Low Maternal Serum PAPP-A (< 0.3 MoM) at First Trimester Screening and Fetal Malformations in Euploid Fetuses

Low values of first trimester maternal serum PAPP-A have demonstrated to correlate with an increased risk of fetal aneuploidies and adverse obstetrics outcomes such as preeclampsia and low birth weight. However, the role of a low first trimester PAPP-A in the identification of fetuses at risk of nonchromosomal malformations has not been clarified. This study aimed to investigate the association between low PAPP-A values (< 0.3MoM) at first trimester screening and the diagnosis of fetal malformations during pregnancy in euploid fetuses.

A retrospective study of women who underwent first trimester screening between 2010 and 2020 to identify all cases with a low PAPP-A (< 0.3 MoM) and normal genetic results after invasive procedure for fetal karyotype and array CGH. Controls were women with a PAPP-A ≥ 0.3 MoM and at low risk for aneuploidies at first trimester screening. We excluded women with multiple gestation and with intrauterine fetal demise. The main outcome was the antenatal diagnosis of fetal malformation during follow-up.

We included in the final analysis 180 women with PAPP-A < 0.3 and a normal genetic testing and 104 women with PAPP-A ≥ 0.3 MoM and low risk for aneuploidies at first trimester screening (controls). A fetal malformation was identified in 11.1% (20/180) of women with a low PAPP-A compared to 2.9% (3/104) of women with PAPP-A ≥ 0.3 MoM (p < 0.001). PAPP-A < 0.3 MoM was the only factor independently associated with a diagnosis of fetal malformation at univariable (OR 4.21, 95% CI 1.22-14.53; p = 0.02) and in the final multivariable logistic regression model (OR 3.7, 95% CI 1.01-13.52; p = 0.047).

Low first trimester PAPP-A is independently associated with fetal malformations in the euploid population. This protein might represent a marker for early identification of patients who might benefit from appropriate prenatal counseling and referral to an expert center for thorough first trimester anatomical evaluation and ultrasound serial follow-up.