Role of Intravenous immunoglobulin in improving pregnancy outcome in women with unexplained recurrent pregnancy loss Randomised Controlled Trial

Recurrent pregnancy loss (RPL) is defined as the loss of ≥2 or ≥3 pregnancies and affects 0·8%–1·4% of couples who are trying to conceive. [1,2] Variety of factors are involved in the pathogenesis of RPL, however, the aetiology of >50% of RPL is unknown and is designated as unexplained RPL. [3,4] The mechanism underlying the pathology of unexplained RPL remains poorly understood. Recent studies have proposed immunological abnormalities, for pathophysiology underlying unexplained RPL.

No standard therapeutic modality for unexplained RPL has been established. Some studies have indicated that intravenous immunoglobulin (IVIG) may have therapeutic efficacy for unexplained RPL. [5,6] Conclusions drawn from previously done IVIG trials are controversial. There are several studies that report beneficial effects of medium-dose IVIG treatment; however, as most of the studies are not homogeneous in terms of the unexplained RPL definition, gestational age in which start and finish the treatment, and design, they cannot be used together in meta-analysis or systematic review to reach an evidence-based level to be recommended in clinical practice.

We assumed that the immunomodulatory effects of high-dose IVIG treatment in early pregnancy restore fecundity in women with unexplained RPL. Therefore, this randomized controlled trial is planned to study the role of high-dose IVIG treatment in 4–6 weeks of gestation in improving the rates of ongoing pregnancy at 22 weeks of gestation and live birth among women with RPL of unexplained aetiology who have a history of ≥3 miscarriages.

It will be a randomized controlled trial, study will be started after obtaining the institutional ethical clearance. Women who fulfill inclusion and exclusion criteria will be invited to participate in the study. They will be explained about the study protocol and written informed consent will be taken. A detailed history will be taken including demographic, obstetrical and medical history in a predesigned proforma. Patients will be recruited from the antenatal OPD after considering recruitment criteria. After recruitment complete general and obstetrical examination will be done. Each pregnancy will be dated based on last menstrual period. Parity and other obstetrical conditions will be noted. Participants will be randomized in two groups, intervention, and control group by randomization number tables. Group 1, will be receiving IVIG along with routine care and group 2, will receive standard treatment according to institute protocol.

IVIG protocol: Patients randomized in group 1 will receive IVIG along with routine care. The active drug used was 5% formulation of intact type human immunoglobulin G. The active drug of 400 mg/kg will be administered by intravenous drip infusion for five consecutive days. Treatment was initiated at 4 to 6 weeks and 6 days of gestation after gestational sac was identified by ultrasonography.

Patients will be followed up till delivery. Any adverse obstetrical outcomes like fetal growth restriction, preterm delivery, gestation at the time of delivery, mode of delivery, and birth outcomes will be noted. After delivery, baby birth weight and any adverse neonatal outcome will be noted.

OUTCOMES: Two populations will be analysed, all women who will receive the study drug (intention-to-treat, ITT) and women who receive the study drug but excluding those who miscarried due to fetal chromosome abnormality (modified-ITT). The primary outcome will be the ongoing pregnancy rate at 22 weeks of gestation. Secondary outcome will be to compare live birth rate in both the groups and risk of fetal growth restriction (FGR) and preterm delivery (PTB) in intervention group