Maria Hoeltzenbein

The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.

Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services.

After maternal exposure to mycophenolate in pregnancy a high number of fetal losses and a specific pattern of birth defects consisting of microtia, cleft lip, and other anomalies have been reported. However, so far, prospective data on pregnancy outcome allowing quantitative risk assessment are missing. We report on 57 prospectively ascertained pregnancies after maternal therapy with mycophenolate (mycophenolate mofetil or mycophenolate sodium) identified by European Teratology Information Services (ETIS) through their risk consultation process. The outcome of these prospective pregnancies was as follows: 16 spontaneous abortions, 12 elective terminations of pregnancy (ETOP) (including two late terminations for multiple malformations consistent with mycophenolate embryopathy), and 29 liveborn infants. The probability of spontaneous abortion was about 45% (95% CI 29 to 66%) estimated using survival analysis technique. Six out of 29 live born infants had major congenital defects: Two with external auditory canal atresia (EACA) (with and without microtia), one with tracheo‐esophageal atresia, one with severe hydronephrosis, one with an atrial septal defect (ASD) and one with a myelomeningocele. Thus, at least four fetuses/infants of our prospective case series had a clinical phenotype consistent with mycophenolate embryopathy. Our results confirm a high incidence of major malformations (26%) after first trimester exposure to mycophenolate. Apart from exposure to mycophenololate, the underlying maternal disease and concomitant medication may also have contributed to the other poor pregnancy outcomes such as a high rate of spontaneous abortions, prematurity (62%), and low birth weight (31%).

No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study.

OBJECTIVE There is increasing awareness of the potential impact of paternal exposures on pregnancy outcome. In particular this applies to MTX, which is used in low doses for the treatment of RA and other inflammatory diseases. MTX is associated with a specific pattern of malformations in fetuses of exposed women, but there is uncertainty concerning the risk of paternal low-dose MTX. The aim of this study was to investigate whether paternal low-dose MTX therapy around conception has an unfavourable effect on pregnancy outcome. METHODS We performed a prospective observational cohort study involving pregnancies fathered by men who were treated with low-dose MTX around conception. Pregnancies were identified through our Teratology Information Service. Pregnancy outcomes were compared with a cohort neither exposed to MTX nor to other teratogens. Outcomes evaluated were major birth defects, spontaneous abortion (SAB), elective termination of pregnancy, gestational age at delivery, and birth weight. RESULTS A total of 113 pregnancies with paternal low-dose MTX treatment were compared with 412 non-exposed pregnancies. Neither the rate of major birth defects [odds ratio (OR) 1.02, 95% CI 0.05, 7.0) nor the risk of SAB (hazard ratio 1.19, 95% CI 0.65, 2.17) was increased. Gestational age at delivery and birth weights did not differ significantly between groups. The rate of electively terminated pregnancies was increased in the MTX-exposed patients compared with controls. CONCLUSION Our study does not confirm an increased risk of adverse pregnancy outcome after paternal low-dose MTX therapy. The reassuring findings do not support the necessity of a 3-month MTX-free interval until conception. In the case of unavoidable paternal MTX therapy, it seems reasonable not to postpone family planning.

Pregnancy outcome after paternal exposure to azathioprine/6-mercaptopurine ☆

There are only few studies with conflicting results on pregnancy outcome after paternal exposure to azathioprine or 6-mercaptopurine. In our study, pregnancy outcome of 115 prospectively followed pregnancies after paternal exposure to azathioprine or 6-mercaptopurine is compared to a control group of 341 pregnancies. The rate of major malformations was not increased (3.0% in exposed versus 2.2% in the control group). There was no specific pattern of birth defects and no indication for chromosomal aberrations in the exposed group. We observed a higher rate of elective terminations of pregnancy in the exposed group and a non-significant increase of spontaneous abortions (cumulative incidence 19% versus 13%, respectively). Further prospective studies are required to address the question of a possibly increased risk for spontaneous abortion.

