Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

Attention-deficit/hyperactivity disorder in children following prenatal exposure to antidepressants: results from the Norwegian mother, father and child cohort study.

OBJECTIVE: To determine the association between child attention-deficit/hyperactivity disorder (ADHD) and prenatal exposure to selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor antidepressants, by timing and duration, with quantification of bias due to exposure misclassification. DESIGN: Norwegian Mother, Father and Child Cohort Study and national health registries. SETTING: Nationwide, Norway. POPULATION: A total of 6395 children born to women who reported depression/anxiety in pregnancy and were either medicated with SSRI/SNRI in pregnancy (n = 818) or non-medicated (n = 5228), or did not report depression/anxiety but used antidepressants 6 months before pregnancy (discontinuers, n = 349). MAIN OUTCOME MEASURE: Diagnosis of ADHD or filled prescription for ADHD medication in children, and mother-reported symptoms of ADHD by child age 5 years. RESULTS: When the hazard was averaged over the duration of the study follow up, there was no difference in ADHD risk between ever in utero SSRI/SNRI-exposed children and comparators (weighted hazard ratio [wHR] 1.07, 95% CI 0.76-1.51 versus non-medicated; wHR 1.53, 95% CI 0.77-3.07 versus discontinuers). Underestimation of effects due to exposure misclassification was modest. In early childhood, the risk for ADHD was lower with prenatal SSRI/SNRI exposure compared with no exposure, and so were ADHD symptoms (weighted ß -0.23, 95% CI -0.39 to -0.08); this risk became elevated at child age 7-9 years (wHR 1.93, 95% CI 1.22-3.05). Maternal depression/anxiety before pregnancy was independently associated with child ADHD. CONCLUSION: Prenatal SSRI/SNRI exposure is unlikely to considerably increase the risk of child ADHD beyond that posed by maternal depression/anxiety. The elevated risk at child age 7-9 years needs to be elucidated. TWEETABLE ABSTRACT: Women with depression who use antidepressants in pregnancy do not have greater risk of having children with ADHD. Findings in school-age children needs follow up.

Register-based study showed that the age when children were prescribed antibiotic tablets and capsules instead of liquids increased from 2004 to 2016.

AIM: We investigated the age when the prescriptions of oral antibiotic formulations for children from birth to 12 years of age changed from being mostly liquid to mostly solid and the associations between solid formulations and child, prescriber and medication characteristics. METHODS: This register-based study comprised data from the Norwegian Prescription Database on oral antibiotics dispensed between 2004 and 2016 when both solid and liquid dosage forms were available in appropriate doses. RESULTS: Just over 1.2 million prescriptions were studied, and the age when children were prescribed oral solid antibiotics gradually increased. The mean age of conversion from liquids to solid formulations was 6.9 years and ranged from 5.7 years in 2004/2005 to 7.9 years in 2015/2016. Patient factors associated with solid dosage forms were the children's increasing age and male gender. Practitioner factors were the prescribers' increasing age, male gender, being a general practitioner and issuing fewer than 23 paediatric antibiotic prescriptions per year. Medication factors were bad-tasting liquids and the size and shape of solid dosage forms. CONCLUSION: The age when children were prescribed antibiotic tablets and capsules increased from 2004 to 2016. The medicine characteristics were quite consistent, so this was probably caused by a shift in formulation preferences.

Requests for new oral antibiotic prescriptions in children within 2 days: a Norwegian population-based study.

