IVIG plus prednisolone does not help improve chances of pregnancy

The use of intravenous immunoglobulin (IVIG) plus prednisolone does not appear to increase conception rates among women with recurrent pregnancy loss who are undergoing assisted reproductive technology (ART), according to a study.

In the intention-to-treat population involving 80 participants, the primary outcome of ongoing pregnancy rates at gestational week 12 were 25.0 percent with IVIG plus prednisolone (active treatment) and 15.0 percent with placebo plus prednisolone (placebo), with the difference not reaching significance (p=0.264). Results were similar in the per-protocol population (n=74; 21.6 percent vs 16.2 percent; p=0.553). [ESHRE 2024, abstract O-032]

“The ongoing pregnancy rate was equal to the live birth rate, as we did not observe any late miscarriages or any stillbirth,” said presenting author Dr Caroline Nørgaard-Pedersen from the Aalborg University Hospital in Aalborg, Denmark.

Among participants who conceived after embryo transfer in the intention-to-treat population, the live birth rate was higher with active treatment at 83.3 percent than with placebo at 42.9 percent with control, although the difference was only borderline significant (p=0.051). Findings were consistent in the per-protocol population (80.0 percent vs 42.9 percent p=0.104).

When participants with aneuploidy were excluded, the pregnancy success rate was still higher, albeit not significantly so, in the active treatment group than in the placebo group for both the intention-to-treat population (90.1 percent vs 50.0 percent; p=0.069) and the per-protocol population (88.9 percent vs 50.0 percent; p=0.159).

Secondary outcomes and safety

Consistent with the primary outcome, secondary outcomes showed a trend favouring active treatment vs placebo but lacked statistical significance, as Nørgaard-Pedersen pointed out. These included perinatal outcomes such as birth weight (3.351 vs 2.947 g) and obstetric complications such as pre-eclampsia (0 percent vs 17 percent) and gestational diabetes (25 percent vs 33 percent).

However, gestational age was significantly higher in the active treatment group (39 vs 37 weeks), which, according to Nørgaard-Pedersen, confirmed the safety of IVIG plus prednisolone.

Taken together, the results suggest that while IVIG plus prednisolone does not increase the overall chance of conceiving following ART, it may indeed boost the success of a live birth among women who became pregnant via ART, that is the same as lowering the miscarriage rate, according to Nørgaard-Pedersen.

“This treatment could potentially increase success rate in patients undergoing ART after multiple unsuccessful treatment attempts,” she added.

“Our research … is particularly significant, because it is the first randomized controlled trial (RCT) to evaluate IVIG and prednisolone efficacy in women suffering simultaneously from infertility and recurrent pregnancy loss,” Nørgaard-Pedersen continued. “[Additionally,] both drugs are considered by the recurrent pregnancy loss guideline group of ESHRE to be potentially effective and [are, thus,] crucial drugs to these women where no other treatment has a verified effect.”

Limitations and protocol

Nevertheless, Nørgaard-Pedersen acknowledged several limitations to the study.

“First of all, it is unknown to what extent aneuploidy affected our findings in this trial. In Denmark, preimplantation genetic testing (PGT) is only used for inheritable diseases and, therefore, PGT for aneuploidy (PGT-A) screening was not possible to include as a study criterion,” the author noted, adding that a PGT-A screening should be considered in future RCTs to explore the impact of aneuploidy in the current population.

“Furthermore, we do not know whether IVIG and prednisolone in combination acts synergistically, additively, or antagonistically,” she continued, suggesting that a future study should include four arms to compare monotherapy and combination therapy.

Finally, the sample size calculation was complicated due to the lack of data on expected ongoing pregnancy weight in the control group, rendering the study to be possibly underpowered, Nørgaard-Pedersen said.

The present study included 80 women (age <41 years, BMI <35 kg/m², antimüllerian hormone level >4pmol/l) with unexplained recurrent pregnancy loss after ART (defined as a history of at least two consecutive early miscarriages [≤10 gestational weeks] following ART-induced conception). These women were randomly assigned to receive 400-mg/kg IVIG plus 5–10-mg/day of oral prednisolone (n=40) or IVIG plus oral placebo (n=40).

Oral treatment was administered from day 1 of menstrual cycle until the time of embryo transfer, while IVIG treatment was given once in a short time interval before or after embryo transfer and repeated three times before gestational week 8. A total of 37 participants in each group received treatment according to the protocol and were included in the per-protocol population.