Drugs In Pregnant Women Research Articles

Efficacité et sécurité de l’acide tranexamique en prévention et/ou en traitement de l’hémorragie du post-partum : une revue systématique de la littérature avec méta-analyse

Objective(s)Assess the efficacy and safety of tranexamic acid administration for the prevention and/or the treatment of postpartum haemorrhage. Study designSystematic review with meta-analysis. Material and methodsSystematic review of the literature with the aim of identifying prospective, randomised, controlled trials that assessed the effect of tranexamic acid on peripartum blood loss and transfusion requirement in three clinical contexts: (i) prevention of post-partum haemorrhage in case of elective caesarean section, (ii) prevention of post-partum haemorrhage in case of vaginal delivery, (iii) treatment of post-partum haemorrhage. ResultsProphylactic administration of tranexamic acid reduced blood loss (mean difference for intraoperative blood loss: −177.9mL, IC 95%: −189.51 to −166.35, total blood loss: −183.94, IC 95%: −198.29 to −169.60), and the incidence of severe post-partum haemorrhage (OR: 0.49, IC 95%: 0.33 to 0.74). None of the published trials assessed the effect of tranexamic acid on blood products administration or transfusion requirement. Only one study assessed and reported the efficacy of tranexamic acid when administered as a treatment for postpartum haemorrhage. A significant reduction in blood loss was reported within 30minutes after randomisation (P=0.03) and confirmed after 6hours (median: 170mL (58–323) vs 221mL (110–543), P=0.04). None of the included studies adequately studied the incidence of side effects after tranexamic acid administration. ConclusionAlthough tranexamic acid administration seemed to significantly reduce blood loss and the incidence of severe post-partum haemorrhage, further prospective trials are needed to confirm the efficacy and safety of tranexamic administration in the treatment of postpartum haemorrhage. Those studies should assess the pharmacokinetic profile and the safety of this drug in pregnant women.

Dexmedetomidine improves intraoperative conditions and quality of postoperative analgesia when added to epidural in elective cesarean section

IntroductionThis study was designed to evaluate the effect of adding dexmedetomidine to regular mixture of epidural drugs for pregnant women undergoing elective caesarian section with special emphasis on their sedative properties, ability to improve quality of intraoperative, postoperative analgesia and neonatal outcome.MethodsFifty women of ASA physical status I or II at term pregnancy were enrolled randomly to receive either plain bupivacaine plus fentanyl (BF group) or plain bupivacaine plus mixture of fentanyl and dexmedetomidine (DBF group). Incidence of hypotension, bradycardia, Apgar scores, intraoperative pain assessment, onset of postoperative pain, sedation scores and side effects were recorded.ResultsNo difference in the times taken for block to reach T4 sensory level, to reach the highest level of sensory block and interval between first neuraxial injection and onset of surgery between the groups. Onset of postoperative pain was significantly delayed in the DBF group (P = 0.001), the need for supplementary fentanyl was significantly less in DBF group (P = 0.03), and no significant difference was obtained between both groups regarding neonatal Apgar scores as well as the incidence of hypotension, bradycardia, nausea, vomiting and duration of motor blockade between the groups. DBF group had significantly less incidence of shivering (P = 0.03).ConclusionAdding dexmedetomidine to regular mixture of epidural anesthetics in women undergoing elective cesarean section improved intraoperative conditions and quality of postoperative analgesia without maternal or neonatal significant side effects.

Ocular changes during pregnancy.

Most ocular changes in pregnancy are harmless. For example, 14% of pregnant women need a new eyeglass prescription. Some changes, however, are serious, such as retinal effects of hypertension, which can be a sign of pre-eclampsia. Ocular changes may give rise to uncertainty about the administration of ophthalmological drugs or the optimal method of childbirth. This review is based on pertinent literature retrieved by a selective search in Medline and on guidelines from Germany and abroad. Recommendations about drugs were taken from the Embryotox and Reprotox databases, the German Red List, and the United States Food and Drug Administration (FDA). 40% to 100% of pregnant women with high blood pressure have retinal changes whose severity is correlated with the severity of pre-eclampsia or eclampsia. Diabetic women should undergo ocular examination before and during pregnancy. Pre-existing retinal changes worsen during pregnancy in 55% of cases. Most ocular diseases can be treated with the usual drugs in pregnant women and nursing mothers, although the evidence for drug safety is derived from case series and the treatment is usually provided off label. Ocular conditions that are present before pregnancy are irrelevant to the choice of a method of childbirth. Pregnant women and nursing mothers can undergo most types of ophthalmological examination and treatment. Recommendations about drug treatment should be checked against current information that can be found on the embryotox.de and reprotox.de websites.