Background: Children commonly refuse to take antibiotics, which may induce parents to request new antibiotic prescriptions with different pharmaceutical characteristics. Objectives: To investigate prescription changes for children 0-12 years receiving oral liquid or solid antibiotic formulations and to explore the relationships between prescription changes and characteristics related to the child, prescriber and antibiotic. Methods: A population-based registry study based on data from the Norwegian Prescription Database (NorPD) from 2004 to 2016. Antibiotic prescription changes were defined as the dispensing of subsequent antibiotics with different pharmaceutical characteristics to the same child within 2 days after initial prescriptions. Data were analysed using multivariable logistic regression and generalized estimating equations. Results: Requests for new prescriptions followed 3.0% of 2 691 483 initial antibiotic prescriptions for children. Young children who received solid formulations (10.9%) and certain poor-tasting antibiotics (8.6%) had the highest proportions of new prescriptions. Penicillin V was most commonly changed, while macrolides/lincosamides dominated subsequent prescriptions. In order of magnitude, the characteristics associated with requests for new prescriptions were the children's ages, poor taste and concentration of liquids, size and shape of solids, prescribers born in recent decades, and girl patients. Reimbursed prescriptions and scored solids were associated with fewer requests. Conclusions: While only 3% of the antibiotic prescriptions were changed, the preference of broad-spectrum over narrow-spectrum antibiotics for young children in this study mirrors international prescription patterns. Avoiding the costs of children's refusal and consequent changes may thus be a motivation for choosing more preferred antibiotics.

Women's beliefs about medication use during their pregnancy: a UK perspective.

Background Previous research has examined the number and extent of medicines taking in pregnant women but not their beliefs and risk perception surrounding their use. Objective To describe beliefs and risk perception associated with medicines use for the treatment of common acute conditions among UK women and explore whether this is related to actual medicines use. Settings Cross-sectional, web-based study in the UK. Methods Pregnant women and mothers within 1 year of giving birth were invited to participate in an online cross-sectional questionnaire-based study via a pregnancy website in the UK. Anonymous data were collected from women regarding their use of medicines (both over-the-counter and prescribed) and their beliefs regarding medicines use during pregnancy. Main outcome measures Pregnant women's beliefs about medicines and their relation to pharmacological treatment of acute conditions in pregnancy. Results Pharmacological treatment of conditions in pregnancy ranged from 65.4 % for urinary tract infections (UTIs) to 1.1 % for sleeping problems. Almost three out of ten women avoided using some medications during pregnancy. For heartburn and UTIs, women who did not treat the condition viewed medicines in general as being overused, more harmful and less beneficial, than those who treated the condition. In general, UK pregnant women perceived medicines to be beneficial and slightly overused. Conclusions Women's beliefs about medications impact on treatment of specific conditions in pregnancy such as heartburn and UTIs. Healthcare professionals should explore patient's beliefs regarding medication at the first maternity care visit to promote appropriate medication use in pregnancy.

Safety classification of herbal medicines used in pregnancy in a multinational study.

BACKGROUND: The use of herbal medicines for health prevention and ailments is an increasing trend worldwide. Women in pregnancy are no exception; the reported prevalence of herbal medicine use in pregnancy ranges from 1 to 60 %. Despite a common perception of safety, herbal medicines may have potent pharmacological actions, and historically, have been used for this reason. METHODS: A multinational, cross-sectional study on how women treat disease and pregnancy-related health ailments was conducted between October 2011 and February 2012 in Europe, North America, and Australia. This study's primary aim was to evaluate and classify the herbal medicines used according to their safety in pregnancy and, secondly, to investigate risk factors associated with the use of contraindicated herbal medicines during pregnancy. RESULTS: In total, 29.3 % of the women (n = 2673) reported the use of herbal medicines in pregnancy; of which we were able to identify 126 specific herbal medicines used by 2379 women (89.0 %). Twenty seven out of 126 herbal medicines were classified as contraindicated in pregnancy, and were used by 476 women (20.0 %). Twenty-eight were classified as safe for use in pregnancy and used by the largest number of women (n = 1128, 47.4 %). The greatest number was classified as requiring caution in pregnancy; these sixty herbal medicines were used by 751 women (31.6 %). Maternal factors associated with the use of contraindicated herbal medicines in pregnancy were found to be working in the home, having a university education, not using folic acid, and consuming alcohol. Interestingly, the recommendation to take a contraindicated herbal medicine was three times more likely to be from a healthcare practitioner (HCP) than an informal source. CONCLUSION: Based on the current literature the majority of women in this study used an herbal medicine that was classified as safe for use in pregnancy. Women who reported taking a contraindicated herb were more likely to have been recommended it use by an HCP rather than informal source(s), indicating an urgent need for more education among HCPs. The paucity of human studies on herbal medicines safety in pregnancy stands in stark contrast to the widespread use of these products among pregnant women.

