A cost-effectiveness analysis of maternal CYP2D6 genetic testing to guide treatment for postpartum pain and avert infant adverse events.

Mothers with a CYP2D6 ultrarapid metabolizer phenotype may expose their infants to risk of adverse events when taking codeine while breastfeeding, by producing more of the active metabolite, morphine. Pharmacogenetic testing may be a valuable tool to identify such mothers, but testing can be costly. The objective of the study was to determine the incremental costs of genotyping to avert neonatal adverse events during maternal pharmacotherapy. A cost-effectiveness analysis, using a decision model, was performed with a hypothetical cohort of prenatal subjects. Parameter estimates, costs and ranges for sensitivity analyses were ascertained from the literature and expert opinion. Sensitivity analyses were conducted to assess the robustness of the results. Probabilistic sensitivity analysis revealed an incremental cost-effectiveness (ICER) of $10 433 (Canadian dollars) for genotyping compared to no genotyping per adverse event averted. Results were sensitive to hospital admission costs. The ICER was lower when evaluating only subjects having caesarean deliveries or those from ethnic populations known to have a high prevalence of ultra-rapid metabolizers. Although genotyping to guide pharmacotherapy was not cost saving, the cost to avert an infant adverse event may represent good value for money in specific populations. With a growing demand for personalized medicine, these findings are relevant for decision makers, clinicians and patients.

The fetal safety of cetirizine: an observational cohort study and meta-analysis.

Cetirizine, a second-generation antihistamine, is an active metabolite of hydroxyzine used in the treatment of allergies, but the data on fetal safety are inconclusive. Pregnant women who were counselled by the 'Motherisk Program' regarding cetirizine exposure were enrolled in a cohort study and compared with pregnant women counselled for non-teratogenic exposures. The objective was to measure the rate of adverse pregnancy outcomes. Subsequently, we also conducted a meta-analysis of cohort studies that examined the pregnancy outcomes of women exposed to hydroxyzine or cetirizine during pregnancy. In the cohort study, there were no significant differences in the rates of major malformations between the cetirizine exposed and comparison group. In the meta-analysis, cetirizine was not associated with increased teratogenic risk. In contrast, a meta-analysis of cetirizine and hydroxyzine studies showed a marginal association with major malformations. Cetirizine is not associated with a clinically important increase in risk of adverse fetal outcomes.

Medication use in pregnancy: a cross-sectional, multinational web-based study.

OBJECTIVES: Intercountry comparability between studies on medication use in pregnancy is difficult due to dissimilarities in study design and methodology. This study aimed to examine patterns and factors associated with medications use in pregnancy from a multinational perspective, with emphasis on type of medication utilised and indication for use. DESIGN: Cross-sectional, web-based study performed within the period from 1 October 2011 to 29 February 2012. Uniform collection of drug utilisation data was performed via an anonymous online questionnaire. SETTING: Multinational study in Europe (Western, Northern and Eastern), North and South America and Australia. PARTICIPANTS: Pregnant women and new mothers with children less than 1 year of age. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of and factors associated with medication use for acute/short-term illnesses, chronic/long-term disorders and over-the-counter (OTC) medication use. RESULTS: The study population included 9459 women, of which 81.2% reported use of at least one medication (prescribed or OTC) during pregnancy. Overall, OTC medication use occurred in 66.9% of the pregnancies, whereas 68.4% and 17% of women reported use of at least one medication for treatment of acute/short-term illnesses and chronic/long-term disorders, respectively. The extent of self-reported medicated illnesses and types of medication used by indication varied across regions, especially in relation to urinary tract infections, depression or OTC nasal sprays. Women with higher age or lower educational level, housewives or women with an unplanned pregnancy were those most often reporting use of medication for chronic/long-term disorders. Immigrant women in Western (adjusted OR (aOR): 0.55, 95% CI 0.34 to 0.87) and Northern Europe (aOR: 0.50, 95% CI 0.31 to 0.83) were less likely to report use of medication for chronic/long-term disorders during pregnancy than non-immigrants. CONCLUSIONS: In this study, the majority of women in Europe, North America, South America and Australia used at least one medication during pregnancy. There was a substantial inter-region variability in the types of medication used.

