Placental Findings in Singleton Stillbirths: A Case-control Study

Placental Findings in Singleton Stillbirths: A Case-control Study Abstract Aims This prospective observational study compared placental lesions of stillbirth cases and live birth controls, and aimed to determine the cause of stillbirth. Methods The study enrolled 85 stillbirths and 85 live births at the time of delivery. Results There was significantly increased incidence of placental abruption (p = 0.005) and gestational diabetes (p = 0.032) in mothers with stillbirths. Histopathological examination of placenta was significantly abnormal in stillbirths compared with live births (p = 0.004). Delayed villous maturation was significantly more in stillbirths (38.82 vs. 16.47%; p = 0.002). Acute (30.59 vs. 16.47%; p = 0.04) and chronic diffuse villitis (16.47 vs. 4.7%; p = 0.02), chorionic plate acute vasculitis (28.235 vs. 14.11%; p = 0.04) were significantly more in stillbirths. Foetal vascular thrombi in the chorionic plate (30.58 vs. 14.12%; p = 0.02) and avascular villi (24.7 vs. 8.23%; p = 0.006) were significantly more in stillbirths. Conclusion These abnormal placental patterns could provide information about the etiopathogenisis in stillbirths of unknown aetiology. placenta, singleton, stillbirth, live birth INTRODUCTION Stillbirth, defined as foetal death after 20 weeks gestation [1], accounts for an estimated 2.65 million deaths worldwide each year [2]. Depending on the cause, the risk of stillbirths in future pregnancies is increased up to 10-fold [3, 4]. Therefore, accurate assessment of the cause, based on placental examination and autopsy findings, is required for future stillbirth prevention [5, 6]. Though a few studies have addressed the importance of these investigations [7], 25–60% of stillbirths remain unexplained [8]. The high proportion of unexplained stillbirths hinders accurate understanding of their cause, which consequently affects targeted healthcare interventions to reduce its incidence [9]. Placental abnormalities are causal or contributory in >60% of stillbirths [10]. Recent perinatal death classification systems such as Tulip classification (The Netherlands) and Recode place great emphasis on placental findings and have recorded lower proportion of unexplained stillbirth [10, 11]. Placenta plays a key role in maintaining healthy pregnancy, and there is evidence of placental pathology in clinical conditions associated with increased rate of stillbirth such as foetal growth restriction, pre-eclampsia and placental abruption [12, 13]. However, a recent cohort study has reported that a range of placental lesions may also be present in clinically uncomplicated pregnancies, and the significance of such lesions in cases of stillbirth remains uncertain [14]. Examination of placental pathology to confirm its contribution to stillbirth has been limited by insufficient sample size, lack of appropriate controls and non-standardized placental examination protocols [15–18]. Robust evidence is therefore required for appropriate interpretation of placental histopathological findings, which may be useful to accurately identify causes of stillbirth. Thus, we sought to compare macroscopic and microscopic abnormalities of the placenta in singleton stillbirths and live births, defined by gestational age (GA) at delivery, in a single-site case-control study with a standardized placental examination protocol. AIM To compare placental lesions for stillbirth cases and live birth controls To determine the cause of stillbirth using pathologic examinations of the placenta MATERIALS AND METHODS A prospective observational study (case-control study) with enrolment of stillbirths and live births at the time of delivery was conducted in a tertiary care hospital. Maternal placenta of the enrolled subjects was sent for histopathological examination. For the study purpose, a case was defined as a foetal death that occurs at ≥20 weeks of clinical GA and weighed ≥1000 g. Control was defined as a live birth that was appropriate for GA (AGA) and weighed ≥1000 g. Consent to enrol in the study was taken from mothers of the respective child. Sample size: Assuming the abnormal placental findings in stillbirths (cases) to be 50% and that in the live births (control) to be 15%, with odds ratio (OR) between abnormal placental findings in the two groups to be 3:1, a sample size of 85 stillbirths (cases) and 85 live births (control) in each group was required to get a power of 80%. Hence, we enrolled 85 stillbirths and 85 live births during the period May–November 2016 to estimate the rate and causality of stillbirths in the hospital. SCREENING AND ENROLMENT Inclusion criteria: A woman was eligible if she had a foetal death (case) at ≥20 weeks of clinical GA weighing ≥1000 g, or delivered a live birth (control) who was AGA weighing ≥1000 g. This inclusion criterion was to avoid extreme preterm population and for ease of comparison of case and control population in the study. Exclusion criteria: She was subsequently excluded if the GA was ≤20 weeks or if the delivery resulted from termination of a living foetus. Data and sample collection Maternal interview was conducted and their antenatal medical records were abstracted. The placental examinations were performed by pathologists using standard protocols. The examiners were not blinded to stillbirth/live birth status. Placental disorders were characterized into three broad categories based on mechanism: developmental, inflammatory and circulatory. Standard definitions were used for macroscopic and microscopic findings [19]. Statistical analysis: All data were analysed using