Medication use and drug-related problems among women at maternity wards-a cross-sectional study from two Norwegian hospitals.

PURPOSE: There is a lack of knowledge about drug-related problems (DRPs) among pregnant and lactating women. The aim of this study was to determine the extent and type of DRPs among pregnant and lactating women in the maternity ward at two Norwegian hospitals. We also aimed to investigate which drugs were involved in the identified DRPs, and the outcome of solving the DRPs. METHODS: Patient-reported treatment reviews were performed to assess the prevalence and type of DRPs among women at the two maternity wards. RESULTS: In all, 212 women were included in the study, of which 89 (42 %) had experienced at least one DRP (105 DRPs in total). "Need for additional drug" (49 cases, 46.7 %) was the most frequent. The most frequent drug group involved in DRPs was drugs acting on the respiratory system, and the most common intervention was raising awareness/providing confidence/giving information during the patient-reported treatment review. CONCLUSIONS: Over four out of ten women in the maternity wards have DRPs, and many have questions about drug use during pregnancy and lactation. Many of the DRPs could probably be avoided by providing patient-reported treatment reviews to pregnant women as a part of antenatal care. Multidisciplinary collaboration including physicians, midwifes, and pharmacists in antenatal care and in maternity ward could possibly prevent DRPs and thereby promote patient safety for pregnant and lactating women.

Pregnancy outcomes after prenatal exposure to echinacea: the Norwegian Mother and Child Cohort Study.

INTRODUCTION: Previous studies have shown that echinacea is among the most widely used herbal medicines during pregnancy in Western countries. Despite its frequent use, we know little about the safety of this herbal medicine during pregnancy. The primary aim of this study was to study the consequences of the use of echinacea on malformations and common adverse pregnancy outcomes. Secondly, we aimed to characterize women using this herb in pregnancy. METHOD: This study is based on the Norwegian Mother and Child Cohort Study (MoBa) and included 68,522 women and their children. Information was retrieved from three self-administered questionnaires completed by the women in pregnancy weeks 17 and 30 and 6 months after birth. Information on pregnancy outcomes was retrieved from the Medical Birth Registry of Norway. Generalized estimating equations analyses were performed to assess the association between exposure to echinacea and pregnancy outcomes. Pearson's chi-square test was used to assess factors related to use of echinacea in pregnancy. RESULTS: Among 68,522 women, 363 (0.5 %) reported the use of echinacea during pregnancy. These women were characterized by high age and delivery before 2002 and were to a less extent smoking in pregnancy. The use of echinacea was not associated with an increased risk of malformations or adverse pregnancy outcomes. CONCLUSION: This study revealed no increased risk of malformations or adverse pregnancy outcomes after the use of echinacea in pregnancy. Studies on the safety of commonly used herbal medications are important to identify herbals that should be avoided in pregnancy.

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.

Characteristics of women with nausea and vomiting of pregnancy who chose to continue compassionate use of placebo after a randomised trial.

The placebo effect has not been characterised in pregnant women suffering from nausea and vomiting of pregnancy (NVP). Our aim was to characterise determinants of the placebo effect in women treated with placebo for NVP. We analysed data from a multicentre, double blind randomised controlled trial of Diclectin (delayed release doxylamine and pyridoxine) vs placebo for the treatment of NVP. A total of 127 women in the placebo arm and 130 in the active arm provided evaluable data for this analysis. Women who chose to continue placebo on a compassionate basis (n = 41) had significantly better improvement in symptoms of NVP and higher Wellbeing scores than those who did not ask to continue compassionate use. Results were similar in the active drug arm. The request to continue compassionate use of either placebo or active drug could be predicted by greater improvement in symptoms of NVP during the trial period.

