Ursula Winterfeld

Pregnancy Outcome After Methotrexate Treatment for Rheumatic Disease Prior to or During Early Pregnancy: A Prospective Multicenter Cohort Study

High‐dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX.

Pregnancy outcome following maternal exposure to statins: a multicentre prospective study

This contribution addresses the risk associated with exposure to statins during pregnancy.

Pregnancy Outcome Following Exposure to Topical Retinoids: A Multicenter Prospective Study

Concerns have been raised about the use of topical retinoids since the publication of isolated cases of characteristic retinoid embryopathy, originally described after oral use. A collaborative study of the European Network of Teratology Information Services was carried out to evaluate the rate of congenital malformations following first‐trimester topical retinoid exposure. A population of 235 exposed pregnant women was compared with 444 controls. No significant differences were observed between groups with regard to the rates of spontaneous abortion (odds ratio [95% confidence interval], 1.5 [0.8–2.7]), minor birth defects (1.3 [0.4–3.7]), and major birth defects (1.8 [0.6–5.4]). No child showed features of retinoid embryopathy. The rate of elective termination in the exposed group was increased 3‐fold (3.4 [1.5–7.8]). In conclusion, these results do not suggest an increased risk of retinoid embryopathy. However, according to current knowledge, topical retinoids cannot be advised for use during pregnancy because their risk/benefit ratio remains questionable.

Pregnancy outcome following maternal exposure to pregabalin may call for concern

Objective: To investigate pregnancy outcomes following maternal use of pregabalin. Methods: This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to pregabalin with those of matched controls (not exposed to any medications known to be teratogenic or to any antiepileptic drugs). Teratology Information Services systematically collected data between 2004 and 2013. Results: Data were collected from 164 exposed pregnancies and 656 controls. A significantly higher major birth defect rate in the pregabalin group was observed after exclusion of chromosomal aberration syndromes, and when cases with exposure during first trimester of pregnancy were analyzed separately (7/116 [6.0%] vs 12/580 [2.1%]; odds ratio 3.0, 95% confidence interval 1.2–7.9, p = 0.03). The rate of live births was lower in the pregabalin group (71.9% vs 85.2%, p < 0.001), primarily due to a higher rate of both elective (9.8% vs 5.0%, p = 0.02) and medically indicated (5.5% vs 1.8%, p = 0.008) pregnancy terminations. In the Cox proportional cause specific hazards model, pregabalin exposure was not associated with a significantly higher risk of spontaneous abortion. Conclusions: This study demonstrated a signal for increased risk of major birth defects after first trimester exposure to pregabalin. However, several limitations such as the small sample size, differences across groups in maternal conditions, and concomitant medication exposure exclude definitive conclusions, so these results call for confirmation through independent studies.

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

Abstract 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.

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

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.

Médicaments et grossesse : modifications pharmacocinétiques et place du suivi thérapeutique pharmacologique

Following the thalidomide tragedy, pharmacological research in pregnant women focused primarily on drug safety for the unborn child and remains only limited regarding the efficacy and safety of treatment for the mother. Significant physiological changes during pregnancy may yet affect the pharmacokinetics of drugs and thus compromise its efficacy and/or safety. Therapeutic drug monitoring (TDM) would maximize the potential effectiveness of treatments, while minimizing the potential risk of toxicity for the mother and the fetus. At present, because of the lack of concentration-response relationship studies in pregnant women, TDM can rely only on individual assessment (based on an effective concentration before pregnancy) and remains reserved only to unexpected situations such as signs of toxicity or unexplained inefficiency.