SPSS version 16 statistical package. Continuous variables with normal distribution (GA, weight at birth) were analysed by two sample t-test/Mann–Whitney test. Categorical data were assessed using Fischer’s exact test/chi square test. A p-value of <0.05 was considered as statistically significant. Analysis was performed by following intention to treat principle. Weighted distributions of characteristics were compared for those enrolled and those analysed, using a modified independent sample test comparing enrolees who were included compared with not included in the analysis. ORs and 95% confidence intervals (CI) were calculated from univariate logistic regression model. All tests were performed at a nominal significance level of α = 0.05. RESULTS Figure 1 describes study enrolment. All the 85 stillbirth and 85 live birth placentas were analysed for the report. Fig. 1. View largeDownload slide Flowchart showing study enrolment. Fig. 1. View largeDownload slide Flowchart showing study enrolment. Table 1 compares weighted distributions of demographic characteristics of the stillbirths and live births. Birth weight and GA of stillbirths and live births were similar. Maternal complications such as placental insufficiency, placenta praevia and anaemia were comparable between the two groups. Pregnancy-induced hypertension (PIH) was found more among mothers with stillbirths than live births, but the difference was not statistically significant. There were significantly increased incidence of placental abruption (14.12 vs. 2.35%; p = 0.005) and gestational diabetes (8.24 vs. 1.18%; p = 0.032) in mothers with stillbirths. Table 1 Study characteristics Main characteristics Stillbirth (n = 85) Live birth (n = 85) p-value Sex (M:F) 1.07:1 0.7:1 0.109 Primiparous (%) 38.82 47.06 0.176 Rupture of membranes (%) 11.76 21.18 0.073 Chorioamnionitis (%) 9.41 17.65 0.089 Placental insufficiency (%) 47.06 36.47 0.107 Placental abruption (%) 14.12 2.35 0.005 Placenta praevia (%) 14.12 17.65 0.338 PIH (%) 31.76 21.18 0.082 Anaemia (%) 18.82 18.82 0.578 Gestational diabetes mellitus (%) 8.24 1.18 0.032 Placental gross appearance 72.94 65.88 0.203 Abnormal placental histology (%) 95.29 81.18 0.004 Maternal age 20–35 years (%) 92.94 97.65 0.139 Maternal education>8th standard (%) 69.41 70.59 0.500 Birth weight (grams) (mean±SD) 1867±589.85 1799±588.22 0.45 Weight gain during pregnancy (kg) 4.39±2.05 3.96±2.09 0.18 Number of antenatal visits 4.68±1.45 4.49±1.63 0.43 Time since last conception 2.84±1.87 2.92±1.90 0.82 GA (weeks) 37.55 35.72 0.63 Placental weight 360.83 373.81 0.40 Main characteristics Stillbirth (n = 85) Live birth (n = 85) p-value Sex (M:F) 1.07:1 0.7:1 0.109 Primiparous (%) 38.82 47.06 0.176 Rupture of membranes (%) 11.76 21.18 0.073 Chorioamnionitis (%) 9.41 17.65 0.089 Placental insufficiency (%) 47.06 36.47 0.107 Placental abruption (%) 14.12 2.35 0.005 Placenta praevia (%) 14.12 17.65 0.338 PIH (%) 31.76 21.18 0.082 Anaemia (%) 18.82 18.82 0.578 Gestational diabetes mellitus (%) 8.24 1.18 0.032 Placental gross appearance 72.94 65.88 0.203 Abnormal placental histology (%) 95.29 81.18 0.004 Maternal age 20–35 years (%) 92.94 97.65 0.139 Maternal education>8th standard (%) 69.41 70.59 0.500 Birth weight (grams) (mean±SD) 1867±589.85 1799±588.22 0.45 Weight gain during pregnancy (kg) 4.39±2.05 3.96±2.09 0.18 Number of antenatal visits 4.68±1.45 4.49±1.63 0.43 Time since last conception 2.84±1.87 2.92±1.90 0.82 GA (weeks) 37.55 35.72 0.63 Placental weight 360.83 373.81 0.40 Table 1 Study characteristics Main characteristics Stillbirth (n = 85) Live birth (n = 85) p-value Sex (M:F) 1.07:1 0.7:1 0.109 Primiparous (%) 38.82 47.06 0.176 Rupture of membranes (%) 11.76 21.18 0.073 Chorioamnionitis (%) 9.41 17.65 0.089 Placental insufficiency (%) 47.06 36.47 0.107 Placental abruption (%) 14.12 2.35 0.005 Placenta praevia (%) 14.12 17.65 0.338 PIH (%) 31.76 21.18 0.082 Anaemia (%) 18.82 18.82 0.578 Gestational diabetes mellitus (%) 8.24 1.18 0.032 Placental gross appearance 72.94 65.88 0.203 Abnormal placental histology (%) 95.29 81.18 0.004 Maternal age 20–35 years (%) 92.94 97.65 0.139 Maternal education>8th standard (%) 69.41 70.59 0.500 Birth weight (grams) (mean±SD) 1867±589.85 1799±588.22 0.45 Weight gain during pregnancy (kg) 4.39±2.05 3.96±2.09 0.18 Number of antenatal visits 4.68±1.45 4.49±1.63 0.43 Time since last conception 2.84±1.87 2.92±1.90 0.82 GA (weeks) 37.55 35.72 0.63 Placental weight 360.83 373.81 0.40 Main characteristics Stillbirth (n = 85) Live birth (n = 85) p-value Sex (M:F) 1.07:1 0.7:1 0.109 Primiparous (%) 38.82 47.06 0.176 Rupture of membranes (%) 11.76 21.18 0.073 Chorioamnionitis (%) 9.41 17.65 0.089 Placental insufficiency (%) 47.06 36.47 0.107 Placental abruption (%) 14.12 2.35 0.005 Placenta praevia (%) 14.12 17.65 0.338 PIH (%) 31.76 21.18 0.082 Anaemia (%) 18.82 18.82 0.578 Gestational diabetes mellitus (%) 8.24 1.18 0.032 Placental gross appearance 72.94 65.88 0.203 Abnormal placental histology (%) 95.29 81.18 0.004 Maternal age 20–35 years (%) 92.94 97.65 0.139 Maternal education>8th standard (%) 69.41 70.59 0.500 Birth weight (grams) (mean±SD) 1867±589.85 1799±588.22 0.45 Weight gain during pregnancy (kg) 4.39±2.05 3.96±2.09 0.18 Number of antenatal visits 4.68±1.45 4.49±1.63 0.43 Time since last conception 2.84±1.87 2.92±1.90 0.82 GA (weeks) 37.55 35.72 0.63 Placental weight 360.83 373.81 0.40 The gross placental appearance was similar in both the groups. The average placental weight was similar in both groups. Histopathological examination of placenta was significantly abnormal in stillbirths compared with live births (95.29 vs. 81.18%; p = 