Hormonal contraception and pelvic girdle pain during pregnancy: a population study of 91,721 pregnancies in the Norwegian Mother and Child Cohort.

STUDY QUESTION: Is pre-pregnancy hormonal contraception use associated with the development of pelvic girdle pain during pregnancy? SUMMARY ANSWER: In contrast to combined oral contraceptive pills, long lifetime exposure to progestin-only contraceptive pills or the use of a progestin intrauterine device during the final year before pregnancy were associated with pelvic girdle pain. WHAT IS ALREADY KNOWN: Pelvic girdle pain severely affects many women during pregnancy. Smaller studies have suggested that hormonal contraceptive use is involved in the underlying mechanisms, but evidence is inconclusive. STUDY DESIGN, SIZE, DURATION: A population study during the years 1999-2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 91,721 pregnancies included in the Norwegian Mother and Child Cohort Study. Data were obtained by two self-administered questionnaires during pregnancy weeks 17 and 30. MAIN RESULTS AND THE ROLE OF CHANCE: Pelvic girdle pain was present in 12.9% of women who had used combined oral contraceptive pills during the last pre-pregnancy year, 16.4% of women who had used progestin-only contraceptive pills, 16.7% of women who had progestin injections and 20.7% of women who had used progestin intrauterine devices, compared with 15.3% of women who did not report use of hormonal contraceptives. After adjustment for other study factors, the use of a progestin intrauterine device was the only factor based on the preceding year associated with pelvic girdle pain [adjusted odds ratios (OR) 1.20; 95% confidence interval (CI): 1.11-1.31]. Long lifetime exposure to progestin-only contraceptive pills was also associated with pelvic girdle pain (adjusted OR 1.49; 95% CI: 1.01-2.20). LIMITATIONS, REASONS FOR CAUTION: The participation rate was 38.5%. However, a recent study on the potential biases of skewed selection in the Norwegian Mother and Child Cohort Study found the prevalence estimates but not the exposure-outcome associations to be influenced by the selection. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest that combined oral contraceptives can be used without fear of developing pelvic girdle pain during pregnancy. However, the influence of progestin intrauterine devices and long-term exposure to progestin-only contraceptive pills requires further study. STUDY FUNDING/COMPETING INTEREST(S): The present study was supported by the Norwegian Research Council. None of the authors has a conflict of interest.

Effects of ibuprofen, diclofenac, naproxen, and piroxicam on the course of pregnancy and pregnancy outcome: a prospective cohort study.

OBJECTIVE: To investigate the individual effects of ibuprofen, diclofenac, naproxen, and piroxicam on pregnancy outcome. DESIGN: Cohort study. SETTING: Norwegian population. POPULATION: A total of 90 417 women and singleton child pairs. METHODS: The Norwegian Mother and Child Cohort Study and Medical Birth Registry of Norway data sets were used. MAIN OUTCOME MEASURES: Infant survival, congenital malformations, structural heart defects, neonatal complications, haemorrhage during pregnancy and postpartum, asthma at age of 18 months. RESULTS: One or more of the four nonsteroidal anti-inflammatory drugs (NSAIDs) were used by 6511 pregnant women (7.2%). No effect on rates of infant survival, congenital malformation, or structural heart defects was found. The use of ibuprofen in the second trimester was significantly associated with low birthweight (adjusted OR 1.7, 95% CI 1.3-2.3), and ibuprofen use in the second and third trimesters was significantly associated with asthma in 18-month-old children (adjusted OR 1.5, 95% CI 1.2-1.9; adjusted OR 1.5, 95% CI 1.1-2.1). The use of diclofenac in the second trimester was significantly associated with low birthweight (adjusted OR 3.1, 95% CI 1.1-9.0), whereas diclofenac use in the third trimester was significantly associated with maternal vaginal bleeding (adjusted OR 1.8, 95% CI 1.1-3.0). No associations with other neonatal complications were found. CONCLUSIONS: The lack of associations with congenital malformations is reassuring. The significant association between diclofenac and ibuprofen use late in pregnancy, and maternal bleeding and asthma in the child, respectively, is consistent with their pharmacological effects. The increased risk of low birthweight may partly have been caused by underlying inflammatory conditions, and was reassuringly similar to the expected baseline risk of low birthweight.

