Premature separation of a normally implanted placenta or abruptio placentae affects up to 1% of pregnancies and is a significant contributor to perinatal mortality and morbidity. There are epidemiological indications that the incidence may be increasing. Early diagnosis of abruption is limited by the reliance on clinical symptoms which may present late and can be nonspecific.

In this issue of the Journal, Blumenfeld et al estimate the association between placental abruption, maternal characteristics and serum analytes used for aneuploidy screening in the first-and second-trimesters. Using results from the California Prenatal Screening Program linked to live birth and hospital discharge records, the authors found significant association between maternal age greater than 34 years, low maternal serum pregnancy associated plasma protein-A (PAPP-A) and elevated alpha-feto protein (AFP) levels and placental abruption. The degree of association appeared higher for elevated AFP levels. The strengths of the study include the large sample size of over 1000 women with abruption and the exclusion of a major potential confounder, hypertensive disorders of pregnancy from the main analysis. Although the use of linked birth certificate data can be considered a limitation of the study, this specific dataset appears more robust because of linkage to hospital records and has been validated by prior studies. The mechanism for the association between maternal age greater than 34 years and placental abruption was not fully explored by the investigators. Another limitation is one that is generalizable to all studies on the subject of placental abruption, that of potential for ascertainment bias. Because placental abruption is a clinical diagnosis, many causes of unexplained vaginal bleeding could be classified as abruption and coded as such in the discharge record. On the other hand, there are many instances of subclinical abruption that will also be undetected and coded as normal. Therefore it may be difficult to predict the direction of such ascertainment bias and in the end may be nondifferential. The gold standard of placental histologic evidence of abruption is not feasible with the present study design. One natural question that arises from the study is whether there is a biologically plausible link between these serum analytes and placental abruption.

Recent studies have shown an association between indices of abnormal placentation in the first-trimester including malsecretion of serum analytes such as PAPP-A, placental growth factors, and other angiogenic markers and adverse pregnancy outcomes. Low levels of PAPP-A drawn in the first-trimester has been associated with abnormal placental morphometry. Specifically, the terminal villi of pregnancies with low-PAPA and fetal growth restriction have been shown to be significantly smaller when compared with a control group with normal PAPP-A levels and uncomplicated pregnancies. Furthermore, significant differences in levels of first-trimester PAPP-A, placental growth factor (PlGF) and a-disintegrin and metalloproteinase 12 (ADAM12s) have been seen in patients who later developed preeclampsia, growth restriction, or delivered prematurely and had pathognomonic histologic lesions for the specific adverse pregnancy complications. These findings include: lesions of maternal under perfusion including 1 or more of the following: infarcts, decidual vasculopathy, distal villous hypoplasia; lesions causing reduced placental reserve including perivillous fibrin/intervillous thrombosis-hematoma, or villitis; infections /inflammatory lesions including chorioamnionitis, funisitis or chorionic vasculitis; and fetal vascular lesions including: avascular villi and occlusive or nonocclusive thrombi. There is also evidence linking abnormal trophoblastic invasion of the decidua, thrombotic changes in the spiral arteries and abruption-induced preterm births. Although these studies were not focused on placental abruption, the close association between abruption and pregnancy complications such as preeclampsia, fetal growth restriction, and preterm birth provides indirect support for the hypothesis raised in the current study by Blumenfeld et al.

The next obvious question is whether the association found between these markers and abruption is robust enough to recommend a formal screening program for abruption. The fact that these serum markers are already available and being used for aneuploidy/neural tube defect screening would make it easy to include abruption screening as a secondary goal. Although this is a tantalizing proposition, the modest screening accuracy reported by many studies attempting to use similar analytes to screen for preeclampsia (a more prevalent pregnancy complication than placental abruption) suggest a need for caution with such optimism. This is further highlighted by the lack of a preclinical stage to abruption that would allow an intervention to prevent this significant pregnancy complication. There is also no intervention that has been investigated that could prevent abruption. Finally with the increasing use of cell-free fetal DNA for aneuploidy screening, a large proportion of the population may not have these serum markers available for abruption screening.

The present study is the beginning of a process of identifying women at high-risk for placental abruption. These women may benefit from closer monitoring. If the findings can be validated by large prospective studies, it will lay the foundation for future trials investigating potential interventions to prevent placental abruption.