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.

Pregnancy outcome following maternal exposure to mirtazapine: a multicenter, prospective study.

This multicenter, observational prospective cohort study addresses the risk associated with exposure to mirtazapine during pregnancy. Pregnancy outcomes after exposure to mirtazapine were compared with 2 matched control groups: (1) exposure to any selective serotonin reuptake inhibitor (SSRI, control subjects with a psychiatric condition) and (2) no exposure to medication known to be teratogenic or any antidepressant (general control subjects). Data were collected by members of the European Network of Teratology Information Services between 1995 and 2011. Observations from 357 exposed pregnancies were compared with 357 pregnancies from each control group. The rate of major birth defects between the mirtazapine and the SSRI group did not differ significantly (4.5% vs 4.2%; odds ratio [OR], 1.1; 95% confidence interval [95% CI], 0.5-2.3; P = 0.9). A trend toward a higher rate of birth defects in the mirtazapine group compared with general control subjects (4.5% vs 1.9%; OR, 2.4; 95% CI, 0.9-6.3; P = 0.08) reached statistical significance after exclusion of chromosomal or genetic anomalies (4.1% vs 1.3%; OR, 3.3; 95% CI, 1.04-10.3; P = 0.03), but this difference became again nonsignificant if cases of exposure not comprising the first trimester were excluded from the analysis (3.4% vs 1.9%; OR, 1.8; 95% CI, 0.6-5.0; P = 0.26). The crude miscarriage rate did not differ significantly between the mirtazapine, the SSRI, and the general control groups (12.1% vs 12.0% vs 9.3%; P = 0.44). However, a higher rate of elective pregnancy termination was observed in the mirtazapine group compared with SSRI and general control subjects (7.8% vs 3.4% vs 5.6%; P = 0.03). This study did not observe a statistically significant difference in the rate of major birth defects after first-trimester exposure between mirtazapine, SSRI-exposed, and nonexposed pregnancies. A marginally higher rate of birth defects was, however, observed in the mirtazapine and SSRI groups compared with the low rate of birth defects in our general control subjects. Overall pregnancy outcome after mirtazapine exposure was similar to that of the SSRI-exposed control group.

The outcomes of pregnancy in women exposed to the new macrolides in the first trimester: a prospective, multicentre, observational study.

BACKGROUND: Macrolides are a group of commonly prescribed antibiotics. There is some doubt surrounding the use of the newer macrolides in pregnancy. OBJECTIVE: The present study aimed to compare outcomes of pregnancies exposed to the new macrolides clarithromycin, azithromycin and roxithromycin with non-teratogenic preparations. METHODS: In this prospective, multinational, multicentre, controlled, observational study, information was obtained either from pregnant women or their healthcare professionals who contacted their local teratogen information services in Italy, Israel, the Czech Republic, the Netherlands and Germany seeking information after exposure to macrolides. The comparison group included women or their healthcare professional who contacted these centres with questions regarding known non-teratogenic preparations. Information on obstetric and other background parameters was collected at enrollment; after delivery, subjects or their healthcare professionals were contacted to ascertain pregnancy outcome parameters and other exposures through the remainder of the pregnancy. RESULTS: A total of 608 women exposed to macrolides during pregnancy were enrolled; 511 of the exposures occurred during the first trimester. The comparison group comprised 773 women exposed to non-teratogenic preparations during the first trimester of pregnancy. No significant difference in the rate of major congenital malformations was found between the study group and the comparison group (3.4% vs 2.4%; p = 0.36; odds ratio (OR) 1.42; 95% CI 0.70, 2.88) or in the rate of cardiovascular malformations (1.6% vs 0.9%; p = 0.265; OR 1.91; 95% CI 0.63, 5.62). No significant differences were found between subgroups of macrolides in the rates of major congenital malformations or cardiac malformations, although for azithromycin this was of borderline significance. CONCLUSIONS: This study, in agreement with earlier smaller studies, suggests that the new macrolides do not pose a significantly increased risk of major congenital malformations or cardiac malformations.