Gender differences in drug bioequivalence: time to rethink practices.

Currently, bioequivalence (BE) studies are carried out exclusively in males, assuming that intrasubject variabilities are similar between the sexes. This article challenges this hypothesis on the basis of available evidence and urges that studies of BE of sufficient power be undertaken in women also for all generic drugs aimed at women.

Maternal characteristics and migraine pharmacotherapy during pregnancy: cross-sectional analysis of data from a large cohort study.

Little is known about factors associated with migraine pharmacotherapy during pregnancy. Of 60 435 pregnant women in a population-based cohort, 3480 (5.8%) reported having migraine during the first 5 months of pregnancy. Of these, 2525 (72.6%) reported using migraine pharmacotherapy, mostly non-narcotic analgesics (54.1%) and triptans (25.4%). After adjustment for sociodemographic factors and comorbidities in logistic regression analysis, high pregestational body mass index [odds ratio (OR) 1.3, 95% confidence interval (CI) 1.2, 1.4], sleep < 5 h (OR 1.6, 95% CI 1.3, 1.9), being on sick-leave (OR 1.3, 95% CI 1.2, 1.5) and acute back/shoulder/neck pain (OR 0.6, 95% CI 0.6, 0.7) were associated with migraine pharmacotherapy during pregnancy. Many women need drug treatment for migraine during pregnancy, and the choice of pharmacotherapy during this period may be influenced by maternal sociodemographic factors and comorbidities.

Guidelines for iron supplementation in pregnancy: compliance among 431 parous Scandinavian women.

OBJECTIVE: The need for iron in pregnancy is rarely met by dietary food intake alone. Therefore, guidelines on iron supplementation have been developed to ensure optimal maternal and foetal iron provision. Today, the World Health Organization recommends iron supplementation during the second half of pregnancy. Our aim was to study compliance to these guidelines among 431 parous Scandinavian women. In addition, the association between maternal socio-demographic and lifestyle factors, maternal haemoglobin (Hb) values and non-compliance was assessed. METHODS: The women were interviewed about iron use at gestational weeks 25, 33 and 37 at the three Scandinavian study sites, Trondheim, Bergen and Uppsala. RESULTS: In all, 27% of the women used iron supplements continuously during the second half of pregnancy, hence complying with the guidelines. Further, 41% of the women reported periodical and 32% no use of iron supplementation during the second half of pregnancy. In the multivariable analyses, high Hb-concentration, living in Uppsala [OR: 3.1 (1.6-6.0)] or Bergen [OR: 4.7 (2.4-9.3)] as opposed to Trondheim, and smoking during pregnancy [OR: 2.0 (1.1-3.5)] were associated with non-compliance to guidelines. CONCLUSION: We conclude that maternal Hb values, demographic factors and smoking during pregnancy are among the factors associated with non-compliance to guidelines on iron supplementation during pregnancy.

Drug use during early pregnancy. The impact of maternal illness, outcome of prior pregnancies and socio-demographic factors.

OBJECTIVE: Socio-demographic factors have been associated with drug use in pregnancy. However, information on maternal illness has rarely been included in previous studies. The aim of this study was therefore to estimate the impact of maternal illness and prior pregnancy outcome on the use of analgesics/antipyretics, anti-infectives and antihistamines in early pregnancy controlling for socio-demographic factors. METHODS: One thousand nine-hundred and forty-five parous pregnant women from Norway and Sweden were included in an interview study. Information on drug use, obstetric history, maternal illness and socio-demographic factors was collected by specially trained midwives at gestational week 17 and form the basis for the present analyses. RESULTS: After control for socio-demographic factors, reported illness was associated with the use of analgesics/antipyretics, anti-infectives and antihistamines during early pregnancy. The use of analgesic/antipyretic and anti-infective drugs differed between study sites. Sociodemographic factors such as age, parity, marital status, education, occupation and smoking habits did not influence drug use in the multivariate analysis. CONCLUSION: Maternal illness during pregnancy was associated with drug use in early pregnancy. When studying factors related to drug use during pregnancy, it is important to include information on maternal illness. Socio-demographic factors may be confounders and lead to erroneous conclusions about the factors related to drug use.

