Rafael Gorodischer

The safety of metoclopramide use in the first trimester of pregnancy.

BACKGROUND In various countries, metoclopramide is the antiemetic drug of choice in pregnant women, but insufficient information exists regarding its safety in pregnancy. METHODS We investigated the safety of metoclopramide use during the first trimester of pregnancy by linking a computerized database of medications dispensed between January 1, 1998, and March 31, 2007, to all women registered in the Clalit Health Services, southern district of Israel, with computerized databases containing maternal and infant hospital records from the district hospital during the same period. We assessed associations between the use of metoclopramide in pregnancy and adverse outcomes for the fetus, adjusting for parity, maternal age, ethnic group, presence or absence of maternal diabetes, smoking status, and presence or absence of peripartum fever. RESULTS There were 113,612 singleton births during the study period. A total of 81,703 of the infants (71.9%) were born to women registered in Clalit Health Services; 3458 of them (4.2%) were exposed to metoclopramide during the first trimester of pregnancy. Exposure to metoclopramide, as compared with no exposure to the drug, was not associated with significantly increased risks of major congenital malformations (5.3% and 4.9%, respectively; odds ratio, 1.04; 95% confidence interval [CI], 0.89 to 1.21), low birth weight (8.5% and 8.3%; odds ratio, 1.01; 95% CI, 0.89 to 1.14), preterm delivery (6.3% and 5.9%; odds ratio, 1.15; 95% CI, 0.99 to 1.34), or perinatal death (1.5% and 2.2%; odds ratio, 0.87; 95% CI, 0.55 to 1.38). The results were materially unchanged when therapeutic abortions of exposed and unexposed fetuses were included in the analysis. CONCLUSIONS In this large cohort of infants, exposure to metoclopramide in the first trimester was not associated with significantly increased risks of any of several adverse outcomes. These findings provide reassurance regarding the safety of metoclopramide for the fetus when the drug is given to women to relieve nausea and vomiting during pregnancy.

Tissue and erythrocyte distribution of digoxin in infants.

The distribution of digoxin in the myocardium, skeletal muscle, erythrocytes, and plasma (or serum) was studied in 19 infants. There was a linear relationship between myocardium and serum concentrations and no saturation was observed over the serum concentration range of 0.5–8.6 ng/ml. Myocardium uptake of digoxin was nearly twice as great in infants as in adults at any given serum concentration. Erythrocyte :plasma concentration ratios of digoxin were one‐third smaller during digitalization than during maintenance digoxin therapy. The latter ratios were also three times greater in infants than found previously in adults. Their findings are consistent with a greater apparent volume of distribution of digoxin in infants and may partly explain the unusually large therapeutic doses needed in infants.

Hypertension and antihypertensive drugs in pregnancy and perinatal outcomes.

OBJECTIVE Despite high rates of hypertension in pregnancy, the effects of hypertension have not been separated appropriately from the effects of the medications that are used. We evaluated the safety of exposure to antihypertensive medications during pregnancy, while accounting for disease effects. STUDY DESIGN A population-based retrospective cohort study was performed that compared all pregnancies of women with hypertension who were either exposed or unexposed to antihypertensive medications. A computerized database of the medications that were dispensed to pregnant women from 1998-2008 was linked with computerized databases that contained maternal and infant hospitalization records from the district hospital during the same period. RESULTS During the study period, 100,029 deliveries occurred; of those, 1964 pregnant women experienced chronic hypertension, and 620 neonates (0.6%) were exposed to at least 1 antihypertensive medication (methyldopa or atenolol) during pregnancy. A higher rate of intrauterine growth restriction (7.2% vs 2.1%, respectively; adjusted odds ratio [OR], 4.37; 95% confidence interval [CI], 3.00-6.36; P < .001), small for gestational age (3% vs 1.7%, respectively; adjusted OR, 2.23; 95% CI, 1.27-3.92; P = .005), and preterm deliveries (<37 weeks, 22.9% vs 8.0%, respectively; adjusted OR, 3.69; 95% CI, 2.90-4.69; P < .001) were noted among the pregnancies of women who were exposed to antihypertensive medications during the third trimester. Importantly, a similar association was detected when we compared women with chronic hypertension who were not treated during pregnancy (n = 1074) to women who had no chronic hypertension and who were unexposed to antihypertensive medications (n = 97,820). CONCLUSION Chronic hypertension with or without treatment during pregnancy is an independent and significant risk factor for adverse perinatal outcomes such as intrauterine growth restriction, small for gestational age, and preterm delivery.

Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy.

