Pregnancy outcomes following maternal macrolide use: A systematic review and meta-analysis.

To determine whether gestational use of all or specific macrolides (azithromycin, clarithromycin, roxithromycin or erythromycin) lead to an increase in rates of overall major congenital malformations, organ-specific malformations, and other adverse pregnancy outcomes in infants. PubMed/MEDLINE, Cochrane Central Register of Controlled Trials and Reprotox® databases were searched. Dichotomous outcomes or calculated log odds ratios and standard errors from observational studies are combined using the random-effects method in Review Manager 5.3. No significant increased risks for major congenital malformation (OR 1.06 [95% CI 0.99, 1.13]) and congenital heart defect (OR 1.05 [95% CI 0.92, 1.19]) following all macrolides use during the first trimester were detected. Prenatal azithromycin use was associated with a significantly increased risk of major congenital malformations in the analysis of cohort studies (OR 1.21 [95% CI 1.08-1.36]). This significance was also present in the sensitivity analysis. There were no statistically significant associations between the risk of organ specific malformations and all or specific macrolide exposures except for the decreased risk in hypospadias following erythromycin use in the meta-analysis of case-control studies (OR 0.38 [95% CI 0.18, 0.81]. Also, a significant 1.5-fold increased risk for spontaneous abortion following macrolide use was detected. A slight yet significantly increased rate of major congenital malformation with azithromycin exposure during pregnancy may be associated with maternal confounders. Nevertheless, level II ultrasound can be suggested following maternal azithromycin use during the first trimester. Future studies should take into account the inclusion of a disease-matched control group and accurate classification of the malformations.

Use of Phenytoin, Phenobarbital Carbamazepine, Levetiracetam Lamotrigine and Valproate in Pregnancy and Breastfeeding: Risk of Major Malformations, Dose-dependency, Monotherapy vs Polytherapy, Pharmacokinetics and Clinical Implications.

It is challenging to balance the fetal risks associated with the use of antiepileptic drugs (AEDs) against maternal and fetal risks of seizure worsening, and therefore it is very important to define and distinguish the possible risks entailed by different AEDs. This paper aims to undertake a comprehensive review regarding the possible risks of four classical (phenytoin, carbamazepine, phenobarbital, and valproate) and two newer (lamotrigine and levetiracetam) AEDs during pregnancy. The review focuses on major and organ-specific malformations, dose-dependent risks, mono vs polytherapy, and clinical pharmacokinetics. A discussion regarding the safety of AED use during breastfeeding is also provided.

Ondansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC).

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step-which has important clinical consequences-is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.

The role of smoking in the development and progression of structural damage in axial SpA patients: A systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to determine whether smoking was associated with the cumulative radiographic spinal damage and radiographic progression in patients with ankylosing spondylitis (AS). Thus, we conducted a systematic review and meta-analysis of the available studies to date. METHODS: An electronic search was conducted from inception to June 21, 2016, in EMBASE, the MEDLINE/PubMed Cochrane Central Register of Controlled Trials databases. Cross-sectional and longitudinal cohort studies investigating the association between smoking and cumulative spinal structural damage or radiographic progression were included. The outcome of interest was the presence of syndesmophytes in cross-sectional studies and radiographic progression in longitudinal studies. The quality assessment was done using the Agency for Healthcare Research and Quality checklist. The authors of potentially relevant studies were contacted regarding the unpublished data. Data from eligible cross-sectional studies were extracted and arranged in a 2x2 table. The odds ratios (ORs) and 95% confidence intervals (CIs) for the dichotomous outcome of interest were computed. RESULTS: The combined data of eight eligible cross-sectional studies for the assessment of association between smoking and cumulative spinal structural damage suggested a significant association (OR, 2.02; 95% CI, 1.51-2.70). No significant heterogeneity was detected between studies (I2=23.0%, p=0.25). The heterogeneity of the longitudinal study data did not permit us to undertake a meta-analysis. Hence, a qualitative review was performed. CONCLUSION: The results of our meta-analysis show that smoking is associated with increased cumulative spinal structural damage in patients with AS. Therefore, rheumatologists should encourage patients with AS to quit smoking.

An Option to Consider for Alternating Hemiplegia of Childhood: Aripiprazole.

Alternating hemiplegia of childhood (AHC) is an infrequent neurological disorder characterized by recurrent transient attacks of hemiplegia that last minutes to days and impress either side of the body, dystonic or tonic attacks, and nystagmus. Cognitive or neurological deficits with progressive course are another findings. Epileptic seizures may occur in some patients. We report the medical treatment in a case of AHC in a-12-year-old male patient with convulsions. The patient did not respond to available therapies for AHC, except for aripiprazole. After the initiation of aripiprazole therapy, duration and frequency of hemiplegia episodes were decreased. Also, he is currently seizure-free with topiramate treatment for 3 months. On follow-up, a compound heterozygous ATP1A3 mutation c.868C > T (p.R290C)/c.684 + 1G > A was determined. Aripiprazole may reduce the attacks of AHC, which are resistant to other available therapies.