0.004). Table 2 shows the prevalence of selected placental findings by type of lesion, comparing stillbirths with live births. Table 2 Selected placental findings for singleton pregnancies, stillbirth compared with live birth Characteristics Stillbirth N = 85 (%) Live birth N = 85 OR (95% CI) p Developmental disorders  Single umbilical artery 6 (7.05) 4 (4.7) 1.54 (0.45–5.27) 0.75  Velamentous insertion 3 (3.52) 1 (1.17) 3.07 (0.43–∞) 0.62  Furcated insertion 0 0 – – Placental membranes  Circummarginate insertion 9 (10.5) 7 (8.23) 1.32 (0.48–3.59) 0.79  Circumvillate insertion 5 (5.88) 1 (3.52) 5.25 (0.79–∞) 0.21  Delayed villous maturity (diffuse) 33 (38.82) 14 (16.47) 3.22 (1.58–6.56) 0.002  Distal villous hypoplasia (diffuse) 44 (51.76) 31 (36.47) 1.87 (1.01–3.44) 0.06 Inflammatory disorders  Acute chorioamnionitis-placental membranes 12 (14.11) 6 (7.05) 2.16 (0.80–5.86) 0.21  Acute chorioamnionitis-chorionic plate 10 (11.76) 8 (9.41) 1.28 (0.49–3.33) 0.80  Acure funisitis 9 (10.58) 2 (2.35) 4.91 (1.15–∞) 0.06  Acute umbilical cord arteritis 6 (7.05) 2 (2.35) 3.15 (0.7–∞) 0.28  Acute umbilical cord phlebitis 11 (12.94) 7 (8.23) 1.66 (0.63–4.36) 0.45  Chorionic plate acute vasculitis 24 (28.23) 12 (14.11) 2.39 (1.12–5.12) 0.04  Chorionic plate vascular degenerative changes 28 (32.94) 20 (23.53) 1.6 (0.82–3.12) 0.23 Villitis  Acute diffuse villitis 26 (30.59) 14 (16.47) 2.23 (1.08–4.62) 0.04  Chronic diffuse villitis 14 (16.47) 4 (4.7) 3.99 (1.39–12.04) 0.02 Circulatory disorders  Retroplacental hematoma 16 (18.82) 7 (8.23) 2.58 (1.02–6.48) 0.07  Parenchymal infarction 28 (32.94) 20 (23.52) 1.59 (0.82–3.12) 0.23   Focal 12 (14.12) 5 (5.88) 2.63 (0.92–7.50) 0.12   Multifocal 12 (14.12) 12 (14.12) 1 (0.43–2.33) 1   Diffuse 4 (4.70) 3 (3.53) 1 (0.43–2.33) 1  Intraparenchymal thrombus 18 (21.17) 10 (11.76) 2.01 (0.88–4.59) 0.15  Perivillous/intervillous fibrin/fibrinoid deposition (diffuse) 47 (55.29) 34 (40.00) 1.85 (1.01–3.4) 0.06  Foetal vascular thrombi in the chorionic plate 26 (30.58) 12 (14.12) 2.68 (1.26–5.7) 0.02  Avascular villi 21 (24.70) 7 (8.23) 3.65 (1.49–8.93) 0.006   Focal 9 (10.59) 2 (2.35) 4.91 (1.15–∞) 0.06   Multifocal 8 (9.41) 4 (4.70) 2.10 (0.64–6.83) 0.37   diffuse 4(4.70) 1 (1.17) 4.15 (0.60–∞) 0.37  Oedema (placental hydrops) 3 (3.53) 1 (1.17) 3.07 (0.43–∞) 0.62  Syncitial knots 12 (14.11) 17 (20.00) 0.66 (0.3–1.46) 0.41 Characteristics Stillbirth N = 85 (%) Live birth N = 85 OR (95% CI) p Developmental disorders  Single umbilical artery 6 (7.05) 4 (4.7) 1.54 (0.45–5.27) 0.75  Velamentous insertion 3 (3.52) 1 (1.17) 3.07 (0.43–∞) 0.62  Furcated insertion 0 0 – – Placental membranes  Circummarginate insertion 9 (10.5) 7 (8.23) 1.32 (0.48–3.59) 0.79  Circumvillate insertion 5 (5.88) 1 (3.52) 5.25 (0.79–∞) 0.21  Delayed villous maturity (diffuse) 33 (38.82) 14 (16.47) 3.22 (1.58–6.56) 0.002  Distal villous hypoplasia (diffuse) 44 (51.76) 31 (36.47) 1.87 (1.01–3.44) 0.06 Inflammatory disorders  Acute chorioamnionitis-placental membranes 12 (14.11) 6 (7.05) 2.16 (0.80–5.86) 0.21  Acute chorioamnionitis-chorionic plate 10 (11.76) 8 (9.41) 1.28 (0.49–3.33) 0.80  Acure funisitis 9 (10.58) 2 (2.35) 4.91 (1.15–∞) 0.06  Acute umbilical cord arteritis 6 (7.05) 2 (2.35) 3.15 (0.7–∞) 0.28  Acute umbilical cord phlebitis 11 (12.94) 7 (8.23) 1.66 (0.63–4.36) 0.45  Chorionic plate acute vasculitis 24 (28.23) 12 (14.11) 2.39 (1.12–5.12) 0.04  Chorionic plate vascular degenerative changes 28 (32.94) 20 (23.53) 1.6 (0.82–3.12) 0.23 Villitis  Acute diffuse villitis 26 (30.59) 14 (16.47) 2.23 (1.08–4.62) 0.04  Chronic diffuse villitis 14 (16.47) 4 (4.7) 3.99 (1.39–12.04) 0.02 Circulatory disorders  Retroplacental hematoma 16 (18.82) 7 (8.23) 2.58 (1.02–6.48) 0.07  Parenchymal infarction 28 (32.94) 20 (23.52) 1.59 (0.82–3.12) 0.23   Focal 12 (14.12) 5 (5.88) 2.63 (0.92–7.50) 0.12   Multifocal 12 (14.12) 12 (14.12) 1 (0.43–2.33) 1   Diffuse 4 (4.70) 3 (3.53) 1 (0.43–2.33) 1  Intraparenchymal thrombus 18 (21.17) 10 (11.76) 2.01 (0.88–4.59) 0.15  Perivillous/intervillous fibrin/fibrinoid deposition (diffuse) 47 (55.29) 34 (40.00) 1.85 (1.01–3.4) 0.06  Foetal vascular thrombi in the chorionic plate 26 (30.58) 12 (14.12) 2.68 (1.26–5.7) 0.02  Avascular villi 21 (24.70) 7 (8.23) 3.65 (1.49–8.93) 0.006   Focal 9 (10.59) 2 (2.35) 4.91 (1.15–∞) 0.06   Multifocal 8 (9.41) 4 (4.70) 2.10 (0.64–6.83) 0.37   diffuse 4(4.70) 1 (1.17) 4.15 (0.60–∞) 0.37  Oedema (placental hydrops) 3 (3.53) 1 (1.17) 3.07 (0.43–∞) 0.62  Syncitial knots 12 (14.11) 17 (20.00) 0.66 (0.3–1.46) 0.41 Table 2 Selected placental findings for singleton pregnancies, stillbirth compared with live birth Characteristics Stillbirth N = 85 (%) Live birth N = 85 OR (95% CI) p Developmental disorders  Single umbilical artery 6 (7.05) 4 (4.7) 1.54 (0.45–5.27) 0.75  Velamentous insertion 3 (3.52) 1 (1.17) 3.07 (0.43–∞) 0.62  Furcated insertion 0 0 – – Placental membranes  Circummarginate insertion 9 (10.5) 7 (8.23) 1.32 (0.48–3.59) 0.79  Circumvillate insertion 5 (5.88) 1 (3.52) 5.25 (0.79–∞) 0.21  Delayed villous maturity (diffuse) 33 (38.82) 14 (16.47) 3.22 (1.58–6.56) 0.002  Distal villous hypoplasia (diffuse) 44 (51.76) 31 (36.47) 1.87 (1.01–3.44) 0.06 Inflammatory disorders  Acute chorioamnionitis-placental membranes 12 (14.11) 6 (7.05) 2.16 (0.80–5.86) 0.21  Acute chorioamnionitis-chorionic plate 10 (11.76) 8 (9.41) 1.28 (0.49–3.33) 0.80  Acure funisitis 9 (10.58) 2 (2.35) 4.91 (1.15–∞) 0.06  Acute umbilical cord arteritis 6 (7.05) 2 (2.35) 3.15 (0.7–∞) 0.28  Acute umbilical cord phlebitis 11 (12.94) 7 (8.23) 1.66 (0.63–4.36) 0.45  Chorionic plate acute vasculitis 24 (28.23) 12 (14.11) 2.39 (1.12–5.12) 0.04  Chorionic