Data from: Placental pathology findings in unexplained pregnancy losses

There are approximately 5 million pregnancies per year in the United States, with 1 million ending in miscarriage (a loss occurring prior to 20 weeks of gestation) and over 20,000 ending in stillbirth at or beyond 20 weeks of gestation. As many as 50% of these losses are unexplained. Our objective was to evaluate the efficacy of expanding the placental pathology diagnostic categories to include the explicit categories of 1) dysmorphic chorionic villi and 2) small placenta to decrease the unexplained fraction. Using a clinical database of 1,256 previously unexplained losses at 6–43 weeks of gestation, the most prevalent abnormality associated with each loss was determined through examination of its placental pathology slides. Of 1,256 cases analyzed from 922 patients, there were 878 (69.9%) miscarriages and 378 (30.1%) antepartum stillbirths. We determined the pathologic diagnoses for 1,150/1,256 (91.6%) of the entire series, 777/878 (88.5%) of the miscarriages (<20 weeks' gestation), and 373/378 (98.7%) of the stillbirths (≥20 weeks' gestation). The most common pathologic feature observed in unexplained miscarriages was dysmorphic chorionic villi (757 cases; 86.2%), a marker associated with genetic abnormalities. The most common pathologic feature observed in unexplained stillbirths was a small placenta (128 cases; 33.9%). Our classification system reinforced the utility of placental examination for elucidating potential mechanisms behind pregnancy loss. The improved rate of diagnosis appeared to be the result of filling a gap in previous pregnancy loss classification systems via inclusion of the categories of dysmorphic chorionic villi and small placenta.Microsoft ExcelCases A case series of 1,527 singleton pregnancies that ended in loss were identified from our tertiary-care consult service. Cases were excluded if the cause of loss could be elucidated from the clinical records alone, such as the presence of aneuploidies. Available demographic, clinical data, and gross description were abstracted from the clinical records when submitted with the consult request. Hematoxylin and eosin placental slides (no autopsy slides) were reviewed by the senior author (HJK). The analysis of this retrospective case series was approved by the Yale University Human Research Protection Program Institutional Review Board (protocol ID 2000029781). Excluded cases Cases with missing pathology slides, or an absence or insufficient number (fewer than five cross sections) of chorionic villi in the placental sample (Fig. 1) were excluded. The second exclusion criterion was an inability to date the clinical gestational age (GA), determined by the patient's last menstrual period (LMP). In the absence of an LMP, the GA was approximated by chorionic villus histologic criteria [42-44]. The remaining cases in which gestational age could not be reliably estimated were excluded from further analysis. All subsequent references to GA are related to LMP dating. Pathologic evaluation The placental pathology of included cases was re-reviewed following the Amsterdam Placental Workshop Group Consensus Statement [45], with the following modifications. This Statement does not include the diagnostic categories of dysmorphic chorionic villi, trophoblast inclusions (TIs), and/or invaginations (Fig. 2). TIs were first described by Boyd and Hamilton in 1964 [46], and later linked specifically to placentas from triploid losses in 1969 [47, 48]. Over time other investigators found that TIs were not a specific marker of triploidy but rather were seen in a wide range of karyotypic and non-karyotypic genetic abnormalities [25, 27-30, 49, 50], and adverse pregnancy outcomes, including stillbirth [20]. Importantly, the frequency of TIs in normal control placentas is very low [51-53]. Therefore, we added dysmorphic chorionic villi (not to be confused with villous dysmaturity [45]) as a diagnostic category, defined as identification of at least one TI and/or multiple invaginations in the examined slides. Additionally, based on normative curves developed by Pinar et al [54], we added the explicit category of small placenta, defined as fixed trimmed disk weight below the 10th percentile for cases ≥20 weeks. Values below the 10th percentile were mathematically extrapolated from the primary Pinar data. Identifying a nonacute cord accident required evidence of cord compression, as manifested by: 1) the presence of squamous metaplasia [55-57] on the umbilical cord surface (Fig. 3A); 2) fetal hypoxia defined as an abnormal increase in fetal nucleated RBCs [58]; 3) and thrombosis within the fetal circulation [59]. A loss was only identified as being caused by an infection when a fetal inflammatory response was observed, evidenced by either fetal neutrophil migration through the fetal chorionic plate vessels and/or through the umbilical cord vessels (funisitis) (Fig. 3B) [60]. A maternal inflammatory response alone, as evidenced by maternal neutrophils migrating into and through either the chorionic plate or external membranes, was not sufficient to identify a loss as being caused by an infection. Maternal immunologic rejection was identified when significant numbers of maternal T-cells infiltrated the chorionic villi (chronic villitis, Fig. 3C) [61-64], or monocytes filled the intervillous space (chronic histiocytic intervillositis; CHI) [65-67]. Abruption occurred when a clear, well-developed fibrin clot was adherent to the maternal surface of the placenta [68]. Fetal maternal hemorrhage was identified when intervillous fibrin forming layered lines of Zahn (indicative of blood clot formation in flowing blood [69]) was admixed with blood containing nucleated red blood cells (indicative of a fetal bleeding source) (Fig. 3E) [70, 71]. In contrast, massive perivillous fibrin (a manifestation of maternal intervillous blood thrombosis [72-74]) was identified when the intervillous space was largely filled with fibrin (Fig. 3F). Classification system After pathologic examination, we identified the most prevalent abnormality associated with the loss. First, any clear and marked case of abruption, cord accident, or fetal bleed was assigned. Next, we identified all cases with evidence of thrombosis or fetal inflammatory response. After losses associated with the above five abnormalities were identified, the remaining cases with a placental weight