The fetal safety of thiopurines for the treatment of inflammatory bowel disease in pregnancy.

Maintaining remission of inflammatory bowel disease (IBD) during pregnancy is critical for positive pregnancy outcomes. Conflicting data exist regarding the association between thiopurine use for IBD treatment in pregnancy and adverse pregnancy outcomes and this meta-analysis aims to clarify this association. A meta-analysis was performed of all original human studies reporting outcomes in pregnancy in patients receiving thiopurines. Nine studies satisfied the inclusion criteria and a total of 494 patients with IBD and 2,782 IBD controls were reported. When compared with healthy women, those receiving thiopurines had an increased risk for congenital malformations (RR 1.45; 95% CI 1.07-1.96; p = 0.02); however, when compared with IBD controls, there was no increased risk (RR 1.37; 95% CI 0.92-2.05; p = 0.1). These data provide support for thiopurines having a minimal risk, if any, to the fetus.

Teratogenicity of angiotensin converting enzyme inhibitors or receptor blockers.

Studies of 1st trimester exposure to ACE inhibitors and angiotensin receptor blockers examining teratogenicity have shown conflicting results. We systematically reviewed the literature and performed a meta-analysis evaluating the risk of major malformations. For the meta-analysis, we included studies comparing 1st trimester exposure to no exposure, or to exposure to other antihypertensives. Additionally, we conducted a qualitative analysis of studies that did not meet the inclusion criteria for the meta-analysis. A significant risk ratio was found when the exposed group was compared with healthy controls but not when compared with other antihypertensives. The qualitative analysis did not demonstrate a specific pattern of major malformations. Our results suggest that 1st trimester exposure to ACE inhibitors and angiotensin receptor blockers is not associated with an elevated risk of major malformations compared with other antihypertensives. A 1st trimester exposure to antihypertensives in general may be associated with an elevated risk of major malformations.

Body composition and muscular strength changes after moderate activity: association with matrix metalloproteinase polymorphisms.

Remodeling of skeletal muscles is regulated by matrix metalloproteinases (MMPs). Functional genetic polymorphism (PM), modulating the expression of some MMPs, might be associated to different body composition and muscular strength improvement after exercise. Genetic PM of MMP-1 (G+/- at -1607), MMP-3 (5A/6A at -1171) and MMP-9 (Cytosine-Adenine microsatellite=(13-27)CA) repeats, around -90), body cell mass (BCM), extracellular water (ECW) and isometric maximal extensor strength (MES) of both legs were determined in 17 old sedentary women at the beginning and at the end of a 24 week physical exercise program. A 12 and 72% increase in BCM and MES, respectively, and 11% reduction in ECW were observed at the end of the program. Carriers of G-insertion in MMP-1, PM increased their BCM (7 kg vs. -1.5, p=0.007) and lost ECW (9% of total body water vs. 0.1%, p=0.004) more than the non-carriers; homozygote for 21 or less CA repeats/allele in MMP-9 PM gained more MES (115 N, interquartile range=IQR=63-132) than carriers of longer microsatellites (63 N, IQR=40-86, p=0.028). MMP-3 did not show any association with body composition and exercise-related strength changes. Exercise in elderly women increases BCM and strength, these changes are associate to specific MMP genotypes.

The safety of higher than standard dose of doxylamine-pyridoxine (Diclectin) for nausea and vomiting of pregnancy.