[The transfer of selective serotonin reuptake inhibitors to human milk]. / Overgang av selektive serotoninreopptakshemmere til morsmelk.

BACKGROUND: This article presents an overview of the excretion of the SSRIs citalopram, paroxetine, fluoxetine, fluvoxamine and sertraline in breast milk. MATERIAL AND METHODS: Published articles on selective serotonin reuptake inhibitors and excretion in breast milk were identified and reviewed. In addition, drug concentrations were measured in milk from eight women using paroxetine (n = 4), citalopram (n = 3) or fluvoxamine (n = 1). RESULTS: Data from the literature indicate that the relative dose to the infant is lowest for fluvoxamine and sertraline, somewhat higher for paroxetine and highest for citalopram and fluoxetine. Adverse effects were reported in three of the 119 breastfed infants. Our own results show minimal excretion of fluvoxamine, small excretion of paroxetine and higher excretion of citalopram into breast milk. INTERPRETATION: If treatment with a selective serotonin reuptake inhibitor is started during the postpartum period, fluoxetine should not be the first alternative. High doses of citalopram should also be used with caution. However, when the use of an SSRI is clearly indicated in a breastfeeding woman, available data generally indicate that the positive effects of breast-feeding outweigh the risks for pharmacological effects in the infant.

Transfer of carisoprodol to breast milk.

There is no published information on the transfer of the centrally acting muscle relaxant carisoprodol and its active metabolite meprobamate into breast milk. The objective of this study was to quantify the excretion of carisoprodol and meprobamate in human milk and estimate the dose received by breast-fed infants. The concentrations of carisoprodol and meprobamate were measured in breast milk on 4 consecutive days at steady-state conditions in one woman using carisoprodol 2100 mg/d. The average milk concentrations were 0.9 microg/mL for carisoprodol and 11.6 microg/mL for meprobamate. Based on the milk concentrations measured, the absolute dose ingested by an exclusively breast-fed infant could be estimated at 1.9 mg/kg per day, and the relative dose would be 4.1% of the weight-adjusted maternal dose. No adverse effects were observed in the infant, but the infant was partly fed with formula because of insufficient maternal milk production. Thus, the authors consider that at least during prolonged use, lactation is generally inadvisable until more clinical data are available.

Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors.

UNLABELLED: Selective serotonin reuptake inhibitors (SSRIs) are a new group of antidepressants used in mild to moderate cases of depression. In studies evaluating the safety of SSRIs during pregnancy, no increase in major anomalies has been reported. This might have led to increasing off-label prescription of SSRIs to pregnant women. Neonatal withdrawal syndrome commonly occurs in infants exposed during the third trimester to drugs known to cause addiction. We report five cases of neonatal withdrawal syndrome after third trimester in utero SSRI exposure. In three cases the mother used paroxetine in doses from 10 to 40 mg, one mother used citalopram 30 mg, and one mother fluoxetine 20 mg. Withdrawal symptoms occurred within few days after birth and lasted up to one month after birth. Four of the infants needed treatment with chlorpromazine. Symptoms were irritability, constant crying, shivering, increased tonus, eating and sleeping difficulties and convulsions. CONCLUSION: Neonatal withdrawal syndrome can occur after third trimester in utero SSRI exposure. Further research should focus on whether it is safe to use SSRIs during the last trimester. All neonates exposed to SSRIs during the last trimester should be followed-up closely for withdrawal symptoms after birth.