Management of Deficient Lactation in Switzerland and Canada: A Survey of Midwives' Current Practices

Support and promotion of breastfeeding are important healthcare issues and a global priority. In the United Nations Chronicle, it states that exclusive breastfeeding for the first 6 months is the ideal. In addition, timely and appropriate complementary feeding from 6 months of age and continued breastfeeding up to 2 years of age and beyond are also recommended. Initiatives for promotion of breastfeeding have also led to the creation of international guidelines such as the strategies proposed by The National Institute for Health and Clinical Excellence for the support of appropriate infant and young child feeding, especially in the first 2 years of life. However, lactation management protocols do not contain clear guidelines for the treatment of insufficient or deficient lactation. Midwives play a key role in educating and supporting mothers regarding human lactation and infant feeding. Despite international efforts to promote breastfeeding, the management of insufficient lactation may differ among countries because of differences in health policies and legislation, as well as in midwife status. Sustainable breastfeeding depends on multiple physiologic and psychosocial factors. Early recognition of risk factors is critical for clinicians who interact with breastfeeding women so that intervention can take place and achievement of full or partial breastfeeding can be preserved. Instruction and optimization of lactation techniques constitute primary interventions to maximize maternal lactation capacity. When these techniques prove to be insufficient, different galactagogues such as medicinal plants/foods, homeopathy, or medication are sometimes recommended. No systematic studies have evaluated the safety or efficacy of lactogenic herbs/foods or homoeopathic remedies, although the traditional use of these plants suggests that they are relatively safe to use and may be effective. We conducted a survey (a convenience sample), to analyze midwives’ current practice for the initiation or augmentation of maternal milk supply in Switzerland and Canada. We used an online anonymous survey during March 2009 in both countries and collected the following information from participating midwives: Types of practices, number of breastfeeding women requiring use of galactogogues, treatment recommendations, and local or national management policies. In Switzerland, 351 of 700 (50%) midwives and in Canada 80 of 175 (46%) completed the questionnaire. The majority of respondents (93% in Switzerland and 100% in Canada) reported their patients sometimes require the use of galactagogues, as well as the following: Instruction of breastfeeding techniques (100% in Switzerland and Canada), lactogenic herbs/foods (96% in Switzerland and Canada), homeopathy (46% vs. 4%), acupuncture (39% vs. 3%), and medication (16% vs. 68%). Only 14% of the respondents in Switzerland and 26% in Canada reported that they followed an official protocol or national guideline. To our knowledge, this is the first study that attempts to provide an overview of current practices in this important field. Mothers report that insufficient milk supply is a reason for discontinuing breastfeeding, and our results confirm this. In our survey, recommended breastfeeding techniques, as suggested by the previously mentioned guidelines, were the preferred and first-line support advised by the respondents. Thus, international guidelines appeared to be applied to maximize maternal lactation capacity, although only a small percentage of respondents stated that they actually work with these protocols in everyday practice. When breastfeeding techniques were considered ineffective to correct insufficient lactation, a majority of the respondents from both countries recommended the use of galactagogues. It is interesting that many of the respondents from both countries considered, on an empirical basis, that herbal preparations as well as pharmaceutical compounds were effective in increasing lactation, which may explain why galactagogues were used on a fairly regular basis by the midwives. The galactagogues most frequently recommended by the Swiss respondents were lactogenic herbs/food, homeopathic remedies, and acupuncture (Table 1); Canadian respondents also recommended herbs/food but did not appear to be as familiar with homeopathic galactagogues or acupuncture, and domperidone was more often advised. Conversely, intranasally administrated oxytocin was the most frequently used medicinal galactogogue by the Swiss midwives. This study had several limitations, so caution should be used when interpreting the results. The midwives who

Pharmacokinetic alterations in pregnancy and use of therapeutic drug monitoring

Following the thalidomide tragedy, pharmacological research in pregnant women focused primarily on drug safety for the unborn child and remains only limited regarding the efficacy and safety of treatment for the mother. Significant physiological changes during pregnancy may yet affect the pharmacokinetics of drugs and thus compromise its efficacy and/or safety. Therapeutic drug monitoring (TDM) would maximize the potential effectiveness of treatments, while minimizing the potential risk of toxicity for the mother and the fetus. At present, because of the lack of concentration-response relationship studies in pregnant women, TDM can rely only on individual assessment (based on an effective concentration before pregnancy) and remains reserved only to unexpected situations such as signs of toxicity or unexplained inefficiency.

