Birth Outcome of Children Fathered by Men Treated with Systemic Corticosteroids during the Conception Period – A Cohort Study based on Nationwide Data

Abstract

Information on the safety of paternal use of medications prior to the time of conception is limited, and there is little available evidence regarding possible adverse effects of paternal use of systemic corticosteroids (SCS). In this cohort study, based on nationwide data, we examined the association between paternal use of SCS prior to conception and adverse birth outcome. The study includes data from all singletons born in Denmark from 1 January 1997 through 2013 (N = 1,013,994). Children fathered by men who redeemed a prescription of SCS within 3 months before conception (N = 2380) constituted the exposed groups. The outcome was congenital abnormalities (CAs), pre-term birth and small-for-gestational age (SGA). We adjusted for co-variates in multi-level logistic regression analyses. The adjusted odds ratios for pre-term birth and SGA were 0.81 (95% CI: 0.55-1.21) and 1.06 (95% CI: 0.68-1.64), respectively. The adjusted odds ratios for CAs were 1.08 (95% CI: 0.87-1.40) in children fathered by men who redeemed one prescription within 3 months before conception and 1.33 (95% CI: 0.99-1.79) in children fathered by men who redeemed two or more prescriptions. This study is the largest to date examining the effect of paternal use of SCS prior to conception on birth outcome. We found no significantly increased risk of pre-term birth or SGA. In children of fathers who redeemed at least two prescriptions of SCS within 3 months before conception, we found an increased risk of CAs, though not statistically significant. The types of CAs did not show a distinct pattern.

The effect of paternal exposure to immunosuppressive drugs on sexual function, reproductive hormones, fertility, pregnancy and offspring outcomes: a systematic review

“…No drug-specific information about systemic corticosteroids in the Danish data was available and both registries have no information about the used dose or indication. Larsen et al only found a higher risk of birth defects in the Danish registries, although it was not statistically significant, after one or two redeemed prescriptions ( Larsen et al , 2018 ). Smaller numbers are reported in transplantation patients ( Penn et al , 1971 ; McGeown and Nevin, 1978 ; Xu et al , 2011 ).…”

Paternal use of medications for inflammatory bowel disease and the risk of hospital‐diagnosed infections in the offspring: a nationwide cohort study

“…During the second and third years of life, the overall risk of childhood infections was not increased after fathers' use of 5-ASA medications, thiopurines or anti-TNF-a agents. The overall risk of childhood infections during the second and third years of life was not significantly increased after fathers' use of corticosteroids.Our former Danish studies as well as a recent study by Meserve et al have shown that there is no increased risk of adverse birth outcomes of the children of fathers with IBD and other immunemediated inflammatory diseases who used thiopurines, methotrexate and biologics just prior to conception [9][10][11][12]. Winter et al found no difference in preterm birth, congenital abnormalities (CAs) or SGA in the children of fathers who used methotrexate within 3 months prior to conception 10.…”

“…The lack of studies on preconception paternal exposure to immunosuppressive drugs and the impact on offspring health was confirmed in a recent large systematic review 6 . Only a few previous studies have been published on adverse birth outcomes (preterm birth, small for gestational age and congenital malformations), even fewer studies on long‐term outcomes, and no studies on childhood infections 9–14 …”

“…6 Only a few previous studies have been published on adverse birth outcomes (preterm birth, small for gestational age and congenital malformations), even fewer studies on long-term outcomes, and no studies on childhood infections. [9][10][11][12][13][14] We hypothesise that for men with IBD, preconception exposure to anti-inflammatory/immunosuppressive medications may potentially affect offspring health outcomes. Of special concern is the risk of childhood infections due to paternal use of corticosteroid, thiopurine and anti-TNFα medications.…”

Does Fatherhood Matter? Preconception Use of Biologics and Immunomodulators by Fathers With Immune-Mediated Diseases and Birth Outcomes of Their Offspring

“…There have been a number of nationwide studies from Denmark regarding the safety of paternal immunosuppressive medications on short-term birth outcomes. [12][13][14][15] In these studies, paternal use of azathioprine/mercaptopurine, infliximab, adalimumab, corticosteroids and methotrexate prior to conception showed reassuring results. Also, Grosen et al [16][17][18] examined sperm integrity in men with inflammatory bowel disease via the Sperm Chromatin Structure Assay, one of the most sensitive methods for assessing sperm DNA integrity.…”