Validation of Correction Factors for Serum Markers for First-Trimester Down Syndrome Screening in Singleton Pregnancies Conceived with Assisted Reproduction

Abstract

Objective: To validate previously computed correction factors for free β-human chorionic gonadotrophin (fβ-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) pregnancies with hormone treatment and to determine the effect on false-positive rate (FPR). Methods: Retrospective study on 249 IVF and 250 ICSI cases and 20,190 controls. Correction factors 1.42 (PAPP-A), 1.17 (fβ-hCG) in IVF; 1.56 (PAPP-A) in ICSI were applied on the absolute serum concentrations. Analysis was done on log₁₀-transformed multiples of medians (MoMs). Results: In the controls, mean PAPP-A and fβ-hCG MoM were 1.004 and 1.062. Before correction, mean PAPP-A MoM was significantly lower in IVF (0.757; p < 0.001) and in ICSI (0.671; p < 0.001) and after correction comparable (1.071; p = 0.053 in IVF; 1.048; p = 0.178 in ICSI). Before correction, mean fβ-hCG MoM was comparable (1.054; p = 0.59 in IVF and 1.051; p = 0.56 in ICSI) and after correction significantly higher in IVF (1.241; p < 0.001). After correction the likelihood for receiving a false-positive result was 1.03 in IVF pregnancies (95% CI 0.98-1.09; p = 0.248) and 1.02 in ICSI pregnancies (95% CI 0.97-1.07; p = 0.448). Conclusions: After correction the FPR in IVF and ICSI pregnancies with hormone treatment reduces to the observed FPR in the controls.

First‐trimester screening for trisomies by cfDNA testing of maternal blood in singleton and twin pregnancies: factors affecting test failure

“…In our previous studies, we also found that, in pregnancies conceived by in‐vitro fertilization, cfDNA test failure is increased, but another study on twin pregnancies analyzed by a different cfDNA technique could not demonstrate such an association. Low fetal fraction in pregnancies conceived by in‐vitro fertilization could be the consequence of the associated impaired placentation; in such pregnancies, the serum concentration of PAPP‐A is decreased by 10–25% and the incidence of pre‐eclampsia is increased. Two likely explanations for these different results are, first, the significantly higher gestational age at sampling (median, 16 (range, 10–35) weeks) in the study of Le Conte et al .…”

Performance of screening for aneuploidies by cell‐free DNA analysis of maternal blood in twin pregnancies

“…We have previously reported significant associations between fetal fraction and serum pregnancy‐associated plasma protein‐A (PAPP‐A) and free β‐human chorionic gonadotropin, whose concentration provides an indirect measure of placental mass. Evidence for impaired placentation in IVF conceptions is provided by reports that in such pregnancies the serum concentration of PAPP‐A is decreased by 10–25% and the incidence of pre‐eclampsia is increased.…”

Low first-trimester PAPP-A in IVF (fresh and frozen-thawed) pregnancies, likely due to a biological cause

“…Most previous studies have reported no change in fβ-hCG levels [9-16, 18, 19, 22, 25, 27-29]. A review by Gjerris et al [49] suggested the conflicting results for fβ-hCG may be due to samples sizes, no distinction between complicated and non-complicated pregnancies, no distinction between pregnancies with and without hormone treatment [50], and influences from the biochemical platforms [8].…”

“…No correction is required for pregnancies achieved via IUI, oocyte donation or frozen-thawed embryo transfer because these groups do not consistently have biochemical changes that adjust the FPR [7]. Engels et al [21] calculated and validated [50] correction factors for the mode of conception for PAPP-A and fβ-hCG in non-complicated singleton pregnancies. The degree of correction is dependent on the local median PAPP-A MoM value.…”