Placental Histology for Targeted Risk Assessment of Recurrent Spontaneous Preterm Birth and Response to 17-alpha hydroxy-progesterone caproate Supplementation.

BACKGROUND: Spontaneous preterm birth significantly increases the risk for a recurrent preterm birth (rPTB). Few identifiable clinical risk factors exist in counseling of rPTB. Furthermore, treatment with progesterone supplementation has not consistently prevented preterm birth in high-risk patients, but may be effective in a subset of such patients. Placental pathology from a prior pregnancy may be used to predict which patients will experience rPTB, or to identify a subset more likely to respond to treatment with antenatal progesterone.

OBJECTIVE: To determine if histologic patterns are associated with rPTB among patients with an index spontaneous preterm birth. A secondary objective was to determine if placental histologic types and/or progesterone receptor density in the decidua is associated with response to progesterone supplementation with intramuscular 17 hydroxyprogesterone caproate (17-OHPC).

STUDY DESIGN: This was a retrospective cohort study at a single institution of singleton pregnancies with an index spontaneous preterm birth and subsequent birth within the same hospital system between 2009 and 2019. Patients were included if placental pathology was available in the index spontaneous preterm birth. Logistic regression was utilized to determine independent association of four histologic types (acute inflammation (AI), maternal vascular malperfusion (MVM), fetal vascular malperfusion, chronic inflammation (CI)) with rPTB. For the secondary endpoint, 17-OHPC response was defined as achievement of > 3 weeks beyond the gestational age at delivery in the index pregnancy. Patients who delivered < 3 weeks from index pregnancy but > 39 weeks were excluded. Logistic regression was used to assess the independent association of placental histology with 17-OHPC response. Sensitivity analyses were completed utilizing only patients with an index birth < 36 weeks, and then excluding those with medically indicated preterm birth in a subsequent pregnancy. A nested case-control immunohistochemical study was done among 20 patients with a subsequent term and 20 patients with a subsequent spontaneous preterm birth. The percent of cells in the maternal decidua positive for progesterone receptor (PR) was correlated with subsequent pregnancy outcome.

RESULTS: A total of 352 patients were included. AI was the most common histologic type seen among patients with spontaneous preterm birth (44.1%), followed by CI (40.9%) and MVM (31.3%). No histologic type was independently associated with rPTB. 155 patients received 17-OHPC in a second pregnancy. Low grade AI was significantly associated with decreased likelihood of 17-OHPC response. Low grade MVM in those with index pregnancy delivered at < 36 weeks was significantly associated with over 4 times increased likelihood of 17-OHPC response when excluding those with an iatrogenic subsequent preterm birth. Progesterone receptor staining was not associated with recurrent preterm birth.

CONCLUSION: While AI was prevalent among spontaneous preterm births, over half of spontaneous preterm births were not associated with AI. Low grade AI was associated with significantly decreased response to 17-OHPC supplementation. Low grade MVM was associated with 4 fold increase likelihood of 17-OHPC response among those with index deliveries < 36 weeks. Further work is needed to determine whether placental pathological examination can be utilized to target treatment in subsequent pregnancies to prevent rPTB.