Paul Merlob

International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?

Abstract Objectives To evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of neural tube defects. Design Retrospective cohort study of births monitored by birth defect registries. Setting 13 birth defects registries monitoring rates of neural tube defects from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. Cases of neural tube defects were ascertained among liveborn infants, stillbirths, and pregnancy terminations (where legal). Policies and recommendations were ascertained by interview and literature review. Main outcome measures Incidences and trends in rates of neural tube defects before and after 1992 (the year of the first recommendations) and before and after the year of local recommendations (when applicable). Results The issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of neural tube defects. Conclusions Recommendations alone did not seem to influence trends in neural tube defects up to six years after the confirmation of the effectiveness of folic acid in clinical trials. New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements.

The spectrum of congenital anomalies of the VATER association: An international study

The spectrum of the VATER association has been debated ever since its description more than two decades ago. To assess the spectrum of congenital anomalies associated with VATER while minimizing the distortions due to small samples and referral patterns typical of clinical series, we studied infants with VATER association reported to the combined registry of infants with multiple congenital anomalies from 17 birth defects registries worldwide that are part of the International Clearinghouse for Birth Defects Monitoring Systems (ICB-DMS). Among approximately 10 million infants born from 1983 through 1991, the ICB-DMS registered 2,295 infants with 3 or more of 25 unrelated major congenital anomalies of unknown cause. Of these infants, 286 had the VATER association, defined as at least three of the five VATER anomalies (vertebral defects, anal atresia, esophageal atresia, renal defects, and radial-ray limb deficiency), when we expected 219 (P<0.001). Of these 286 infants, 51 had at least four VATER anomalies, and 8 had all five anomalies. We found that preaxial but not other limb anomalies were significantly associated with any combination of the four nonlimb VATER anomalies (P<0.001). Of the 286 infants with VATER association, 214 (74.8%) had additional defects. Genital defects, cardiovascular anomalies, and small intestinal atresias were positively associated with VATER association (P<0.001). Infants with VATER association that included both renal anomalies and anorectal atresia were significantly more likely to have genital defects. Finally, a subset of infants with VATER association also had defects described in other associations, including diaphragmatic defects, oral clefts, bladder exstrophy, omphalocele, and neural tube defects. These results offer evidence for the specificity of the VATER association, suggest the existence of distinct subsets within the association, and raise the question of a common pathway for patterns of VATER and other types of defects in at least a subset of infants with multiple congenital anomalies.

The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS)

The European Network of the Teratology Information Services (ENTIS) has collected and evaluated data on 689 pregnancies in which exposure to tricyclic and nontricyclic antidepressants occurred. Data were collected prospectively from the time of in utero exposure and all the cases were followed up to the first few weeks of postnatal life using standardized procedures. In most cases, no longer term follow-up data were available. Approximately two-thirds of the mothers were on multidrug therapy, and of those, half took a benzodiazepine. About 95% of the patients were exposed during the first trimester. The most striking feature of the pregnancy outcomes is that 97% of live-born babies were morphologically normal. The incidence of spontaneous abortion and late fetal/neonatal deaths were within the normal range. Fourteen live-born babies and one fetus had either major or minor malformations, and six had minor anomalies. However, there was no increase in either a particular type of malformation or a specific pattern of defects. Another 31 infants without malformations had neonatal problems; these were usually associated with chronic multidrug therapy, especially near term. Elective termination of pregnancy occurred more frequently in the multidrug groups (86 out of 488) than in the monotherapy groups (20 out of 201), but data concerning the condition of the fetus are not available in the majority of the cases. Overall, no causal relationship could be established between in utero exposure to antidepressants and adverse pregnancy outcome.

Teratogenic effects of antiepileptic drugs : Use of an international database on malformations and drug exposure (MADRE)

Summary: Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations.

Gestational diabetes mellitus. A survey of perinatal complications in the 1980s.

Neonatal morbidity was assessed in the offspring of 878 mothers with gestational diabetes mellitus (GDM), 132 mothers with pre-GDM, and 380 control subjects. Compared with the control group, the GDM group had a higher incidence of complications, including macrosomia, hypoglycemia, hyperbilirubinemia, hypocalcemia, polycythemia, and major congenital anomalies (P < 0.05). Although our GDM patients were stringently managed with diet or diet plus insulin, as indicated, and maintained almost euglycemic values, these neonatal complications could not be eliminated. Our data may be consistent with observations published during the last decade that even subtle degrees of maternal hyperglycemia can have a detrimental effect on perinatal outcome. Most neonatal complications readily respond to therapy if diagnosed and treated early and promptly. Macrosomia can have a detrimental effect on delivery (trauma) and later long-term implications during childhood. Tight metabolic control with diet and, when indicated, insulin treatment may be advantageous in reducing fetal birth weight. Criteria of how tight the metabolic control should be remain to be accurately defined.