plate vascular degenerative changes 28 (32.94) 20 (23.53) 1.6 (0.82–3.12) 0.23 Villitis  Acute diffuse villitis 26 (30.59) 14 (16.47) 2.23 (1.08–4.62) 0.04  Chronic diffuse villitis 14 (16.47) 4 (4.7) 3.99 (1.39–12.04) 0.02 Circulatory disorders  Retroplacental hematoma 16 (18.82) 7 (8.23) 2.58 (1.02–6.48) 0.07  Parenchymal infarction 28 (32.94) 20 (23.52) 1.59 (0.82–3.12) 0.23   Focal 12 (14.12) 5 (5.88) 2.63 (0.92–7.50) 0.12   Multifocal 12 (14.12) 12 (14.12) 1 (0.43–2.33) 1   Diffuse 4 (4.70) 3 (3.53) 1 (0.43–2.33) 1  Intraparenchymal thrombus 18 (21.17) 10 (11.76) 2.01 (0.88–4.59) 0.15  Perivillous/intervillous fibrin/fibrinoid deposition (diffuse) 47 (55.29) 34 (40.00) 1.85 (1.01–3.4) 0.06  Foetal vascular thrombi in the chorionic plate 26 (30.58) 12 (14.12) 2.68 (1.26–5.7) 0.02  Avascular villi 21 (24.70) 7 (8.23) 3.65 (1.49–8.93) 0.006   Focal 9 (10.59) 2 (2.35) 4.91 (1.15–∞) 0.06   Multifocal 8 (9.41) 4 (4.70) 2.10 (0.64–6.83) 0.37   diffuse 4(4.70) 1 (1.17) 4.15 (0.60–∞) 0.37  Oedema (placental hydrops) 3 (3.53) 1 (1.17) 3.07 (0.43–∞) 0.62  Syncitial knots 12 (14.11) 17 (20.00) 0.66 (0.3–1.46) 0.41 Characteristics Stillbirth N = 85 (%) Live birth N = 85 OR (95% CI) p Developmental disorders  Single umbilical artery 6 (7.05) 4 (4.7) 1.54 (0.45–5.27) 0.75  Velamentous insertion 3 (3.52) 1 (1.17) 3.07 (0.43–∞) 0.62  Furcated insertion 0 0 – – Placental membranes  Circummarginate insertion 9 (10.5) 7 (8.23) 1.32 (0.48–3.59) 0.79  Circumvillate insertion 5 (5.88) 1 (3.52) 5.25 (0.79–∞) 0.21  Delayed villous maturity (diffuse) 33 (38.82) 14 (16.47) 3.22 (1.58–6.56) 0.002  Distal villous hypoplasia (diffuse) 44 (51.76) 31 (36.47) 1.87 (1.01–3.44) 0.06 Inflammatory disorders  Acute chorioamnionitis-placental membranes 12 (14.11) 6 (7.05) 2.16 (0.80–5.86) 0.21  Acute chorioamnionitis-chorionic plate 10 (11.76) 8 (9.41) 1.28 (0.49–3.33) 0.80  Acure funisitis 9 (10.58) 2 (2.35) 4.91 (1.15–∞) 0.06  Acute umbilical cord arteritis 6 (7.05) 2 (2.35) 3.15 (0.7–∞) 0.28  Acute umbilical cord phlebitis 11 (12.94) 7 (8.23) 1.66 (0.63–4.36) 0.45  Chorionic plate acute vasculitis 24 (28.23) 12 (14.11) 2.39 (1.12–5.12) 0.04  Chorionic plate vascular degenerative changes 28 (32.94) 20 (23.53) 1.6 (0.82–3.12) 0.23 Villitis  Acute diffuse villitis 26 (30.59) 14 (16.47) 2.23 (1.08–4.62) 0.04  Chronic diffuse villitis 14 (16.47) 4 (4.7) 3.99 (1.39–12.04) 0.02 Circulatory disorders  Retroplacental hematoma 16 (18.82) 7 (8.23) 2.58 (1.02–6.48) 0.07  Parenchymal infarction 28 (32.94) 20 (23.52) 1.59 (0.82–3.12) 0.23   Focal 12 (14.12) 5 (5.88) 2.63 (0.92–7.50) 0.12   Multifocal 12 (14.12) 12 (14.12) 1 (0.43–2.33) 1   Diffuse 4 (4.70) 3 (3.53) 1 (0.43–2.33) 1  Intraparenchymal thrombus 18 (21.17) 10 (11.76) 2.01 (0.88–4.59) 0.15  Perivillous/intervillous fibrin/fibrinoid deposition (diffuse) 47 (55.29) 34 (40.00) 1.85 (1.01–3.4) 0.06  Foetal vascular thrombi in the chorionic plate 26 (30.58) 12 (14.12) 2.68 (1.26–5.7) 0.02  Avascular villi 21 (24.70) 7 (8.23) 3.65 (1.49–8.93) 0.006   Focal 9 (10.59) 2 (2.35) 4.91 (1.15–∞) 0.06   Multifocal 8 (9.41) 4 (4.70) 2.10 (0.64–6.83) 0.37   diffuse 4(4.70) 1 (1.17) 4.15 (0.60–∞) 0.37  Oedema (placental hydrops) 3 (3.53) 1 (1.17) 3.07 (0.43–∞) 0.62  Syncitial knots 12 (14.11) 17 (20.00) 0.66 (0.3–1.46) 0.41 The developmental disorders of placenta such as single umbilical artery, placental membrane abnormalities such as circum marginate placenta and circum villate placenta were more prevalent in stillbirths but with no significant difference. Delayed villous maturation (DVM) was significantly more in stillbirths (38.82 vs. 16.47%; p = 0.002), and distal villous hypoplasia (DVH) was more prevalent in stillbirths, showing a trend towards significant difference (51.76 vs. 36.47%; p = 0.06) (Fig. 2). Fig. 2. View largeDownload slide Microphotograph showing delayed villous hypoplasia. Fig. 2. View largeDownload slide Microphotograph showing delayed villous hypoplasia. Acute chorioamnionitis of the placental membranes and chorionic plate was similar in the two groups. Acute umbilical cord arteritis and phlebitis and chorionic plate vascular degenerative changes were comparable between the two groups. Acute funisitis was more prevalent in stillbirths with a trend towards significant change (10.58 vs. 2.35%; p = 0.06). Chorionic plate acute vasculitis was significantly more in stillbirths (28.235 vs. 14.11%; p = 0.04). Acute diffuse (30.59 vs. 16.47%; p = 0.04) and chronic diffuse villitis (16.47 vs. 4.7%; p = 0.02) were significantly more in stillbirths than live births (Fig. 3). Fig. 3. View largeDownload slide Microphotograph showing acute diffuse villitis. Fig. 3. View largeDownload slide Microphotograph showing acute diffuse villitis. Maternal circulatory disorders (parenchymal infarction) were similar in two groups (Fig. 4). Retro placental haematoma (18.82 vs. 8.23%; p = 0.07) and perivillous/intervillous fibrin deposits (55.29 vs. 40%; p = 0.06) were more prevalent in stillbirths with a trend towards significant change (Fig. 5). Fig. 4. View largeDownload slide Microphotograph showing parenchymal infarction. Fig. 4. View largeDownload slide Microphotograph showing parenchymal infarction. Fig. 5. View largeDownload slide Microphotograph showing intervillous fibrin deposits. Fig. 5. View largeDownload slide Microphotograph showing intervillous fibrin deposits. Foetal vascular thrombi in the chorionic plate (30.58 vs. 14.12%; p = 0.02) and avascular villi (24.7 vs. 8.23%; p = 0.006) were significantly more in stillbirths than live births. The prevalence of focal avascular villi (10.59 vs. 2.35%; p = 0.06) showed a trend towards significant difference in the