P-494 Relevance of intravenous immunoglobulins in patients with unexplained recurrent miscarriages that occurred at the same gestational weeks every time
Authors: Matsubayashi H , Suzuki Y , Ohara Y , Karino A , Saito S , Ishibashi Y , Hoshiba M , Usui K , Doshida M , Takeuchi T , Ishikawa T 
Published: June 2023

Abstract

Study question
Are intravenous immunoglobulins (IVIG) effective for the selected patients who experienced unexplained recurrent miscarriages (RM) that occurred at the same gestational weeks every time?

Summary answer
IVIG before and after the gestational week-limit (GWL), where miscarriage occurred at the same gestational weeks every time,may improve pregnancy outcomes in RM patients.

What is known already
Treatment for patients with unexplained RM are challenging. Since the efficacy of immunotherapy with paternal mononuclear cells has been denied in 1999, some treatment options (e.g., intralipid, G-CSF) have been published with conflicting results. In terms of IVIG, the same story has been described. Because previous studies for IVIG treatment included very heterogeneous group of patients, different dose, different intervals of IVIG, and different starting time of infusions. Recently, a double-blind, randomized, placebo-controlled study for unexplained RM women has been published in 2022, which revealed that IVIG (0.4g/kg) for five consecutive days at 4-5 weeks of gestation improved pregnancy outcomes.

Study design, size, duration
We performed a retrospective study between September 2013 and May 2021 in two fertility centers. We included 106 patients in the study who experienced 2 or more miscarriages between 5 and 21 weeks of gestation that occurred at the same gestational weeks every time, who had all negative results for our routine RM work up and still unsuccessful result after treating these conditions, and whose products of conceptus (POC) revealed at least one normal karyotype.

Participants/materials, setting, methods
IVIG (Venoglobulin IH 5%, Japan Blood Products Organization, 0.4g/kg) was injected twice before and after 1 week of GWL. If the GWL was 8 weeks of gestation, IVIG should be injected 7 and 9 weeks. We defined successful IVIG treatment as live birth. When the pregnancy ended in miscarriage, POC was performed as much as possible. All participants provided written informed consent, and Institutional Review Board approval was obtained.

Main results and the role of chance
Of 106 patients, average age was 37.5 years (28-47 years) and the mean number of previous miscarriages was 3.1. Total 128 cycles of IVIG attempt resulted in 90 (70.3%) successful pregnancies, 36 miscarriages and 2 biochemical pregnancies. After excluding abnormal karyotype of POC (N = 7), 68.6% (83/121) was successful. Per patients, 81.1% (86/106) had at least one live birth. Of 32 patients who experienced miscarriages at the first IVIG attempt, 16 patients got pregnant. Following second IVIG attempt resulted in 12 live births (75.0%). The average weight of live birth babies was 3038g and the birth week was 38.8 weeks of gestation (34-41 wk) for singleton pregnancy (N = 83), whereas 2529g with 35.9 weeks of gestation (33-37 wk) for twin pregnancy (N = 7). Four (4/83, 4.8%) and five (5/7, 71.4%) preterm deliveries were observed for singleton and twin pregnancy, respectively. One baby showed pulmonary hemorrhage resulting in hospitalization in the Neonatal Intensive Care Unit, other live birth babies were without any abnormal findings. Hypertensive disorders of pregnancy were noted in two women resulting in cesarian section delivery.

Limitations, reasons for caution
This study was retrospective study without any control group and was conducted at only two fertility centers. In future clinical research, it is necessary to conduct randomized controlled trials using placebo group to demonstrate the effectiveness of IVIG before and after the GWL using euploid blastocysts.

Wider implications of the findings
IVIG before and after the GWL adjusted for each patient may improve pregnancy outcomes in RM patients. Although IVIG is expensive, the current method requires only two IVIG injections, that may be acceptable for much more patients who want to avoid miscarriages and who didn’t use IVIG for economic reasons.

Trial registration number
not applicable