Case of the Month: February

A Multifactorial Approach to Recurrent Pregnancy Loss and Intrauterine Fetal Demise

A 30-year-old female presented to the hospital after experiencing a missed abortion at 8 weeks’ gestational age due to absent cardiac activity in the fetus. First-trimester pregnancy loss in a previous pregnancy. There was no family history of any genetic disorders, nor was there any history of spontaneous abortions. The uterus was noted to be anteverted but there were no other complications during pregnancy.

Genetic Investigations:

Chromosomal microarray analysis of the product of conception from the first pregnancy revealed a gain of chromosome 6, consistent with trisomy 6, while parental karyotyping was normal, suggesting a sporadic chromosomal event. In the second pregnancy, whole exome sequencing of the POC identified a heterozygous likely pathogenic missense variant in the AMPD2 gene (c.1859G>A; p.Arg420His) and a heterozygous variant of uncertain significance in the BICD2 gene (c.2519T>G; p.Leu840Arg); however, in the absence of biallelic pathogenic variants or a clearly pathogenic dominant variant, these findings were unlikely to be independently causative. Maternal thrombophilia testing detected homozygous PAI-1 (4G/4G) and MTHFR C677T (T/T) variants, indicating a hypercoagulable state associated with adverse pregnancy outcomes. Subsequent couple carrier screening by whole exome sequencing identified multiple heterozygous pathogenic and likely pathogenic variants, confirming carrier status in both partners, with no shared biallelic pathogenic variants detected.

Interpretation:

Overall, the findings suggest that maternal thrombophilia is the most likely contributor to the pregnancy loss, both of which are associated with impaired fibrinolysis and hypercoagulability, supported by placental infarction and known associations with IUFD and recurrent pregnancy loss. These findings are clinically significant, as thrombophilia states are well known to increase the risk of placental insufficiency, fetal growth restriction, recurrent pregnancy loss, and late pregnancy complications such as IUFD. The fetal genetic variants identified on WES are unlikely to be independently causative, as they were heterozygous and did not reveal biallelic pathogenic variants.

Conclusion:

Testing provided a comprehensive evaluation of both fetal and maternal contributors to the adverse pregnancy outcomes. WES helped exclude a shared biallelic monogenic disorder as the cause of pregnancy loss, thereby refining recurrence risk and enabling informed counseling regarding the low likelihood of a recessive genetic condition in future pregnancies. Maternal thrombophilia testing identified a hypercoagulable state, offering a plausible mechanism for placental insufficiency and IUFD and allowing for targeted preventive strategies in subsequent pregnancies. Together, these investigations guided evidence-based recommendations for future reproductive planning, including optimized antenatal surveillance, thromboprophylaxis where indicated, and consideration of prenatal or preimplantation genetic testing.