Allopurinol Use during Pregnancy - Outcome of 31 Prospectively Ascertained Cases and a Phenotype Possibly Indicative for Teratogenicity

Allopurinol is a purine analogue that inhibits xanthine oxidase. It is mainly used for the treatment of hyperuricemia in patients with gout or tumor lysis syndrome. Experience with allopurinol in pregnancy is scarce. In 2011, Kozenko et al. reported on a child with multiple malformations after maternal treatment with allopurinol throughout pregnancy. Possible teratogenicity of allopurinol was proposed due to the similarity of the pattern of malformations in children with mycophenolate embryopathy. A possible common mechanism of both drugs, i.e. disruption of purine synthesis, was discussed. We report on the outcome of 31 prospectively ascertained pregnancies with allopurinol exposure at least during first trimester. Pregnancy outcomes were 2 spontaneous abortions, 2 elective terminations of pregnancy and 27 live born children. The overall rate of major malformations (3.7%) and of spontaneous abortions (cumulative incidence 11%, 95%-CI 3–40) were both within the normal range. However, there was one child with severe malformations including microphthalmia, cleft lip and palate, renal hypoplasia, low-set ears, hearing deficit, bilateral cryptorchidism, and micropenis. The striking similarity of the anomalies in this child and the case described by Kozenko et al. might be considered as a signal for teratogenicity. Thus, we would recommend caution with allopurinol treatment in the first trimester, until further data are available.

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data

OBJECTIVES Analyze the cumulative evidence for pregnancy outcomes after maternal exposure to tocilizumab, an anti-interleukin-6-receptor monoclonal antibody used for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. At present, published experience on tocilizumab use during pregnancy is very limited. METHODS We have analyzed all pregnancy-related reports documented in the Roche Global Safety Database until December 31, 2014 (n = 501). RESULTS After exclusion of ongoing pregnancies, duplicates, and cases retrieved from the literature, 399 women were found to have been exposed to tocilizumab shortly before or during pregnancy, with pregnancy outcomes being reported in 288 pregnancies (72.2%). Of these 288 pregnancies, 180 were prospectively reported resulting in 109 live births (60.6%), 39 spontaneous abortions (21.7%), 31 elective terminations of pregnancy (17.2%), and 1 stillbirth. The rate of malformations was 4.5%. Co-medications included methotrexate in 21.1% of the prospectively ascertained cases. Compared to the general population, an increased rate of preterm birth (31.2%) was observed. Retrospectively reported pregnancies (n = 108) resulted in 55 live births (50.9%), 31 spontaneous abortions (28.7%), and 22 elective terminations (20.4%). Three infants/fetuses with congenital anomalies were reported in this group. No increased risks for adverse pregnancy outcomes were observed after paternal exposure in 13 pregnancies with known outcome. CONCLUSIONS No indication for a substantially increased malformation risk was observed. Considering the limitations of global safety databases, the data do not yet prove safety, but provide information for physicians and patients to make informed decisions. This is particularly important after inadvertent exposure to tocilizumab, shortly before or during early pregnancy.

Pregnancy Outcome After First Trimester Use of Methyldopa: A Prospective Cohort Study.

Published experience on first trimester exposure to methyldopa is still limited, although it is recommended as first-line treatment for hypertensive disorders in pregnancy in most countries. The primary aim of this prospective observational cohort study was to analyze the rate of major birth defects and spontaneous abortions in women with methyldopa therapy for chronic hypertension. Outcomes of 261 pregnancies with first trimester exposure to methyldopa and 526 comparison pregnancies without chronic hypertension reported to the German Embryotox pharmacovigilance institute were evaluated. The rate of major birth defects in the exposed cohort was not significantly increased compared with the comparison cohort (3.7% versus 2.5%; adjusted odds ratio, 1.24; 95% confidence interval, 0.4–4.0). There was a tendency toward a higher rate of spontaneous abortions in exposed women. The risk of preterm birth was significantly higher, and adjusted birth weight scores were significantly lower in the methyldopa group. Head circumferences were significantly reduced in exposed boys only. There was neither evidence for an increased risk for birth defects or increase in early pregnancy loss nor evidence for growth restriction or a reduced head circumference in a sensitivity analysis comparing monotherapies with methyldopa to metoprolol. However, the significantly increased risk of preterm birth in methyldopa-treated pregnancies was confirmed. In conclusion, our study does not indicate a teratogenic risk of methyldopa. Further studies are needed to confirm its safety in the first trimester and clarify the influence of hypertension and methyldopa on preterm birth and intrauterine growth. Clinical Trial Registration— URL: https://drks-neu.uniklinik-freiburg.de/drks_web/. Unique identifier: DRKS00010502.