Antiepileptika bei Frauen im gebärfähigen Alter und in der Schwangerschaft

ZusammenfassungHintergrundViele Heilberufler nutzen Fachinformationen als eine von verschiedenen möglichen Informationsquellen zu Risiken einer Arzneimittelanwendung bei Frauen im gebärfähigen Alter und in der Schwangerschaft. Ziel dieser Arbeit ist es, eine Übersicht über das teratogene Potenzial verschiedener Antiepileptika zu präsentieren und mit den Angaben ausgewählter Fachinformationen zu vergleichen.MethodenEs wurde eine Literaturrecherche zum teratogenen Risiko von 19 Antiepileptika durchgeführt. Die Ergebnisse wurden mit den Angaben der Fachinformationen von 38 in der Schweiz und in Deutschland erhältlichen Fertigarzneimitteln verglichen.ErgebnisseIn allen Fachinformationen wird das teratogene Risiko anhand epidemiologischer Daten diskutiert. Eine Quantifizierung des Fehlbildungsrisikos und die Anzahl dokumentierter Schwangerschaften fehlen jedoch meistens. Angaben zur Notwendigkeit der Überwachung von Plasmaspiegeln während der Schwangerschaft mit etwaiger Dosisanpassung fehlen in fünf schweizer und zwei deutschen Fachinformationen.DiskussionDie Angaben in den Fachinformationen der untersuchten Antiepileptika zur Anwendung bei Frauen im gebärfähigen Alter und in der Schwangerschaft sind heterogen und entsprechen überwiegend nicht dem aktuellen Kenntnisstand. Eine durch die zuständigen Behörden angestoßene Überarbeitung der Fachinformationen scheint notwendig zu sein, damit diese Dokumente für Heilberufler tatsächlich von Nutzen sein können.SummaryBackgroundHealthcare professionals regularly read the summary of product characteristics (SmPC) as one of the various sources of information on the risks of drug use in women of childbearing age and during pregnancy. The aim of this article is to present an overview of the teratogenic potential of various antiepileptic drugs and to compare these data with the information provided by the SmPCs.MethodsA literature search on the teratogenic risks of 19 antiepileptic agents was conducted and the results were compared with the information on the use in women of childbearing age and during pregnancy provided by the SmPCs of 38 commercial products available in Switzerland and Germany.ResultsThe teratogenic risk is discussed in all available SmPCs. Quantification of the risk for birth defects and the numbers of documented pregnancies are mostly missing. Reproductive safety information in SmPCs showed poor concordance with risk levels reported in the literature. Recommendations concerning the need to monitor plasma levels and possibly perform dose adjustments during pregnancy to prevent treatment failure were missing in five Swiss and two German SmPCs.DiscussionThe information regarding use in women of childbearing age and during pregnancy provided by the SmPCs is heterogeneous and poorly reflects the current state of knowledge. Regular updates of SmPCs are warranted in order for these documents to be of reliable use for health care professionals.BACKGROUND Healthcare professionals regularly read the summary of product characteristics (SmPC) as one of the various sources of information on the risks of drug use in women of childbearing age and during pregnancy. The aim of this article is to present an overview of the teratogenic potential of various antiepileptic drugs and to compare these data with the information provided by the SmPCs. METHODS A literature search on the teratogenic risks of 19 antiepileptic agents was conducted and the results were compared with the information on the use in women of childbearing age and during pregnancy provided by the SmPCs of 38 commercial products available in Switzerland and Germany. RESULTS The teratogenic risk is discussed in all available SmPCs. Quantification of the risk for birth defects and the numbers of documented pregnancies are mostly missing. Reproductive safety information in SmPCs showed poor concordance with risk levels reported in the literature. Recommendations concerning the need to monitor plasma levels and possibly perform dose adjustments during pregnancy to prevent treatment failure were missing in five Swiss and two German SmPCs. DISCUSSION The information regarding use in women of childbearing age and during pregnancy provided by the SmPCs is heterogeneous and poorly reflects the current state of knowledge. Regular updates of SmPCs are warranted in order for these documents to be of reliable use for health care professionals.