stillbirths. DISCUSSION The most common placental findings in stillbirths were abnormalities of the foetal villous capillaries, inflammatory lesions, villitis and foetal circulatory disorders. These included terminal villous immaturity, chorionic plate acute vasculitis, acute and chronic diffuse villitis, foetal vascular thrombi in chorionic plate and avascular villi. Notably, the prevalence of terminal villous immaturity and hypoplasia, acute diffuse villitis and fibrin deposition was >30% in this study reflecting the causality associated with stillbirth. Similarly maternal complications such as placental abruption and gestational diabetes were significantly associated with stillbirths. The common findings in both stillbirths and live births were developmental disorders, placental membrane abnormalities, inflammation and maternal circulatory disorders (retro placental haematoma, parenchymal infarction and thrombus, fibrin). Our results provide valuable insight into the causality and possible associations of stillbirths. DVM and DVH are characteristically associated with abnormal uterine artery Doppler secondary to poor perfusion in villous vessels [20]. They are more common with maternal glucose intolerance, anaemia, smoking, air pollution, pregnancy at high altitudes and genetic abnormalities (aneuploidy, Beckwith–Wiedemann syndrome) [20, 21]. This study showed a strong association of DVM with placental insufficiency. Given the fact that DVM has significant association with stillbirths, and placental insufficiency was strongly associated with DVM, strict monitoring of pregnancy for causes related to placental insufficiency should be recommended. Acute villitis of placenta, which is usually of infectious aetiology, is commonly associated with premature rupture of membranes, prolonged labour, repeated vaginal examination and women belonging to lower socio-economic status with poor access to healthcare [22, 23]. The significant association of acute villitis, which is a preventable condition, stresses the need for strict vigilance during the pregnancy period and timely management to avoid stillbirths. Similarly, chorionic plate vasculitis caused by infection of the chorionic vessels is preventable if timely interventions are taken. Acute chorioamnionitis were common in both stillbirths and live births placentas. Placental inflammation because of infection is an important cause for both stillbirth and preterm birth and likely precipitates labour leading to preterm delivery [24, 25]. The most likely mechanism for placental inflammation leading to stillbirth is the inability to tolerate infection-precipitated labour by some foetuses [26]. The results in this study were similar to previous studies, which proved strong association between foetal vascular thrombi and avascular villi with conditions causing compromised umbilical blood flow such as PIH [27]. Several findings had greater prevalence among stillbirths than live births such as increased fibrin deposits, distal villous hypoplasia and funisitis with a trend towards significant difference, which demands further evaluation with larger sample size. The major strength of this study was the inclusion of live birth age-matched controls and use of standardized placental pathology protocol to allow comparison of lesions between stillbirths and live births prospectively. The use of population-based design increases the strength of the study. This is the first study that compared prospectively the various maternal and infant characteristics of stillbirths and live births, which had similar birth weight and GA. This study confirms a significant relationship between placental histopathological abnormalities and stillbirths. The study further points to the occurrence of preventable and treatable causes of stillbirths in a given study population based on a geographical area. Exclusion of stillbirths and live births who weigh <1 kg was the major limitation in our study. Pathologists could not be blinded to stillbirth/live birth status because of the need to perform both clinical and research placental examinations, which was yet another limitation. The placental findings associated with stillbirth have been well evaluated [10, 15–18, 28–30]. However, these studies could not determine the true association of placental pathology to stillbirth because of the lack of control group. A few studies lacked standardized placental examination protocols and failed to consider the GA of the stillbirth. Moreover, the study group did not reflect the general population of stillbirths and live births. Our study attempted to address these weaknesses. The data we found will allow clinicians to interpret placental findings of stillbirths. This can provide meaningful explanations to parents. Though we could find no placental lesion, which was exclusively found in stillbirths, the clinician can comment about the frequency of a finding by describing about the lesion prevalence. The strength of association between a placental lesion and stillbirths could be explained using the ORs and associated maternal and infant characteristics described previously. In conclusion, our study compares a population of stillbirths with live births who weighed >1 kg, analysing the differences in placental characteristics. We confirm that stillbirths do have significant placental histopathological abnormalities compared with age-matched live births. The identification of these abnormal placental patterns could provide information about the etiopathogenisis in stillbirths of unknown aetiology. ACKNOWLEDGEMENTS The authors thank the Dean, Seth GS Medical College and KEM hospital, Mumbai for permitting them to publish the manuscript. The authors also acknowledge the Department of Obstetrics and Gynaecology, KEM hospital for helping in the participant enrolment. REFERENCES 1 Facts about still birth . Prevention Cfdca, ed. Vol CDC 24/7; saving lives, protecting people, 2015 . 