Certain Cardiac Abnormalities Not Linked to Prenatal Antidepressant Use, Study Finds

When choosing to stop antidepressant therapy during pregnancy, both physician and patient must balance the potential risks of treatment versus nontreatment.

A Study of Handling Cytotoxic Drugs and Risk of Birth Defects in Offspring of Female Veterinarians

We examined the association of occupational exposure to handling cytotoxic drugs at work with risk of birth defects among a cohort of female veterinarians. This study is a follow up survey of 321 female participants (633 pregnancies) who participated in the Health Risks of Australian Veterinarian project. Data on pregnancies and exposure during each pregnancy was obtained by self-administered mailed questionnaire. Female veterinarians handling cytotoxic drugs during their pregnancy had a two-fold increased risk of birth defects in their offspring (RR = 2.08, 95% CI (1.05–4.15)). Results were consistent in subgroup analysis of those who graduated during the period of 1961 to 1980 (RR = 5.04, 95% CI (1.81, 14.03) and in those working specifically in small and large animal practice. There was no increased risk in the subgroup that graduated after 1980. Women with unplanned pregnancies were more likely to handle cytotoxic drugs on a daily basis (RR = 1.86, 95% CI, 1.00–3.48) and had a higher increased risk of birth defects than those who planned their pregnancies in recent graduates and in those who worked specifically in small animal practice (RR = 2.53, 95% CI, 1.18–5.42). This study suggests that the adverse effects of handling cytotoxic drugs in pregnant women may include an increased risk of birth defects. Pregnancy intention status is an important health behavior and should be considered in prenatal programs.

OP0120 A Systematic Analysis of the Safety of Prescribing Anti-Rheumatic Immunosuppressive and Biologic Drugs in Pregnant Women with Inflammatory Arthritis

BackgroundThe use of anti-rheumatic drugs in pregnancy is often complicated by concerns over their potential for adverse effects. Given that rheumatic diseases often affect women of childbearing age and may...

FRI0320 Pregnancy Outcomes in Rheumatoid Arthritis Patients Treated with Tocilizumab

BackgroundBiological agents (“biologics”), such as anti-tumor necrosis factor (TNF) agents and interleukin-6 (IL-6) inhibitors, have been widely used in recent years for the treatment of rheumatoid arthritis (RA) to achieve...

Effect of Gestational Exposure to Novel Antipsychotics on Body Weight Gain in Rats

Clinical literature demonstrates that nearly all atypical antipsychotic drugs (AAPDs) are associated with weight gain. The magnitude of weight gain, however, varies between doses of drugs and exposure period as well as in different age groups. Data on AAPDs like quetiapine (QUE), risperidone and weight gain have been found variable in clinical and preclinical trials. The metabolic safety of these drugs in pregnant women has not been thoroughly investigated so far. Therefore, present study is designed to investigate the effect of gestational exposure to equivalent therapeutic doses of AAPDs, QUE and RISP on weight gain in female pregnant rats. The results indicate that there was mild reduction in body weight gain and food consumption in RISP exposed rats. Similarly, mild weight loss was also observed in QUE exposed dams inspite of significant drug induced anorexia/hypophagia. These drugs were found either neutral in weight gain or may induce mild weight loss in female adult rats. This study also demonstrates that multifunctional mechanisms might be involved for alteration in feeding pattern and body weight gain.