Use of ondansetron during pregnancy and the risk of major congenital malformations: A systematic review and meta-analysis.

AIMS: To investigate whether ondansetron use during pregnancy is associated with increased rates of major or subgroups of malformations. METHODS: PubMed/MEDLINE, Cochrane and Reprotox® databases were searched. Observational studies comprising an exposed and control group (healthy and/or disease-matched) were included. RESULTS: No significant increased risk for major malformations, heart defects, orofacial clefts, genitourinary malformations or hypospadias were identified in our primary analysis. A significant heterogeneity existed for isolated cleft palate. Elevated point estimates and altered statistical significances were present for some of the outcomes among secondary analyses. CONCLUSIONS: Ondansetron use during pregnancy was not associated with a significant increase in rate of major or selected subgroups of malformations in our primary analysis. However, results of the secondary analyses warrant the need for continued surveillance. These results may be reassuring for pregnant women in whom ondansetron use is clinically indicated since the absolute risks of possible concerns appear to be low.

Pregnancy outcomes following quinolone and fluoroquinolone exposure during pregnancy: A systematic review and meta-analysis.

OBJECTIVE: To investigate whether maternal exposure to quinolones, fluoroquinolones and specifically ciprofloxacin is associated with major malformations and other adverse pregnancy outcomes. METHODS: MEDLINE/PubMed, Embase and Reprotox® databases were searched. Observational studies with an exposed and control group were included. RESULTS: Analysis of 8 cohort and 2 case-control studies showed no significant increases in rates of major malformations for quinolone (OR, 1.04; 95% CI 0.89-1.21), fluoroquinolone (RR, 0.89; 95% CI 0.70-1.14) and ciprofloxacin exposure (RR, 0.72; 95% CI 0.43-1.19). For fluoroquinolones, live birth rate was significantly decreased (RD, -0.04; 95% CI -0.08 to -0.01) whereas elective termination rate (RD, 0.04; 95% CI 0.02-0.05) was significantly increased. CONCLUSIONS: Quinolone, fluoroquinolone and ciprofloxacin exposure were not associated with a significant increase in major malformations and adverse pregnancy outcomes, other than significantly decreased live birth rate and increased elective termination rate which may be the indicators of misperceived teratogenic risk.

Pregnancy outcomes after maternal betahistine exposure: A case series.

OBJECTIVE: To investigate the pregnancy outcomes of women who were exposed to betahistine during their pregnancies. METHODS: We identified and evaluated the outcomes of 27 pregnant women who were referred to Terafar (Teratology Information Service, Izmir, Turkey) for a teratological risk assessment. RESULTS: Of 24 pregnancies with known outcomes, 21 resulted in live births (including two pairs of twins) whereas two ended with miscarriage and three with elective terminations. Among the 20 live births for whom the malformation details were available, there were 17 normal outcomes, one major and two minor congenital malformations. CONCLUSIONS: Despite a number of limitations, this case series may be of value regarding counseling pregnant women with inadvertent betahistine exposure. Further epidemiological studies with larger sample sizes and control groups are necessary to draw more definite conclusions.

Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services.

AIMS: Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. This study aims to evaluate the safety of metformin in early pregnancy. METHOD: We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during the first trimester for different indications relative to a matched unexposed reference group. RESULTS: The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group [adjusted odds ratio (OR) 1.70; 95% CI 0.70-4.38]. Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group [adjusted hazard ratio (HR) 1.57; 95% CI 0.90-2.74]. The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95% CI 1.44-4.36) and 1.38 (95% CI 0.74-2.59) when compared to the reference. CONCLUSION: Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks.

Evaluation of the neuropathic pain in the smokers.

OBJECTIVES: Nicotine addiction is one of the most important causes of the general failure of treatment and keeping the habit of smoking. Peripheral neuropathy is a leading factor of smoking. This study aimed to analyze the association of neuropathic pain and addiction levels of individuals. METHODS: The study was performed on the day on which the smokers visited the hospital for any reason. The Douleur Neuropathique 4 (DN-4) Scale and Fagerström Addiction Survey were administered to the individuals after obtaining their consent. RESULTS: In total, 444 individuals were included in the study, and 57.2% of them were males (n = 254). The age average of the individuals with neuropathic pain (46.4±12.3 years) was significantly higher than that of those without pain. The individuals with pain smoked approximately 31.8±18.3 packet/year cigarettes, whereas those without pain smoked approximately 22.4 ± 15.5 packet/year cigarettes; the difference was significant statistically (p<0.05). According to multivariate logistic regression analysis with the backward elimination method, the existence of pain was found to be PR = 2.22 (95% GA, 1.26-3.91) in terms of sex, DM existence was found to be PR = 1.97 (95% GA, 1.02-3.81), and for each standard deviation increase (2.7) in Fagerström scale, PR was 1.29 (95% GA, 1.14-1.46). CONCLUSION: Smoking is a risk factor for neuropathic pain. In our study, the possibility of neuropathic pain increases as the duration of smoking and addiction level increase, and with diabetes, this rate increases even more. It is extremely important that the smokers should be informed regarding these facts and possibilities.