A delayed-release combination of doxylamine-pyridoxine (D-P) (Diclectin) is the only approved antiemetic medication for use in pregnancy in Canada. The standard recommended dose is up to 4 tablets a day, regardless of body weight or severity of symptoms. The objective of this study was to determine the incidence of adverse maternal and fetal effects and pregnancy outcome in 225 women taking Diclectin at the recommended (n = 123) or higher than recommended (n = 102) doses. In this observational, prospective study, one-third (33.6%) of women reported having adverse effects (sleepiness, tiredness, and/or drowsiness) temporally related to the medication. There was no association between the dose per kg and rates of reported maternal adverse effects with doses ranging from 0.1 mg/kg to 2.0 mg/kg (1-12 tablets). Nausea and vomiting of pregnancy (NVP) was reported as severe by the majority (75.8%) of women. Mean birth weight (BW) was 3,400 g and gestational age (GA) 39 weeks. Multivariate analysis revealed that only prepregnancy weight and GA predicted lower BW, not the dose of D-P or the severity of NVP. There were two pregnancies with major malformation, a finding that is consistent with the rates of birth defects in the general population. It was concluded that the higher than standard dose of Diclectin, when calculated per kg of body weight, does not affect either the incidence of maternal adverse effects or pregnancy outcome. If needed, Diclectin can be given at doses higher than 4 tablets/day to normalize for body weight or optimize efficacy.

Fetal effects of cocaine: an updated meta-analysis.

BACKGROUND: A very large number of women in the reproductive age group consume cocaine, leading to grave concerns regarding the long term health of millions of children after in utero exposure. The results of controlled studies have been contradictory, leading to confusion, and, possible, misinformation and misperception of teratogenic risk. OBJECTIVE: To systematically review available data on pregnancy outcome when the mother consumed cocaine. METHODS: A meta-analysis of all epidemiologic studies based on a priori criteria was conducted. Comparisons of adverse events in subgroups of exposed vs. unexposed children were performed. Analyses were based on several exposure groups: mainly cocaine, cocaine plus polydrug, polydrug but no cocaine, and drug free. RESULTS: Thirty three studies met our inclusion criteria. For all end points of interest (rates of major malformations, low birth weight, prematurity, placental abruption, premature rupture of membrane [PROM], and mean birth weight, length and head circumference), cocaine-exposed infants had higher risks than children of women not exposed to any drug. However, most of these adverse effects were nullified when cocaine exposed children were compared to children exposed to polydrug but no cocaine. Only the risk of placental abruption and premature rupture of membranes were statistically associated with cocaine use itself. CONCLUSIONS: Many of the perinatal adverse effects commonly attributed to cocaine may be caused by the multiple confounders that can occur in a cocaine using mother. Only the risk for placental abruption and PROM could be statistically related to cocaine. For other adverse effects, additional studies will be needed to ensure adequate statistical power.

Leflunomide: new antirheumatic drug. Effect on pregnancy outcomes.

QUESTION: I am treating a 34-year-old woman with rheumatoid arthritis. She began taking the new drug leflunomide (Arava) 6 months ago and had good clinical response. She is now planning her first pregnancy. What should she do? ANSWER: Leflunomide is a new and effective disease-modifying antirheumatic drug. Animal studies have shown an increased rate of malformations and fetal death in various species, but there are no data on pregnancy outcomes in humans treated with leflunomide. Since the drug has a prolonged and unpredictable elimination half-life, it should be stopped during pregnancy. The manufacturer recommends that patients who wish to become pregnant be treated with cholestyramine, which enhances elimination.

Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies.

BACKGROUND: Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age. Information regarding human pregnancy outcome with corticosteroids is limited. METHODS: We collected prospectively and followed up 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure. The primary outcome was the rate of major birth defects. A meta-analysis of all epidemiological studies was conducted. The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals. A cumulative summary odds ratio was also calculated by combining studies in chronological order. Chi-squared for homogeneity was determined to establish the comparability of the studies. RESULTS: In our prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups. In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI 0.80, 2.60] and 3.03 [95% CI 1.08, 8. 54] when Heinonen et al. ('77) was removed. This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids. In addition, summary odds ratio for case-control studies examining oral clefts was significant (3.35 [95% CI 1.97, 5.69]). CONCLUSIONS: Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft, which is consistent with the existing animal studies.

Which drugs are contraindicated during breastfeeding? Practice guidelines.

QUESTION: Many breastfeeding mothers are concerned about taking medications that might affect their babies. Are there any guidelines on which drugs are safe? ANSWER: Only a few drugs pose a clinically significant risk to breastfed babies. In general, antineoplastics, drugs of abuse, some anticonvulsants, ergot alkaloids, and radiopharmaceuticals should not be taken, and levels of amiodarone, cyclosporine, and lithium should be monitored.