2 Cousens S , Blencowe H , Stanton C , et al. National, regional, and worldwide estimates of stillbirth rates in 2009 with trends since 1995: a systematic analysis . Lancet 2011 ; 377 : 1319 – 30 . Google Scholar CrossRef Search ADS PubMed 3 Reddy UM. Prediction and prevention of recurrent stillbirth . Obstet Gynecol 2007 ; 110 : 1151 – 64 . Google Scholar CrossRef Search ADS PubMed 4 Samueloff A , Xenakis EM , Berkus MD , et al. Recurrent stillbirth. Significance and characteristics . J Reprod Med 1993 ; 38 : 883 – 6 . Google Scholar PubMed 5 Korteweg FJ , Erwich JJ , Timmer A , et al. Evaluation of 1025 fetal deaths: proposed diagnostic workup . Am J Obstet Gynecol 2012 ; 206 : 53.e51 – e12 . Google Scholar CrossRef Search ADS 6 VanderWielen B , Zaleski C , Cold C , et al. Wisconsin stillbirth services program: a multifocal approach to stillbirth analysis . Am J Med Genet Part A 2011 ; 155a : 1073 – 80 . Google Scholar CrossRef Search ADS PubMed 7 ACOG Practice Bulletin No. 102: management of stillbirth . Obstet Gynecol 2009 ; 113 : 748 – 61 . CrossRef Search ADS PubMed 8 Smith GC , Fretts RC. Stillbirth . Lancet 2007 ; 370 : 1715 – 25 . Google Scholar CrossRef Search ADS PubMed 9 Lawn JE , Blencowe H , Pattinson R , et al. Stillbirths: where? When? Why? How to make the data count? Lancet 2011 ; 377 : 1448 – 63 . Google Scholar CrossRef Search ADS PubMed 10 Flenady V , Froen JF , Pinar H , et al. An evaluation of classification systems for stillbirth . BMC Pregnancy Childbirth 2009 ; 9 : 24. Google Scholar CrossRef Search ADS PubMed 11 Vergani P , Cozzolino S , Pozzi E , et al. Identifying the causes of stillbirth: a comparison of four classification systems . Am J Obstet Gynecol 2008 ; 199 : 319.e311 – 314 . 12 Froen JF , Gardosi JO , Thurmann A , et al. Restricted fetal growth in sudden intrauterine unexplained death . Acta Obstet Gynecol Scand 2004 ; 83 : 801 – 7 . Google Scholar CrossRef Search ADS PubMed 13 Redman CW , Sargent IL. Latest advances in understanding preeclampsia . Science 2005 ; 308 : 1592 – 4 . Google Scholar CrossRef Search ADS PubMed 14 Pathak S , Lees CC , Hackett G , et al. Frequency and clinical significance of placental histological lesions in an unselected population at or near term . Virchows Arch 2011 ; 459 : 565 – 72 . Google Scholar CrossRef Search ADS PubMed 15 Larsen LG , Graem N. Morphological findings and value of placental examination at fetal and perinatal autopsy . APMIS 1999 ; 107 : 337 – 45 . Google Scholar CrossRef Search ADS PubMed 16 Ogunyemi D , Jackson U , Buyske S , et al. Clinical and pathologic correlates of stillbirths in a single institution . Acta Obstet Gynecol Scand 1998 ; 77 : 722 – 8 . Google Scholar CrossRef Search ADS PubMed 17 Burke CJ , Tannenberg AE. Intrapartum stillbirths in hospital unrelated to uteroplacental vascular insufficiency . Pediatr Dev Pathol 2007 ; 10 : 35 – 40 . Google Scholar CrossRef Search ADS PubMed 18 Korteweg FJ , Gordijn SJ , Timmer A , et al. A placental cause of intra-uterine fetal death depends on the perinatal mortality classification system used . Placenta 2008 ; 29 : 71 – 80 . Google Scholar CrossRef Search ADS PubMed 19 Baergen R. Manual of Benirschke and Kaufmann's Pathology of the Human Placenta . NewYork, NY : Springer 2005 . 20 Dicke JM , Huettner P , Yan S , et al. Umbilical artery Doppler indices in small for gestational age fetuses: correlation with adverse outcomes and placental abnormalities . J Ultrasound Med 2009 ; 28 : 1603 – 10 . Google Scholar CrossRef Search ADS PubMed 21 Fitzgerald BKJ , Keating S. Distal villous hypoplasia . Diagn Histopathol 2012 ; 18 : 195 – 200 . Google Scholar CrossRef Search ADS 22 Bae GE , Yoon N , Choi M , et al. Acute placental villitis as evidence of fetal sepsis: an autopsy case report . Pediatric Dev Pathol 2016 ; 19 : 165 – 8 . Google Scholar CrossRef Search ADS 23 Katzman PJ. Chronic inflammatory lesions of the placenta . Semin Perinatol 2015 ; 39 : 20 – 6 . Google Scholar CrossRef Search ADS PubMed 24 Goldenberg RL , Thompson C. The infectious origins of stillbirth . Am J Obstet Gynecol 2003 ; 189 : 861 – 73 . Google Scholar CrossRef Search ADS PubMed 25 Goldenberg RL , Culhane JF , Johnson DC. Maternal infection and adverse fetal and neonatal outcomes . Clin Perinatol 2005 ; 32 : 523 – 59 . Google Scholar CrossRef Search ADS PubMed 26 Goldenberg RL , McClure EM , Saleem S , et al. Infection-related stillbirths . Lancet 2010 ; 375 : 1482 – 90 . Google Scholar CrossRef Search ADS PubMed 27 Rogers BB , Momirova V , Dizon-Townson D , et al. Avascular villi, increased syncytial knots, and hypervascular villi are associated with pregnancies complicated by factor V Leiden mutation . Pediatr Dev Pathol 2010 ; 13 : 341 – 7 . Google Scholar CrossRef Search ADS PubMed 28 Amir H , Weintraub A , Aricha-Tamir B , et al. A piece in the puzzle of intrauterine fetal death: pathological findings in placentas from term and preterm intrauterine fetal death pregnancies . J Matern Fetal Neonatal Med 2009 ; 22 : 759 – 64 . Google Scholar CrossRef Search ADS PubMed 29 Heazell AE , Martindale EA. Can post-mortem examination of the placenta help determine the cause of stillbirth? J Obstet Gynaecol 2009 ; 29 : 225 – 8 . Google Scholar CrossRef Search ADS PubMed 30 Helgadottir LB , Turowski G , Skjeldestad FE , et al. Classification of stillbirths and risk factors by cause of death–a case-control study . Acta Obstet Gynecol Scand 2013 ; 92 : 325 – 33 . Google Scholar CrossRef Search ADS PubMed © The Author(s) [2018]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