Objective. Nonsteroidal antiinflammatory drugs (NSAID) are among the most common medicines used by pregnant women. Published data are controversial regarding fetal safety following intrauterine exposure to NSAID. We investigated exposure to NSAID in the first trimester in a large cohort of infants and fetuses. Methods. A computerized database of medications dispensed from 1998 to 2009 to all women registered in the “Clalit” health maintenance organization in Southern Israel was linked with 2 computerized databases containing maternal and infant hospitalization records. Pregnancy terminations for medical reasons were analyzed. The following confounders were controlled for: parity, maternal age, ethnicity, maternal pregestational diabetes, maternal inflammatory disease, and year of birth or pregnancy termination. First trimester exposure to nonselective cyclooxygenase (COX) inhibitors and to selective COX-2 inhibitors as groups and to individual drugs was analyzed. Results. There were 110,783 pregnancies during the study period: 109,544 singleton births and 1239 pregnancy terminations for medical reasons. In total, 5267 mothers were exposed to NSAID during the first trimester of pregnancy: 5153 to nonselective COX inhibitors and 114 to COX-2 selective inhibitors. Exposure to NSAID in the first trimester, as groups (nonselective COX and selective COX-2 inhibitors) and as individual drugs, was not associated with an increased risk of major congenital malformations in general (adjusted OR 1.07, 95% CI 0.96−1.21 for nonselective; and adjusted OR 1.40, 95% CI 0.70−2.78, for selective COX-2 inhibitors), although an increased risk for musculoskeletal malformations was found following exposure to COX-2 selective inhibitors (adjusted OR 3.39, 95% CI 1.37−8.34). Conclusion. Intrauterine exposure to NSAID was not associated with increased risk for major congenital malformations. Further studies are needed to assess the risk for malformations after exposure to COX-2 selective inhibitors.

Hypophosphatasia: a developmental anomaly of alkaline phosphatase?

Extract: This report deals with quantitative and qualitative investigations of alkaline phosphatase in two unrelated infants with the severe infantile form of hypophosphatasia. Both affected infants had no detectable leukocyte alkaline phosphatase activities and both sets of parents and one sibling tended to have low but variable leukocyte enzyme activities. Normal duodenal juice alkaline phosphatase activity was present in the one patient in whom it was measured and a wide range of variation in enzymic activity was observed in the stools. There was no significant difference in the stool enzyme activity between both patients with hypophosphatasia (42.01 ± 9.77 U) and control infants (40.55 ± 6.29 U). However, the heterozygous parents had values significantly lower than the control adults (2.10 ± 0.47 as compared with 19.10 ± 4.44 U). Intestinal bacteria did not contribute significantly to the stool alkaline phosphatase activity. Enzyme activity was present in the bile of one of the patients and nearly absent in that of the other.Three “inducers” of alkaline phosphatase were given to both patients (phenobarbital, vitamin A, and corticosteroid). No clinical improvement or rise in serum alkaline phosphatase activity was observed during the trial of therapy with these agents. However, a significant increase in the activity of serum acid phosphatase was demonstrated during the course of vitamin A administration, suggesting an in vivo action of vitamin A on the lysosomes through decreasing the stability of the membrane and releasing acid phosphatase to the serum.Quantitative determination of tissue alkaline phosphatases from autopsy tissues was highly variable: no activity was found in bone, lungs, or spleen of either infant; there was a discrepancy in liver and kidney alkaline phosphatase values (zero in one patient and present in the other) and activity was present in the intestinal mucosa of both.Qualitative analysis of kidney, liver, and intestinal alkaline phosphatase revealed some differences between the patients and control subjects in heat inactivation and phenylalanine inhibition (Table 3). Starch gel electrophoresis of the liver preparation of one patient disclosed a single band which had greater mobility than that of six control subjects matched for age. Liver extracts from a premature and from full term newborns showed two bands. The single band of the patients liver enzyme corresponded to the newborns fast moving component. In addition, the intestinal enzyme prepared from the same patient had an extra band when compared with age-matched control subjects.Speculation: Among the many quantitative and qualitative alterations in alkaline phosphatases found in these two infants with the severe form of hypophosphatasia, the most striking finding was the presence in the liver of one of the cases of what appeared to be a form of the enzyme normally present only during very early postnatal life. The defective regulation of the various alkaline phosphatase isozymic forms during development may thus represent the basic defect in this disease.