[Thalidomide epidemics: 50 years after]. / Thalidomidová epidemie - 50 let poté

Thalidomide tragedy and the subsequent epidemics of congenital anomalies is one of the most tragic but also enlightening chapters in the history of modern medicine. Many thousands of children were born with various anomalies - especially with limb deformities - because of the mass usage of thalidomide by pregnant women. The numbers of the spontaneous abortions and fetal deaths will remain unknown forever. In year 2012 we have a sad 50th anniversary of final recognition of thalidomide teratogenous potential. The causes of this tragedy and subsequent actions are summarized in our text.Key words: thalidomide, teratogenesis, congenital anomalies.

Appetite suppressants in pregnancy.

OBJECTIVES: Both, obesity as well as anorexia may be associated with infertility and other complications of pregnancy. Weight loss during pregnancy is therefore considered a risk factor. Weight loss and appetite suppressant are contraindicated during pregnancy, but the unintended exposure is probably not associated with higher risk. Our work was focused on trends in the appetite suppressants use in the Czech Republic and their embryotoxicity. METHODS: The pregnancies exposed to various appetite suppressants were followed prospectively in the years 1997-2012. The study group was compared to the comparison group which enrolled pregnant women exposed to non-teratogenic drugs. Drugs used as appetite suppressants were sibutramine and phentermine. RESULTS: Number of calls for this type of exposure was rare till 2005. Their number started to increase until 2009. Later, number of calls decreased because both drugs were withdrawn from the market. This finding reflects increasing tendency for the weight control in the group of fertile women in the Czech Republic. In our study, we did not reveal differences in pregnancy outcomes between study and comparison groups. CONCLUSIONS: However, we should be aware of the increasing food supplements exposure, that could be used as alternative to the appetite suppressants. Their potential risk results from the limited or completely absent control of their origin. Some of them have probably only placebo effect, but some of them could represent the risk.

Antidepressant drug exposure during pregnancy. CZTIS small prospective study.

OBJECTIVES: Antidepressant drugs are used frequently during pregnancy. The risk assessment of SSRI exposure is still evaluated and re-opened due to studies indicating possible increase of inborn defects, neonatal abstinence syndrome and cognitive ability or behavioral defects. METHODS: In our study, we prospectively followed groups of pregnancies in years 2002-2009, that were exposed to SSRI. As control group we used 1) women exposed to new atypical antidepressant and anti-psychotics - APD (risperidone, mirtazapine, venlafaxine, trazodone, aripiprazole, ziprasidone, olanzapine), 2) women exposed to nonteratogenic drugs and 3) the general population according to Institute of Health Informations and Statistics (ÚZIS.) Data were analyzed using software Statistica for Windows No.5.5. RESULTS: The total number of queries on psychotropic drugs performs in CZTIS more than 30% of all calls, constantly. We enrolled a total of 43 women exposed to SSRI and 37 women (1x twins) exposed to new psychotropic drugs (APD) in the study. Exposure to SSRI was often associated with poly-therapy. The most frequent SSRI used were citalopram and/or escitalopram (56%), and setraline (26%). Other SSRI were used sporadically. We observed significantly higher frequency of elective terminations in group of SSRI and higher frequency of abortions a prematurity in APD group. Frequency of malformations does not varied, being in all groups in expected range. CONCLUSIONS: We confirmed that SSRI exposure during pregnancy was not associated with the higher risk of major malformation. However, number of cases was low and did not allow the statistical treatment with higher power.

Embryotoxicity of mirtazapine: a study using Chick Embryotoxicity Screening Test.

