In this multicentre, randomized, double-blind placebo-controlled trial, women with a twin pregnancy who are at risk for late preterm birth will be enrolled. Figure 1 shows the model of the study design. After providing written informed consents, the women will be randomly assigned to betamethasone or placebo administration. Except for the administration of antenatal corticosteroids or placebo, the participants will be treated according to obstetric guidelines at the discretion of the attending physician.
This study will be conducted at obstetric departments of two hospitals in South Korea, Seoul National University Hospital and Cheil General Hospital and Women’s Healthcare Centre. They are tertiary referral hospitals and the number of twin delivery is approximately 300–400/year in each centre.
Women with a twin pregnancy who are at risk for late preterm delivery will be enrolled at 34 0/7 to 36 5/7 weeks of gestation. The risk for late preterm delivery includes preterm labour with cervical change, preterm premature rupture of membranes, or maternal-foetal indications that require preterm delivery because of maternal (hypertensive disorder, maternal underlying diseases, etc) or foetal causes (oligohydramnios, foetal growth restriction, etc). After screening for eligibility, information regarding the study will be provided and written informed consent will be obtained. Inclusion criteria and exclusion criteria are shown in Table 1. Dropout criteria include patient’s withdrawal of content, occurrence of severe adverse reaction, or clinical situation that does not permit continuation of trial protocol at the discretion of the investigators.
Random assignment method
Enrolled women will be randomly assigned in a 1:1 ratio to antenatal corticosteroids (Group 1) or placebo (Group 2). The randomization will be done by a web-based randomization system that is operated by the medical research collaborating center of Seoul National University Hospital. Unblinded researchers will be designated at the beginning of this trial, including an unblinded pharmacist and unblinded investigators, and they will not participate in the subsequent process of data management and data analysis. The unblinded researchers will prepare the antenatal corticosteroids or placebo according to the treatment assignment. Neither the enrolled pregnant women nor the other investigators (except predeterminate unblinded researchers) will be aware of the result of random assignment.
The sample size was calculated to determine how many neonates will be needed to detect a 30% reduction by antenatal corticosteroids: 20% in the placebo group versus 14% in the antenatal corticosteroids group. We estimated the risk of primary outcome in the placebo group as 20%, with a correlation coefficient between co-twins of 0.32, according to our retrospective twin cohort data. We adopted a risk reduction rate of 30% (from 20 to 14%), according data in previous study . Assuming 80% power, a type I error of 5%, and the ratio of 1:1 between placebo and antenatal corticosteroids, we determined we would require 1616 neonates (808 twin pregnancies).
The antenatal corticosteroids will be betamethasone sodium phosphate 5.2 mg (betamethasone 4.0 mg) in 1 ample (1 mL), produced by Dawon Parm (Korea). Both betamethasone and placebo (normal saline) are colourless liquids. The eligible participants for the inclusion and exclusion criteria will be randomized into two groups: Group 1, antenatal corticosteroids group; Group 2, placebo group. Group 1 consists of pregnant women who will be administered intramuscular betamethasone 12 mg (3 mL) twice in a 24-h interval. Group 2 will be administered the same amount (3 mL) of normal saline twice with the same interval. Once the drug is determined by randomization, the unblinded researchers will prepare and administer betamethasone or placebo to participants.
The data on obstetric and neonatal outcome will be gathered. The primary outcome is severe respiratory complications (the use of continuous positive airway pressure or high-flow nasal cannula for at least 12 h, supplemental oxygen administration with a fraction of oxygen 0.3 or more for at least 24 h, mechanical ventilation, or extracorporeal membranes oxygenation) or perinatal death within the first 72 h of delivery. Secondary outcomes are neonatal mortality and/or other neonatal morbidities (Table 2).
The patients will be monitored for symptoms in terms of adverse effects. The physicians will check the patients’ vital signs and the occurrence of adverse side effects after injection. Symptoms such as nausea/vomiting, allergic reaction, and local reaction at the injection site will be reported. The administration of the study drug can be interrupted in the occurrence of severe side effects, such as adrenal insufficiency, Cushing’s syndrome, and infection. However, serious side effects after antenatal corticosteroids (betamethasone) were not reported in previous studies in pregnant women [14, 25,26,27].
The efficacy of betamethasone will be assessed by comparing the primary and secondary outcomes of each group. Efficacy analysis will be conducted based on intention-to-treat and per-protocol principle. Categorical variables will be compared by the chi-square or Fisher’s exact test. For continuous variables, the Mann-Whitney U test will be used. The analysis will be performed by a generalized estimating equation to consider the possibility of the familial correlation between the neonates from a single mother in twin pregnancies . A p value of less than 0.05 will be considered significant, and relative risks and 95% confidence intervals will be reported. All analyses will be performed using IBM SPSS Statistics version 23 and R version 3.5.0 (http://www.r-project.org).