Pregnancy Outcome After First Trimester Use of Methyldopa

Published experience on first trimester exposure to methyldopa is still limited, although it is recommended as first-line treatment for hypertensive disorders in pregnancy in most countries. The primary aim of this prospective observational cohort study was to analyze the rate of major birth defects and spontaneous abortions in women with methyldopa therapy for chronic hypertension. Outcomes of 261 pregnancies with first trimester exposure to methyldopa and 526 comparison pregnancies without chronic hypertension reported to the German Embryotox pharmacovigilance institute were evaluated. The rate of major birth defects in the exposed cohort was not significantly increased compared with the comparison cohort (3.7% versus 2.5%; adjusted odds ratio, 1.24; 95% confidence interval, 0.4–4.0). There was a tendency toward a higher rate of spontaneous abortions in exposed women. The risk of preterm birth was significantly higher, and adjusted birth weight scores were significantly lower in the methyldopa group. Head circumferences were significantly reduced in exposed boys only. There was neither evidence for an increased risk for birth defects or increase in early pregnancy loss nor evidence for growth restriction or a reduced head circumference in a sensitivity analysis comparing monotherapies with methyldopa to metoprolol. However, the significantly increased risk of preterm birth in methyldopa-treated pregnancies was confirmed. In conclusion, our study does not indicate a teratogenic risk of methyldopa. Further studies are needed to confirm its safety in the first trimester and clarify the influence of hypertension and methyldopa on preterm birth and intrauterine growth. Clinical Trial Registration— URL: https://drks-neu.uniklinik-freiburg.de/drks_web/. Unique identifier: DRKS00010502.

Pregnancy Outcome After First Trimester Use of MethyldopaNovelty and Significance: A Prospective Cohort Study

Published experience on first trimester exposure to methyldopa is still limited, although it is recommended as first-line treatment for hypertensive disorders in pregnancy in most countries. The primary aim of this prospective observational cohort study was to analyze the rate of major birth defects and spontaneous abortions in women with methyldopa therapy for chronic hypertension. Outcomes of 261 pregnancies with first trimester exposure to methyldopa and 526 comparison pregnancies without chronic hypertension reported to the German Embryotox pharmacovigilance institute were evaluated. The rate of major birth defects in the exposed cohort was not significantly increased compared with the comparison cohort (3.7% versus 2.5%; adjusted odds ratio, 1.24; 95% confidence interval, 0.4–4.0). There was a tendency toward a higher rate of spontaneous abortions in exposed women. The risk of preterm birth was significantly higher, and adjusted birth weight scores were significantly lower in the methyldopa group. Head circumferences were significantly reduced in exposed boys only. There was neither evidence for an increased risk for birth defects or increase in early pregnancy loss nor evidence for growth restriction or a reduced head circumference in a sensitivity analysis comparing monotherapies with methyldopa to metoprolol. However, the significantly increased risk of preterm birth in methyldopa-treated pregnancies was confirmed. In conclusion, our study does not indicate a teratogenic risk of methyldopa. Further studies are needed to confirm its safety in the first trimester and clarify the influence of hypertension and methyldopa on preterm birth and intrauterine growth. Clinical Trial Registration— URL: https://drks-neu.uniklinik-freiburg.de/drks_web/. Unique identifier: DRKS00010502.