Developmental cardiotoxicity effects of four commonly used antiepileptic drugs in embryonic chick heart micromass culture and embryonic stem cell culture systems

Antiepileptic drugs (AEDs) are commonly used drugs in pregnant women with epilepsy. Prenatal exposure to AEDs increases the risk of major or minor congenital malformation during embryonic development. The precise mode of action and intracellular mechanisms of these AEDs during embryonic development remains unclear. To determine relative teratogenic risk of AEDs, four AED drugs including valproic acid (VPA), phenytoin (PHT), phenobarbital (PB), and trimethadione (TMD) were tested using two in vitro systems (the embryonic chick heart micromass (MM) culture and the in vitro differentiating mouse embryonic stem cells into cardiomyocytes culture systems). Cardiomyocyte cultures (the heart MM and ES cell-derived cardiomyocytes) were treated with or without different concentrations of PHT, PB, TMD (10–100μM), and VPA (100–2000μM). 5-Fluorouracil (5-FU) (1–10μM) and l-ascorbic acid (10–1000μM) were used as positive and negative controls. It was found that these four commonly used AEDs and 5-FU tested have the potential to inhibit embryonic heart cell differentiation (p<0.05) without inducing any cytotoxicity. VPA at higher concentrations (⩾800μM), and 5-FU at all doses proved to be cytotoxic in the differentiating ES cell culture system. The results demonstrated in this study suggest that the use of these four commonly prescribed AEDs during pregnancy may have an effect on embryonic heart development, and may be associated with congenital cardiovascular defects.

123. A Systematic Analysis of the Safety of Prescribing Anti-Rheumatic Immunosuppressive and Biologic Drugs in Pregnant Women with Inflammatory Arthritis

123. A Systematic Analysis of the Safety of Prescribing Anti-Rheumatic Immunosuppressive and Biologic Drugs in Pregnant Women with Inflammatory Arthritis

Editorial: Safety of Immunosuppressive Drugs in Pregnant Women With Systemic Inflammatory Diseases

In the U.S., it is estimated that more than 4.5 million patients are affected by systemic inflammatory conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis, other inflammatory arthropathy, and inflammatory bowel disease (IBD). (1-3) These diseases often occur in women of childbearing ages. The safety of treatment for systemic inflammatory diseases during pregnancy is a major concern for both patients and their providers. For patients with no or minimal symptoms of systemic inflammatory diseases at conception, discontinuing immunosuppressive therapy before or right after conception might be an ideal option. Patients with active disease, however, need to continue immunosuppressive drugs to control the disease even during pregnancy as the disease activity seems to be an important predictor of pregnancy outcome across different systemic inflammatory diseases.(4-6)

Brief Report: Risk of Adverse Fetal Outcomes Associated With Immunosuppressive Medications for Chronic Immune‐Mediated Diseases in Pregnancy

ObjectiveTo assess the risk of adverse fetal outcomes following exposure to individual immunosuppressive drugs in pregnant women with chronic immune‐mediated diseases.MethodsHealth plan data were obtained from the Tennessee Medicaid and Kaiser Permanente Northern California and Southern California claims databases, with linkage to both vital records and medical records. Women with inflammatory arthropathies, those with systemic lupus erythematosus, and those with inflammatory bowel disease who filled prescriptions for immunosuppressive treatments during pregnancy were included. Major congenital malformations, fetal deaths, and life‐threatening neonatal complications were identified from the electronic data and validated with medical record review.ResultsThe cohort included 608 infants, including 437 with exposure to immunosuppressive drugs during the mother's pregnancy (402 during the first trimester, and 35 during the second and third trimester only) and 171 whose mothers filled prescriptions for immunosuppressive treatments before, but not during, pregnancy. There were 25 pregnancies (4.1% of the cohort) with confirmed major congenital malformations, and 10 fetal deaths (1.6% of the cohort). Among 113 preterm infants with exposures during pregnancy, 23 (20.4%) had life‐threatening neonatal complications, and among 485 term infants, 10 (2.1%) had life‐threatening complications. Compared to the reference group (treatment before, but not during, pregnancy), the risk ratios (RRs) for adverse fetal outcomes associated with immunosuppressive treatments (by exposure category) during pregnancy included the following: methotrexate (RR 1.39, 95% confidence interval [95% CI] 0.43–4.53), tumor necrosis factor inhibitors (RR 0.98, 95% CI 0.38–2.55), hydroxychloroquine (RR 1.33, 95% CI 0.69–2.55), and other immunosuppressive medications (RR 0.98, 95% CI 0.48–1.98).ConclusionIn this study, there was no evidence of a large increase in risk of adverse fetal outcomes from first‐trimester exposure to immunosuppressive medications, although the confidence intervals for the risk ratios were wide. Further studies will be needed as use of these medications increases over time.