Fetal Safety of Macrolides

ABSTRACT Macrolide antibiotics are largely used in pregnancy for different bacterial infections. Their fetal safety has been studied by several groups, yielding opposing results. In particular, there have been studies claiming an association between macrolides and cardiovascular malformations. Exposure in early infancy has been associated with pyloric stenosis and intussusception. This has led to an avoidance in prescribing macrolides to pregnant women in several Scandinavian countries. The Objectives of the present study was to investigate the fetal safety of this class of drug by linking a large administrative database of drug dispensing and pregnancy outcome in Southern Israel. A computerized database of medications dispensed from 1999 to 2009 to all women registered in the Clalit health maintenance organization in southern Israel was linked with two computerized databases containing maternal and infant hospitalization records. Also, medical pregnancy termination data were analyzed. The following confounders were controlled for: maternal age, ethnicity, maternal pregestational diabetes, parity, and the year the mother gave birth or went through medical pregnancy termination. First- and third-trimester exposures to macrolide antibiotics as a group and to individual drugs were analyzed. During the study period there were 105,492 pregnancies among Clalit women that met the inclusion criteria. Of these, 104,380 ended in live births or dead fetuses and 1,112 in abortion due to medical reasons. In the first trimester of pregnancy, 1,033 women were exposed to macrolides. There was no association between macrolides and either major malformations [odds ratio (OR), 1.08; 95% confidence interval (CI), 0.84 to 1.38)] or specific malformations, after accounting for maternal age, parity, ethnicity, prepregnancy diabetes, and year of exposure. During the third trimester of pregnancy, 959 women were exposed to macrolides. There was no association between such exposure and perinatal mortality, low birth weight, low Apgar score, or preterm delivery. Similarly, no associations were demonstrated with pyloric stenosis or intussusception. Use of macrolides in the first trimester of pregnancy is not associated with an increased risk of major malformations. Exposure in the third trimester is not likely to increase neonatal risks for pyloric stenosis or intussusception in a clinically meaningful manner.

Bias Toward the Null Hypothesis in Pregnancy Drug Studies That Do Not Include Data on Medical Terminations of Pregnancy: The Folic Acid Antagonists

Most studies on safety/risk of drugs in pregnancy consider the proportion of births (but not pregnancy terminations) affected by the drug from all exposed infants. Lack of data on pregnancy terminations could bias results. A computerized database for medications dispensed to pregnant women in southern Israel was linked with records from the district hospital; 84 823 deliveries and 998 medical pregnancy terminations took place; 571 of the women were exposed to folic acid antagonists in the first trimester. When only births were examined, there was no association between folic acid antagonists and fetal malformations. When data on pregnancy terminations were examined and births and pregnancy terminations were combined, there was a significant risk (neural tube defects: odds ratio 18.83, 95% confidence interval 9.24–38.37; cardiovascular defects: odds ratio 3.86, 95% confidence interval 1.67–8.88; and neural tube defects: odds ratio 6.30, 95% confidence interval 3.34–9.15; cardiovascular defects: odds ratio 1.76, 95% confidence interval 1.05–2.92, respectively). Inclusion of only birth data in observational studies of drugs in pregnancy constitutes a source of bias toward the null hypothesis.

Hippuric acid synthesizing system during development: Kinetic studies and inhibition with salicylic acid

Abstract p- Aminohippurate synthesis was investigated in mouse liver suspensions. It was found to be an age-dependent reaction with minimal activity in the neonatal period and adult values attained at 1 month of age. Sodium salicylate strongly inhibited the reaction; this inhibition was not suppressed by K or Mg ions. Kinetic studies indicated that the salicylate inhibition of p- aminohippurate synthesis is competitive in nature. Developmental kinetic experiments disclosed slightly different K m values in young versus adult animals; however, K i values at 7 and 68 days differed markedly.

Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring

Fetal exposure to H2 blockers (H2Bs) or proton pump inhibitors (PPIs) has been reported to be associated with asthma in children. We evaluated the risk of asthma in offspring following prenatal H2Bs. We enrolled 91 428 children and their mothers who resided in southern Israel during 1998–2011. The computerized medications database was linked with records from the district hospital. Of the eligible children, 11 227 developed asthma, and overall 5.5% had been exposed to H2Bs or PPIs prenatally. The risk of developing asthma was slightly higher in the group exposed to H2Bs or PPIs (RR, 1.09; P = .023). At greater risk were children whose mothers purchased these medications more than 3 times (RR, 1.22; P = .038) or exposed to >20 defined daily doses or prenatally exposed to lansoprazole. The statistical association was significant and depended on magnitude of exposure and specific medication, but the absolute risk was low. The association between maternal consumption of H2Bs or PPIs and asthma and childhood remained statistically significant 2 years after delivery, raising the possibility of confounding by the indication phenomenon. In view of the findings, a causal relationship could not be ascertained, and an unidentified etiological factor could be operative.

BeMORE: a novel method for detection of adverse fetal effects induced by drugs.

We describe a unique new collaboration which allows linkage of administrative databases in Southern Israel, and hence ascertain risk/safety of prescription drugs in pregnancy. The advantages of this system include availability of rigorous data confounders, solid data on maternal conditions for which the drug is given, ability to capture all cases of elective abortions and not just live births, and ability to construct drug doses.