Placental Findings in Singleton Stillbirths: A Case-control Study

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Oxford University Press
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© The Author(s) [2018]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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0142-6338
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1465-3664
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10.1093/tropej/fmy006
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Abstract

Abstract Aims This prospective observational study compared placental lesions of stillbirth cases and live birth controls, and aimed to determine the cause of stillbirth. Methods The study enrolled 85 stillbirths and 85 live births at the time of delivery. Results There was significantly increased incidence of placental abruption (p = 0.005) and gestational diabetes (p = 0.032) in mothers with stillbirths. Histopathological examination of placenta was significantly abnormal in stillbirths compared with live births (p = 0.004). Delayed villous maturation was significantly more in stillbirths (38.82 vs. 16.47%; p = 0.002). Acute (30.59 vs. 16.47%; p = 0.04) and chronic diffuse villitis (16.47 vs. 4.7%; p = 0.02), chorionic plate acute vasculitis (28.235 vs. 14.11%; p = 0.04) were significantly more in stillbirths. Foetal vascular thrombi in the chorionic plate (30.58 vs. 14.12%; p = 0.02) and avascular villi (24.7 vs. 8.23%; p = 0.006) were significantly more in stillbirths. Conclusion These abnormal placental patterns could provide information about the etiopathogenisis in stillbirths of unknown aetiology. placenta, singleton, stillbirth, live birth INTRODUCTION Stillbirth, defined as foetal death after 20 weeks gestation [1], accounts for an estimated 2.65 million deaths worldwide each year [2]. Depending on the cause, the risk of stillbirths in future pregnancies is increased up to 10-fold [3, 4]. Therefore, accurate assessment of the cause, based on placental examination and autopsy findings, is required for future stillbirth prevention [5, 6]. Though a few studies have addressed the importance of these investigations [7], 25–60% of stillbirths remain unexplained [8]. The high proportion of unexplained stillbirths hinders accurate understanding of their cause, which consequently affects targeted healthcare interventions to reduce its incidence [9]. Placental abnormalities are causal or contributory in >60% of stillbirths [10]. Recent perinatal death classification systems such as Tulip classification (The Netherlands) and Recode place great emphasis on placental findings and have recorded lower proportion of unexplained stillbirth [10, 11]. Placenta plays a key role in maintaining healthy pregnancy, and there is evidence of placental pathology in clinical conditions associated with increased rate of stillbirth such as foetal growth restriction, pre-eclampsia and placental abruption [12, 13]. However, a recent cohort study has reported that a range of placental lesions may also be present in clinically uncomplicated pregnancies, and the significance of such lesions in cases of stillbirth remains uncertain [14]. Examination of placental pathology to confirm its contribution to stillbirth has been limited by insufficient sample size, lack of appropriate controls and non-standardized placental examination protocols [15–18]. Robust evidence is therefore required for appropriate interpretation of placental histopathological findings, which may be useful to accurately identify causes of stillbirth. Thus, we sought to compare macroscopic and microscopic abnormalities of the placenta in singleton stillbirths and live births, defined by gestational age (GA) at delivery, in a single-site case-control study with a standardized placental examination protocol. AIM To compare placental lesions for stillbirth cases and live birth controls To determine the cause of stillbirth using pathologic examinations of the placenta MATERIALS AND METHODS A prospective observational study (case-control study) with enrolment of stillbirths and live births at the time of delivery was conducted in a tertiary care hospital. Maternal placenta of the enrolled subjects was sent for histopathological examination. For the study purpose, a case was defined as a foetal death that occurs at ≥20 weeks of clinical GA and weighed ≥1000 g. Control was defined as a live birth that was appropriate for GA (AGA) and weighed ≥1000 g. Consent to enrol in the study was taken from mothers of the respective child. Sample size: Assuming the abnormal placental findings in stillbirths (cases) to be 50% and that in the live births (control) to be 15%, with odds ratio (OR) between abnormal placental findings in the two groups to be 3:1, a sample size of 85 stillbirths (cases) and 85 live births (control) in each group was required to get a power of 80%. Hence, we enrolled 85 stillbirths and 85 live births during the period May–November 2016 to estimate the rate and causality of stillbirths in the hospital. SCREENING AND ENROLMENT Inclusion criteria: A woman was eligible if she had a foetal death (case) at ≥20 weeks of clinical GA weighing ≥1000 g, or delivered a live birth (control) who was AGA weighing ≥1000 g. This inclusion criterion was to avoid extreme preterm population and for ease of comparison of case and control population in the study. Exclusion criteria: She was subsequently