Prevalence of the use of nonsteroidal anti-inflammatory drugs in pregnant women in Lubumbashi (Democratic Republic of Congo)

Malgré l'importance de leurs effets secondaires sur la femme enceinte et le fœtus, les anti-inflammatoires non stéroïdiens (AINS) continuent à être largement utilisés par les femmes enceintes. Leur rapport bénéfice-risque n'est pas toujours bien évalué en pratique courante. L'objectif de ce travail est d’évaluer l'usage des AINS chez la femme enceinte, de discuter les risques potentiels encourus aussi bien par la mère que par le fœtus, et enfin d'en tirer des recommandations éventuelles à la femme enceinte. Du 22 août au 11 septembre 2012, une enquête a été menée auprès de 145 femmes enceintes suivies en consultation prénatale à l'Hôpital Sendwe. Un formulaire reprenant les informations sur les AINS consommés a été remis à chacune d'elle. Les résultats montrent que 75% des femmes interrogées reconnaissent avoir consommé des AINS surtout en automédication et principalement pendant les deux derniers trimestres de la grossesse pour soulager des douleurs d'origines diverses. Cette étude montre que des efforts restent encore à déployer à Lubumbashi afin de combattre l'utilisation des AINS surtout en automédication chez la femme enceinte.

Impact of Antiretroviral Drugs in Pregnant Women and Their Children in Africa: HIV Resistance and Treatment Outcomes

The global community has committed itself to eliminating new pediatric HIV infections by 2015 and improving maternal, newborn, and child health and survival in the context of HIV. Such objectives require regimens to prevent mother-to-child transmission (pMTCT) which, while being highly efficacious, protect the efficacy of future first-line antiretroviral therapy (ART). Major obstacles to eliminating vertical transmissions globally include low rates of adherence to ART and non-completion of the 'pMTCT cascade' due to programmatic and structural challenges faced by healthcare systems in low-income countries. Providing all pregnant women with lifelong ART regardless of CD4 count/disease stage (Option B+) could be the most effective option to prevent both HIV transmission and resistance, assuming adherence is successfully maintained. This strategy is more likely to achieve sustained undetectable HIV viremia, does not involve ART interruptions, is simpler to implement, and is cost-effective. Where Option B+ is not available, options A (short course zidovudine with single-dose nevirapine and an ARV "tail") and B (combination ART during pregnancy and breastfeeding, with ART cessation after weaning in women not qualifying for ART for their own health) are also efficacious, highly cost-effective and associated with infrequent resistance selection if taken properly.

A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age-dependent changes in maternal physiology and hepatic CYP3A activity. For verification, the disposition of CYP1A2-metabolized drug theophylline (THEO) and CYP2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX), and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during the third trimester (T3). Predicted mean postpartum to third trimester (PP:T3) ratios of THEO area under the curve (AUC), maximum plasma concentration, and minimum plasma concentration were 0.76, 0.95, and 0.66 versus observed values 0.75, 0.89, and 0.72, respectively. The predicted mean PAR steady-state plasma concentration (Css) ratio (PP:T3) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T3) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T3) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T3 was required to recover the observed PP:T3 ratios of PAR Css, DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy.