Maternal SSRI discontinuation, use, psychiatric disorder and the risk of autism in children: a meta-analysis of cohort studies.

We undertook an exclusive meta-analysis of cohort studies investigating the possible link between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and autism spectrum disorders (ASD) in children to further investigate our previous suggestion of confounding by indication. The point estimates regarding the following cohorts were extracted and pooled: (1) pregnant women who discontinued SSRI until 3 months before pregnancy; (2) pregnant women who were exposed to SSRI during pregnancy; and (3) pregnant women with maternal psychiatric disorder but no exposure to SSRI during pregnancy. Although the pooled point estimate of the first cohort showed a trend for increase, it did not reach significance. The pooled point estimates of the latter cohorts showed a significant association with ASD which strengthens our previous suggestion of confounding by indication. Future studies should be adequately designed to differentiate whether the previously suggested association is a result of maternal psychiatric disorder or SSRI exposure or both.

Counselling pregnant women at the crossroads of Europe and Asia: effect of Teratology Information Service in Turkey.

Background Previous studies from western countries demonstrated the effectiveness of Teratology Information Service (TIS) counselling in reducing the teratogenic risk perception of pregnant women. Objective To assess whether TIS counselling would be effective in reducing the teratogenic risk perception of the Turkish pregnant women. Setting A TIS (Terafar) operating in a university hospital in Turkey. Methods A cross-sectional survey study. Pregnant women with non-teratogenic medication exposures were asked to assign scores on visual analogue scales (VAS) in response to the questions aiming to measure their teratogenic risk perception. The mean score before and after counselling were compared and the associations with maternal socio-demographic characteristics were analysed using SPSS (Version 20.0). Main outcome measures The differences in the mean scores of the perception regarding the baseline risk of pregnancy, own teratogenic risk and the likelihood of termination of pregnancy before and after counselling and their possible associations with maternal socio-demographic characteristics. Results 102 pregnant women participated in the study. The counselling significantly reduced the mean own teratogenic risk perception score and the mean score for the likelihood of termination of pregnancy whereas the mean baseline risk perception score was not significantly changed. Pregnancy week <8 and the exposed number of active ingredients <3 were significantly associated with the difference in the mean score for the likelihood of termination of pregnancy. Conclusions TIS counselling lowers the teratogenic risk perception of Turkish pregnant women and increases their likelihood to continue the pregnancy as it does in the western countries.

Effect of nitrergic system on colonic motility in a rat model of irritable bowel syndrome.

AIM: The aim of this study is to investigate whether nitric oxide (NO)-mediated colonic motility was altered in rat irritable bowel syndrome (IBS) model, using different isoforms of NO-synthase (NOS) inhibitors. MATERIALS AND METHODS: The animal model of IBS-like visceral hypersensitivity was induced by intra-colonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8 to 21. Control animals received saline instead of AA. Experiments were performed at the end of 8 weeks. Distal colon tissues were resected and direct effects of different NOS inhibitors; N-omega-nitro-L-arginine methyl ester hydrochloride, (L-NAME), ARL-17477 dihydrochloride hydrate (ARL 17477), N-[3-(Aminomethyl) phenyl] methyl]-ethanimidamidedihydrochloride (1400 W), and N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) were evaluated concentration-dependently in vitro tissue bath. Besides, morphology of both groups was assessed with hematoxylin and eosin (H and E) staining and the impact of NO antibodies was determined using the immunohistochemical method. RESULTS: The mean pressure values of spontaneous contractions and KCL (80 mmol/L) responses of distal colonic segments were similar in normal and IBS rats. L-NAME and ARL-17477 significantly increased the mean pressure of spontaneous colonic contractions in normal rats versus own base values (P < 0.05), but this increase did not significantly different when compared to IBS rats. In H and E staining, there was no difference with regard to morphology between two groups. Neuronal NOS (nNOS) immunoreactivity was found to be significantly decreased in IBS when compared to control groups (P < 0.05). CONCLUSION: L-NAME and ARL-17477 mediated mean pressure values were found to be slightly decreased in IBS rats. These findings may be related to a decrease in nNOS level in IBS.