OBJECTIVE: Mirtazapine is a new antidepressant used in last years, however experience with it during pregnancy is unsatisfactory on the present. Its wide therapeutic range and only little proved side effects may be an advantage for treatment during pregnancy. Aim of our study was to contribute to the knowledge on possible risks. MATERIALS AND METHODS: For embryotoxicity testing we used an alternative method - CHEST, that used chicken embryos as experimental model. Fertilized eggs of outbred Grey Leghorn stock (AVCR farm Kolec) were treated on embryonic day (ED) 4 by Mirtazapine, incubated till 9ED, when they were weighed and examined. Summing the proportions of dead and malformed embryos, the beginning of the embryotoxicity dose range was estimated. RESULTS: Mirtazapine solved in 15% DMSO in water revealed low embryotoxicity corresponding data from preclinical studies. If 100% DMSO was used as a solvent, the dose 0.05 µg/3 µL resulted in 57% mortality (LD50). Typical malformations were microphtalmia and malformation (shortening) of limbs on left side, which is a place of contact the embryonic body with maximal Mirtazapine concentration. Approximation of doses in chick embryos to mammals is complicated by low solubility of mirtazapine. CONCLUSIONS: If the embryotoxic dose was close to LD50, risk at therapeutical doses will be probably low. Mirtazapine according to results of testing and cases published in literature is relatively safe for pregnant women, only higher rate of abortions was demonstrated, however more information is needed to exclude all potential risks.

Drugs during lactation accenting boron exposure.

OBJECTIVES: The benefits of breastfeeding are generally accepted. Risk of drug usage for baby due to lactation is well assessed minimally in certain cases. However, information given about drugs are often insufficient, frustrating, and not recommending lactation. In Czech Teratology Information Service (CZTIS) counselling we use these information. RESULTS: We have given advice in 58 cases inquiring the CZTIS about the risk of drug exposure during lactation. The most frequent queries were on chronic disease treatment following the drug exposure during pregnancy. Remaining cases were associated with acute infections. Mothers suffered from idiopathic bowel disease and psychiatric patients want to be informed before delivery about possibility to breastfeed their babies. Treatment of epilepsy, another frequent disease, is associated with better level of knowledge of both, neurologists and patients. Breastfeeding is recommended according to management in care of epileptic women. CONCLUSION: In our counselling we consider the factors which are involved in drug transfer in the milk and mechanisms and steps of transfer as well. We follow the classification of drugs during lactation by their effect on infants: absolutely contraindicated, temporary cessation of breastfeeding, drugs of special concern and drugs compatible with breastfeeding.

Czech Teratology Information Service: comparison of treatments by psychotropic and antiepileptic drugs.

OBJECTIVES: Care, treatment and follow-up in psychiatric and epileptic pregnant women were compared with women inquiring Czech Teratology Information Service (CZTIS) due to other exposure to drugs during pregnancy. METHODS: Data were collected by CZTIS, member of European Network of Teratology Information Services from 1996. Exposed groups were compared with pregnant women exposed to drugs which were not classified as major teratogens or hyperthermia. Groups do not vary in age, reproductive history and other parameters. RESULTS: We observed higher frequency of miscarriage and voluntary termination of pregnancy in the group of psychiatric patients. The number of malformation in prospective follow-up cases was lower than in control group. CONCLUSIONS: Chronic diseases as epilepsy or psychiatric disorders have to be treated during pregnancy. Women should obtain accurate information about possible risk before pregnancy. Co-operation is needed in these cases. Physicians should keep in mind that appropriate information is to be given to the patient according to her disease, education and comprehension of the problem. If there is any doubt they should organize help for their patients.

Indicators of functional differentiation of the chick embryonic kidney.

Relevant indicators of the functional capability of the embryonic kidney were tested in the chick mesonephros chosen as an ideal model accessible to direct observation in vivo. Evidence of glomerular filtration (GF) was checked up by the arterial injection of 2% lissamine green (LG) followed by measurement of the LG passage time on days 5, 6 and 7. Presence of the electrogenic transport was investigated by determining the transepithelial potential difference (TPD) which distinguished proximal and distal tubules of the 6-day nephrons. GF and tubular reabsorption could be demonstrated from day 5 by the storage of trypan blue (TB) in proximal tubules after intra-amniotic administration of the dye. The distribution of tubule staining corresponded to the proximal-distal gradient of the nephron differentiation. Activities of embrane enzymes, alkaline phosphatase and 5'-nucleotidase, were detected from day 4. They preceded the ultrastructural maturation in the differentiating proximal tubule epithelia. A semiquantitative evaluation of enzyme activities by the method of measuring of the minimum incubation time (MIT) together with the TB storage, appeared reliable and relevant indicators of the functional properties of mesonephric nephrons, suitable for distinguishing between more and less advanced stages of the nephron development.