Physician characteristics and prescription drug use during pregnancy: a population-based study

PurposeWe aimed to explore the relationship between physician characteristics and their prescribing behavior regarding category D and X drugs for pregnant women by using a population-based data set in Taiwan. MethodsThe sampled population for the study included 14,430 women. These women received a total of 198,420 prescriptions during pregnancy. We performed multivariate logistic regression analysis by using generalized estimated equations to assess the odds ratio (OR) of the prescription for categories D and X drugs among doctors after adjusting for maternal age and chronic disease. ResultsOf the total 198,420 prescriptions, 4.2% were prescribed category D and X drugs. The covariate-adjusted odds for physicians aged between 40 and 49 years and 50 and 59 years for prescribing category D and X drugs to pregnant women were 1.22 (95% confidence interval [95% CI], 1.15–1.31) and 1.51 (95% CI, 1.40–1.64) times that of physicians aged between 30 and 39 years, respectively. Male physicians were less likely to prescribe category D and X drugs to pregnant women than female physicians (OR, 0.69; 95% CI, 0.63–0.75). In addition, physicians specializing in “other” specialties were more likely (OR, 1.46; 95% CI, 1.41–1.54) to prescribe category D and X drugs compared with those specializing in obstetrics/gynecology, whereas physicians practicing in central Taiwan were less likely (OR, 0.85; 95% CI, 0.80–0.89) than their counterparts in other regions of Taiwan to prescribe category D and X drugs. ConclusionsWe conclude that physician characteristics, including sex, age, specialty, and practice location, were associated with the prescription of category D and X drugs for pregnant women.

A PBPK Model to Predict Disposition of CYP3A‐Metabolized Drugs in Pregnant Women: Verification and Discerning the Site of CYP3A Induction

Besides logistical and ethical concerns, evaluation of safety and efficacy of medications in pregnant women is complicated by marked changes in pharmacokinetics (PK) of drugs. For example, CYP3A activity is induced during the third trimester (T3). We explored whether a previously published physiologically based pharmacokinetic (PBPK) model could quantitatively predict PK profiles of CYP3A-metabolized drugs during T3, and discern the site of CYP3A induction (i.e., liver, intestine, or both). The model accounted for gestational age-dependent changes in maternal physiological function and hepatic CYP3A activity. For model verification, mean plasma area under the curve (AUC), peak plasma concentration (Cmax), and trough plasma concentration (Cmin) of midazolam (MDZ), nifedipine (NIF), and indinavir (IDV) were predicted and compared with published studies. The PBPK model successfully predicted MDZ, NIF, and IDV disposition during T3. A sensitivity analysis suggested that CYP3A induction in T3 is most likely hepatic and not intestinal. Our PBPK model is a useful tool to evaluate different dosing regimens during T3 for drugs cleared primarily via CYP3A metabolism.

A dramatic fetal outcome following transplacental transfer of dasatinib

Chronic myeloid leukemia is a chronic myeloproliferative disorder of hematopoietic stem cells that occurs in 10% of cases in women of childbearing age. Treatment is mainly based on tyrosine kinase inhibitors such as imatinib, dasatinib, or nilotinib. However, the maternal and embryofetal safety of these drugs in pregnant women is poorly documented. Here, we report the case of a 23-year-old woman diagnosed with a chronic myeloid leukemia. She was treated with dasatinib while she was diagnosed as being pregnant at 7 weeks of gestation. Obstetric monitoring showed fetal hydrops associated with severe fetal bicytopenia, leading to termination of pregnancy at 16 weeks of gestation. Dasatinib concentrations were 4 ng/ml in maternal plasma (usual concentration), 3 ng/ml in fetal plasma, and 2 ng/ml in amniotic fluid. Fetal karyotype was normal. To our knowledge, this is the first report clearly quantifying the amount of transplacental transfer of dasatinib. Moreover, fetal hematological toxicity (leukopenia and thrombocytopenia), edema, ascites, and pleural effusions described in this case report are well-known side effects of dasatinib in adults. Hence, this case highlights the imputability of dasatinib in this adverse outcome, and clearly questions its safety during pregnancy.

