The relationship between antenatal indomethacin as a tocolytic drug and neonatal outcomes: a retrospective cohort study.

INTRODUCTION: Preterm birth is associated with increased mortality and morbidity. Tocolytic drugs, such as indomethacin, are often used to postpone preterm delivery. Indomethacin has been proven to be more effective than other tocolytic agents in terms of delaying birth but is often prescribed with caution because of its potential association with adverse neonatal outcomes. We aim to study the effects of antenatal indomethacin on neonatal outcomes after controlling for potential confounders, as compared to nifedipine and/or atosiban. METHODS: In this cohort study, we performed a retrospective analysis of maternal and neonatal data. Women were included if they received indomethacin, nifedipine or atosiban as a tocolytic drug for imminent preterm labor and gave birth at a gestational age (GA) between 235/7 and 320/7 weeks, between 2010 and 2015. Main outcome measures were: neonatal death, necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), patent ductus arteriosus (PDA) and its treatment. RESULTS: Four hundred seventy-four women, delivering 610 infants were investigated. The incidence of the following adverse neonatal outcomes were significantly higher after indomethacin use: neonatal death (p = .017), NEC (p = .026), SIP (p = .008), PDA (p = .000) and PDA ligation (p = .000). However, these associations showed to be nonsignificant after adjusting for confounders (adjusted odds ratio neonatal mortality 1.6 (0.7-3.8)), NEC 1.6 (0.6-4.4), SIP 2.8 (0.3-30.0), PDA 1.1 (0.6-2.2) and PDA ligation 2.2 (0.7-6.5). CONCLUSIONS: The presumed association between antenatal indomethacin exposure and several adverse neonatal outcomes may be based upon indication bias. Taking important confounding factors, such as GA at birth and neonatal birth weight into account, antenatal indomethacin exposure does not result in a higher incidence of adverse neonatal outcomes. However, there may be a higher risk for spontaneous intestinal perforation.

Dermatological side effects rarely interfere with the continuation of checkpoint inhibitor immunotherapy for cancer.

BACKGROUND: Immunotherapy with checkpoint inhibitors (CPIs) is an emerging anticancer treatment strategy, which may cause a variety of skin reactions. In this study, we sought to analyze and classify the cutaneous side effects (CSE) of the CPIs nivolumab, pembrolizumab, and ipilimumab with respect to prevalence, type, and severity, and to review their potential interference with CPI immunotherapy. METHODS: In this retrospective analysis, medical records were analyzed with respect to incidence, type, and severity of CSE in patients on CPI immunotherapy for cancer. The implications for immunotherapy maintenance were scrutinized. RESULTS: From 2012 to 2019, 352 consecutive patients were treated with CPIs for cancer, of which 46 patients (13.1%) experienced CSE. The incidence of CSE was less with nivolumab (n = 16; 9.5%) and pembrolizumab monotherapy (n = 9; 9.6%) as compared to ipilimumab (n = 10; 23.3%) and combination therapy (n = 11; 23.9%); P < 0.05. Skin toxicity could be stratified by rash/eczema (n = 28; 60.9%), autoimmune (n = 8; 17.4%, vitiligo n = 5, lichen sclerosus n = 2, psoriasis guttata n = 1), lichenoid reaction (n = 5; 10.9%), pruritus (n = 4; 8.7%), and a miscellaneous group (n = 3; 6.5%). The limited severity grades of CSE caused immunotherapy disruption in only three (0.9%) cases. Interestingly, 80% of melanoma patients who developed vitiligo during immunotherapy had stable disease or disease remission. CONCLUSION: CPIs in cancer patients may result in a distinct set of CSE, with drug rash and eczematous rash being the most common. CTLA-4 blocker ipilimumab and combination therapy are more prone to elicit skin toxicity than the PD-1 inhibitors nivolumab and pembrolizumab, although this rarely interferes with the continuation of immunotherapy.