Skin Barrier Properties in Different Body Areas in Neonates

Objective. The aim of the study was to investigate skin barrier function in neonates in different anatomic sites during the first 2 days of life. Design. The study population consisted of 44 healthy full-term newborn infants. Transepidermal water loss (TEWL), stratum corneum hydration (SCH), and skin surface pH were measured in different anatomic sites (forehead, flexor part of forearm, upper back, abdomen, inguinal region, palms, and soles) during the first 10 hours of life and 24 hours later. Measurements were recorded with a Tevameter, a Corneometer, and a skin pH meter with a flat glass electrode. Results were compared with those in 20 healthy adults. Results. TEWL was lower in infants than in adults in the forehead, palms, soles, and higher in the forearms. It was significantly higher on day 1 than on day 2 in the soles, palms, and forearms, and in the forearm, palms, and inguinal region compared with the other anatomic sites. SCH was significantly lower in the infants on the forehead, back, and abdomen, and higher on the forearms and palms; it was significantly higher on the first day of life on the forearms and palms, and lower in the inguinal region. Skin surface pH was significantly higher in the infants in all body sites (>6.6 in most measurements). On day 2, it was significantly lower than on day 1, but still higher than in adults. SCH correlated positively with TEWL in the neonates but not in the adults. None of the variables were related to gestational age, sex, mode of delivery, or body weight. Conclusions. Changes take place in SCH, water loss, and pH in the first 2 days after birth, suggesting that the stratum corneum barrier is still in the process of adapting to extrauterine life. The significant anatomic variability in TEWL and SCH should be taken into account in evaluating the permeation of skin care products and topical medications in newborns.

Congenital malformations in twins: An international study

Data provided by nine registries based in European and Latin America countries were analyzed to assess whether there is an excess of malformations in twins compared to singletons. Specific congenital malformations were coded according to the ninth revision of the International Classification of Diseases (ICD). Malformation rates and rate ratios (RR) for twins compared to singletons were calculated for each registry, and the homogeneity of the RRs was tested using the test of Breslow and Day. If departure from homogeneity in the different registries was not significant, registry-adjusted RRs with 95% confidence intervals were calculated. Overall, among 260,865 twins, 5,572 malformations were reported. A total of 101 different types of malformations or groups of defects was identified, and a homogeneous estimate of the RRs among registries was found for 91.1% of the malformations. Thirty-nine of the 92 malformations with homogeneous estimates of RRs were more common in twins than in singletons. For the remaining nine malformations, heterogeneous estimates of RRs were obtained. This study confirms the majority of already known associations and further identifies previously unreported malformations associated with twins. In conclusion, there is an excess of malformations in twins compared with singletons, and all anatomical sites are involved. The number of specific malformations associated with twins is higher than that previously reported in smaller studies.

Vitamin K antagonists and pregnancy outcome - A multi-centre prospective study

Vitamin K antagonists (VKA) are known to act as teratogens; however, there is still uncertainty about the relative risk for birth defects and the most sensitive period. In a multi-centre (n = 12), observational, prospective study we compared 666 pregnant women exposed to phenprocoumon (n = 280), acenocoumarol (n = 226), fluindione (n = 99), warfarin (n = 63) and phenindione (n = 2) to a non-exposed control group (n = 1,094). Data were collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) during individual risk counselling between 1988 and 2004. Main outcome measures were coumarin embryopathy and other birth defects, miscarriage rate, birth-weight, and prematurity. The rate of major birth defects after 1st trimester exposure was significantly increased (OR 3.86, 95% CI 1.86-8.00). However, there were only two coumarin embryopathies (0.6%; both phenprocoumon). Prematurity was more frequent (16.0% vs. 7.6%, OR 2.61, 95% CI 1.76-3.86), mean gestational age at delivery (37.9 vs.39.4, p<0.001), and mean birth weight of term infants (3,166 g vs. 3,411 g; p < 0.001) were lower compared to the controls. Using the methodology of survival analysis, miscarriage rate reached 42% vs. 14% (hazard ratio 3.36; 95% CI 2.28-4.93). In conclusion, use of VKA during pregnancy increases the risk of structural defects and other adverse pregnancy outcomes. The risk for coumarin embryopathy is, however, very small, in particular when therapy during the 1(st) trimester did not take place later than week 8 after the 1(st) day of the last menstrual period. Therefore, elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy. Close follow-up by the obstetrician including level II ultrasound should be recommended in any case of VKA exposure during pregnancy.

Gastroschisis and associated defects: An international study†

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non‐isolated cases. Case‐by‐case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non‐isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio‐vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb‐body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non‐syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non‐isolated cases and a thorough case‐by‐case review.

Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE To study potential teratogenic effects of quinolone exposure during pregnancy. STUDY DESIGN Prospective follow-up study. Subjects are pregnant women who contacted a teratology information center for risk information on quinolone treatment. A total of 549 pregnancies was collected by the European Network of Teratology Information Services between 1986 and 1994. In addition 116 prospectively documented pregnancies and 25 retrospective case reports on malformed children from other databases were analyzed. RESULTS The malformation rate among the live-born babies in the prospective ENTIS cohort was approximately 4.8%. No specific patterns of congenital abnormalities were found. The results do not suggest an elevated risk for spontaneous abortion, prematurity, intrauterine growth retardation and postnatal disorders. CONCLUSION The present study does not reveal any clear adverse reactions (fetal and neonatal toxicity, including birth defects) due to the in utero exposure to quinolones. Hence, termination of pregnancy because of such exposure is not indicated. However, considering the limitations of this study and the fact that diseases urgently requiring quinolone treatment are rare, it appears advisable to prefer penicillin, cephalosporins and erythromycin as antibiotics of choice.