Outcomes after anti-rheumatic drug use before and during pregnancy: a cohort study among 150 000 pregnant women and expectant fathers

Objectives: To study (i) the drug utilization pattern of anti-rheumatic drugs in pregnant women and expectant fathers and (ii) the association between the use of anti-rheumatic drugs during pregnancy and the risk of congenital malformations.Method: Pregnancies registered in the Medical Birth Registry of Norway (MBRN) were linked to the Norwegian Prescription Database (NorPD) in the period 2004–2007. Prescriptions for anti-rheumatic drugs issued to women 3 months prior to and during pregnancy and to men 3 months prior to conception were identified. Congenital malformations were recorded according to the European Surveillance of Congenital Anomalies (EUROCAT) guidelines.Results: In 154 976 singleton pregnancies, 1461 of the women (0.9%) and 1198 (0.8%) of the known fathers (150 530) were dispensed anti-rheumatic drugs at least once during the study period: 723 had non-steroidal anti-inflammatory drugs (NSAIDs), 633 prednisolone (CS), 119 sulfasalazine (SASP), 101 azathioprine (AZA), 58 hydroxychloroquine (HQC), 37 etanercept (ETAN), eight methotrexate (MTX), two leflunomide (LEF), and three adalumimab (ADA). Odds ratios (ORs) for malformations in children born of women (w) or men (m) who had received the drugs were ORw = 1.06 [95% confidence interval (CI) 0.85–1.32] and ORm = 1.19 (95% CI 0.93–1.51), respectively, and for major malformation ORw = 1.05 (95% CI 0.79–1.40) and ORm = 1.26 (95% CI 0.93–1.71), respectively. None of the children whose mother had received MTX, LEF, ETAN, or ADA were reported to be born with major malformations.Conclusions: This study revealed no major malformations of the alert drugs MTX, LEF, ETAN, or ADA. Although the numbers are limited, this provides important population-based information to both expectant parents and prescribers.

From no to yes: the history and ethics of including pregnant women in clinical trials

How often have you seen or heard ‘do not take this medication if you are pregnant (or nursing)’? Whether in media advertisements, pharmacies or provider offices, pregnant women are often warned to avoid many things. However, often the evidence behind these recommendations is not clearcut. The reason is that for a long time, pregnant women were excluded from participating in clinical trials. The ethical framework that led to telling women ‘no’ to participating in clinical trials continues to make it difficult to recruit women into research studies. However, the importance of including pregnant women and instead saying ‘yes’ is critical for the future of pregnancy therapeutics. The last few decades have seen major changes in the landscape of research ethics. Very few areas have seen changes the scope of those seen regarding the inclusion of pregnant women in clinical trials, particularly medication trials. In the wake of many revelations of unethical research, including problems arising from research involving drugs in pregnant women, children and the fetus, a protectionist research ethics model was adopted. Codified by the National Research Act in 1974, reproductive-aged women were excluded from many trials to avoid accidental early fetal exposure. Vulnerable populations such as pregnant women were given additional protections, such that unless there was a compelling reason for inclusion, pregnant women would not be included in research. The general proscription model, however, was unsustainable as both clinicians and researchers realized that clinical trial data was not always generalizable from studied populations (usually men) to pregnant women. Pregnancy introduces an array of physiological changes that render dosing models from many clinical trials irrelevant. Owing to these changes, drug concentrations in pregnant women may be too low to be effective [1–3]. However, there was great concern about including pregnant women in clinical trials due to the often unknown effects drugs may have on the developing fetus. The lack of long-term developmental safety information for almost any drug further compounded this concern. In addition, animal model data had given false reassurance in the high-profile case of thalidomide. During the late 1980s, however, a growing debate occurred about including pregnant women in clinical trials. Two landmark clinical trials helped push the ethical discussion forward and away from the strict protectionist model. The international studies demonstrating that prenatal vitamin supplementation (with folic acid) could reduce the incidence of recurrent and primary neural tube defects represented a departure from prior clinical trials that were centered on treating a condition [4,5]. These studies were about giving drugs (even if only prenatal “As the inclusion of pregnant women in clinical trials has moved from ‘no’ to ‘yes’, ethical models and the informed consent process are guiding forces leading to medical answers and breakthroughs that improve the lives of pregnant women and their babies.”