

Acquired C1 inhibitor (C1-INH) deficiency with consequent angioedema is a rare condition that may indicate an underlying lymphoproliferative disorder. The defect is caused by increased catabolism, which is often associated with the presence of serum autoantibodies to C1-INH. The present report describes 3 patients with systemic lupus erythematosus who developed typical symptoms of acquired angioedema, characterized by recurrent swelling of subcutaneous and mucous tissues. The 3 patients demonstrated a major classical pathway-mediated complement consumption, with very low levels of C3 antigen and decreased levels of C1-INH antigen. Neither antibodies to C1-INH nor associated lymphoproliferative disease was found. No patient had clinical and biologic signs of lupus activity at the time the angioedema occurred. All patients were treated with steroids and exhibited a good response, without relapse of angioedema and with normalization of plasma levels of C1-INH. In lupus patients who present with an angioedema syndrome, acquired or hereditary angioedema must be sought by examining parameters of the classical pathway and levels of C1-INH. Our observations suggest the existence of a new form of acquired C1-INH deficiency associated with a major classical pathway-mediated complement consumption and systemic autoimmunity.

[Follow-up of 'medications and pregnancy' at the Midi-Pyrenees Pharmacovigilance Center']. / Bilan du suivi des questions 'médicaments et grossesse' au Centre Midi-Pyrénées de Pharmacovigilance.

The follow-up of 283 gestations recorded by the Midi-Pyrénées Pharmacovigilance Centre concerned 544 medications, 17 solvents and 12 illicit drugs. Pregnancy outcomes were live births for 74.2 per cent of the women and voluntary (14.8 per cent), spontaneous (8.5 per cent) or therapeutic (1.8 per cent) abortions. Among the newborns, 11 had a malformation and 18 a neonatal disease. We observed an increased risk of neonatal disease for women exposed to illicit drugs during the third trimester of their pregnancy (OR = 14.28 [1.19-747.40] p = 0.0155) and for smokers (OR = 19.11 [2.11-445.00] p = 0.0011). Moreover, an increase of teratogenic risk was associated with a first trimester exposure to neurologic drugs (OR = 14.28 [2.08-100.00] p = 0.006). Women included in the present survey were more often exposed to potentially harmful drugs than the general population. However, the rates of obstetric and/or neonatal complications appear similar to those reported in France as a whole.

Prescription of drugs during pregnancy in France.

A survey of the records of the French Health Insurance Service of drug prescriptions during pregnancy in 1000 women living in Haute-Garonne, southwest France, showed that 99% of the women received a prescription for at least one drug during pregnancy with a mean of 13.6 medications per woman. 1.6% of women received one or more prescriptions of drugs from the US Food and Drug Administration X category (fetal risk outweighs benefits). 59% of women had a prescription of drugs from the D category (fetal risk but benefits may be acceptable) and 79% of women were exposed to drugs for which information about safety in pregnancy was not available from animal or human studies.

Differential signaling of human Mel1a and Mel1b melatonin receptors through the cyclic guanosine 3'-5'-monophosphate pathway.

Cyclic guanosine 3'-5'-monophosphate (cGMP) has recently been shown to constitute a second messenger for Xenopus laevis melatonin Mel1c receptors. To verify whether cGMP levels are also modulated by mammalian melatonin receptors, we cloned the genes encoding the human Mel1a and Mel1b receptor subtypes and expressed them in human embryonic kidney cells. Pharmacological profiles and inhibition of forskolin-stimulated adenosine 3'-5'-cyclic monophosphate levels by melatonin confirmed functional expression of high-affinity melatonin receptors. Mel1b receptor-transfected cells modulated cGMP levels in a dose-dependent manner via the soluble guanylyl cyclase pathway. In contrast, Mel1a receptors had no effect on cGMP levels. These results demonstrate that mammalian melatonin receptors modulate cGMP levels and reveal for the first time differences in signaling between melatonin receptor subtypes, which may explain the necessity to express different receptor subtypes.