Pregnancy outcome after in utero exposure to itraconazole: a prospective cohort study.

OBJECTIVE: This study was undertaken to determine whether itraconazole use during the first trimester of pregnancy was associated with increased risks of major malformations, spontaneous abortions, premature deliveries, and neonatal complications. STUDY DESIGN: In a prospective cohort study pregnant women exposed to oral itraconazole were matched with control subjects not exposed to any known teratogens. Primary outcome was the rate of major malformations. Secondary outcomes were live birth rate, rates of spontaneous abortion and therapeutic abortion, gestational age at delivery, birth weight, and neonatal complications. RESULTS: A total of 229 women exposed to itraconazole were reported to the manufacturer, 198 of whom used the drug during the first trimester of pregnancy. The rate of major malformations in the study group (156 live births) was 3.2%, compared with 4.8% in the control group (187 live births; relative risk, 0.67; 95% confidence interval, 0. 23-1.95). The rate of any pregnancy loss was higher in the exposed group (relative risk, 1.75; 95% confidence interval, 1.47-2.09). Birth weight was lower in the itraconazole group, although that difference may not be clinically significant. Gestational age at birth, rate of preterm delivery, Apgar scores at 1 and 5 minutes, and neonatal complications were comparable between the groups. CONCLUSION: Our study supports the hypothesis that the use of itraconazole during pregnancy is safe. Further surveillance and reporting of pregnancy outcomes will help to support this conclusion.

Choice of breastfeeding and physicians' advice: a cohort study of women receiving propylthiouracil.

OBJECTIVE: To examine the gap between the current social/medical practice and the evidence-based recommendation in favor of breastfeeding during maternal propylthiouracil (PTU) therapy. DESIGN: Prospective, observational, cohort study. SUBJECTS: Women requiring PTU during pregnancy, and endocrinologists and family physicians in Ontario, Canada. INTERVENTIONS: Questionnaire. MAIN OUTCOME MEASURES: Women were interviewed postpartum regarding their choice of infant feeding method and relevant advice received from physicians. Physicians were questioned about their advice to nursing women receiving PTU. RESULTS: Of 78 women, 66 had live births. Thirty-six required PTU postpartum (group 1), and 30 did not (group 2). Thirty-six healthy women served as controls (group 3). Breastfeeding initiation rates for groups 1, 2, and 3 were 44%, 83%, and 83%, respectively. In group 1, 15 women who breastfed received advice from 22 physicians regarding breastfeeding (20 in favor, 1 against, and 1 equivocal). Eleven who formula fed received advice from 17 physicians (4 in favor, 12 against, and 1 equivocal). A logistic regression analysis of group 1 showed that physicians' advice was the only significant predictor of the woman's choice to breastfeed during PTU therapy (relative risk: 5.48; 95% confidence interval: 1.28-23.40). The physician survey showed that 44% of endocrinologists do not recommend breastfeeding during PTU therapy. CONCLUSIONS: A substantial proportion of the lactating patients on PTU still receive advice against breastfeeding from their physicians. Physicians' advice and attitudes toward breastfeeding during PTU therapy are a major factor in women's final decision to breastfeed. Physicians' compliance with evidence-based data will facilitate breastfeeding in this group.propylthiouracil, breastfeeding, decision-making.

Reporting bias in retrospective ascertainment of drug-induced embryopathy.

The rate of congenital malformations after first-trimester exposure to itraconazole was four times higher when ascertained retrospectively than prospectively (13.0 vs 3.2%, p=0.006). Reporting bias in retrospective studies should be acknowledged in interpretation of such data.

Disposition of maternal ketoconazole in breast milk.

Infant exposure to ketoconazole in human milk was calculated to be 0.4% on average (maximum 1.4%) of those expected from therapeutic doses given directly to infants. Potential risk of adverse reactions from this low exposure level seem to be outweighed by the benefits of breast-feeding.