excluded if the GA was ≤20 weeks or if the delivery resulted from termination of a living foetus. Data and sample collection Maternal interview was conducted and their antenatal medical records were abstracted. The placental examinations were performed by pathologists using standard protocols. The examiners were not blinded to stillbirth/live birth status. Placental disorders were characterized into three broad categories based on mechanism: developmental, inflammatory and circulatory. Standard definitions were used for macroscopic and microscopic findings [19]. Statistical analysis: All data were analysed using SPSS version 16 statistical package. Continuous variables with normal distribution (GA, weight at birth) were analysed by two sample t-test/Mann–Whitney test. Categorical data were assessed using Fischer’s exact test/chi square test. A p-value of <0.05 was considered as statistically significant. Analysis was performed by following intention to treat principle. Weighted distributions of characteristics were compared for those enrolled and those analysed, using a modified independent sample test comparing enrolees who were included compared with not included in the analysis. ORs and 95% confidence intervals (CI) were calculated from univariate logistic regression model. All tests were performed at a nominal significance level of α = 0.05. RESULTS Figure 1 describes study enrolment. All the 85 stillbirth and 85 live birth placentas were analysed for the report. Fig. 1. View largeDownload slide Flowchart showing study enrolment. Fig. 1. View largeDownload slide Flowchart showing study enrolment. Table 1 compares weighted distributions of demographic characteristics of the stillbirths and live births. Birth weight and GA of stillbirths and live births were similar. Maternal complications such as placental insufficiency, placenta praevia and anaemia were comparable between the two groups. Pregnancy-induced hypertension (PIH) was found more among mothers with stillbirths than live births, but the difference was not statistically significant. There were significantly increased incidence of placental abruption (14.12 vs. 2.35%; p = 0.005) and gestational diabetes (8.24 vs. 1.18%; p = 0.032) in mothers with stillbirths. Table 1 Study characteristics Main characteristics Stillbirth (n = 85) Live birth (n = 85) p-value Sex (M:F) 1.07:1 0.7:1 0.109 Primiparous (%) 38.82 47.06 0.176 Rupture of membranes (%) 11.76 21.18 0.073 Chorioamnionitis (%) 9.41 17.65 0.089 Placental insufficiency (%) 47.06 36.47 0.107 Placental abruption (%) 14.12 2.35 0.005 Placenta praevia (%) 14.12 17.65 0.338 PIH (%) 31.76 21.18 0.082 Anaemia (%) 18.82 18.82 0.578 Gestational diabetes mellitus (%) 8.24 1.18 0.032 Placental gross appearance 72.94 65.88 0.203 Abnormal placental histology (%) 95.29 81.18 0.004 Maternal age 20–35 years (%) 92.94 97.65 0.139 Maternal education>8th standard (%) 69.41 70.59 0.500 Birth weight (grams) (mean±SD) 1867±589.85 1799±588.22 0.45 Weight gain during pregnancy (kg) 4.39±2.05 3.96±2.09 0.18 Number of antenatal visits 4.68±1.45 4.49±1.63 0.43 Time since last conception 2.84±1.87 2.92±1.90 0.82 GA (weeks) 37.55 35.72 0.63 Placental weight 360.83 373.81 0.40 Main characteristics Stillbirth (n = 85) Live birth (n = 85) p-value Sex (M:F) 1.07:1 0.7:1 0.109 Primiparous (%) 38.82 47.06 0.176 Rupture of membranes (%) 11.76 21.18 0.073 Chorioamnionitis (%) 9.41 17.65 0.089 Placental insufficiency (%) 47.06 36.47 0.107 Placental abruption (%) 14.12 2.35 0.005 Placenta praevia (%) 14.12 17.65 0.338 PIH (%) 31.76 21.18 0.082 Anaemia (%) 18.82 18.82 0.578 Gestational diabetes mellitus (%) 8.24 1.18 0.032 Placental gross appearance 72.94 65.88 0.203 Abnormal placental histology (%) 95.29 81.18 0.004 Maternal age 20–35 years (%) 92.94 97.65 0.139 Maternal education>8th standard (%) 69.41 70.59 0.500 Birth weight (grams) (mean±SD) 1867±589.85 1799±588.22 0.45 Weight gain during pregnancy (kg) 4.39±2.05 3.96±2.09 0.18 Number of antenatal visits 4.68±1.45 4.49±1.63 0.43 Time since last conception 2.84±1.87 2.92±1.90 0.82 GA (weeks) 37.55 35.72 0.63 Placental weight 360.83 373.81 0.40 Table 1 Study characteristics Main characteristics Stillbirth (n = 85) Live birth (n = 85) p-value Sex (M:F) 1.07:1 0.7:1 0.109 Primiparous (%) 38.82 47.06 0.176 Rupture of membranes (%) 11.76 21.18 0.073 Chorioamnionitis (%) 9.41 17.65 0.089 Placental insufficiency (%) 47.06 36.47 0.107 Placental abruption (%) 14.12 2.35 0.005 Placenta praevia (%) 14.12 17.65 0.338 PIH (%) 31.76 21.18 0.082 Anaemia (%) 18.82 18.82 0.578 Gestational diabetes mellitus (%) 8.24 1.18 0.032 Placental gross appearance 72.94 65.88 0.203 Abnormal placental histology (%) 95.29 81.18 0.004 Maternal age 20–35 years (%) 92.94 97.65 0.139 Maternal education>8th standard (%) 69.41 70.59 0.500 Birth weight (grams) (mean±SD) 1867±589.85 1799±588.22 0.45 Weight gain during pregnancy (kg) 4.39±2.05 3.96±2.09 0.18 Number of antenatal visits 4.68±1.45 4.49±1.63 0.43 Time since last conception 2.84±1.87 2.92±1.90 0.82 GA (weeks) 37.55 35.72 0.63 Placental weight 360.83 373.81 0.40 Main characteristics Stillbirth (n = 85) Live birth (n = 85) p-value Sex (M:F) 1.07:1 0.7:1 0.109 Primiparous (%) 38.82 47.06 0.176 Rupture of membranes (%) 11.76 21.18 0.073 Chorioamnionitis (%) 9.41 17.65 0.089 Placental insufficiency (%) 47.06 36.47 0.107 Placental abruption (%) 14.12 2.35 0.005 Placenta praevia (%) 14.12 17.65 0.338 PIH (%) 31.76 21.18 0.082 Anaemia (%) 18.82 18.82 0.578 Gestational diabetes mellitus (%) 8.24 1.18 0.032 Placental gross appearance 72.94 65.88 0.203 Abnormal placental histology (%) 95.29 81.18 0.004 Maternal age 20–35 years (%) 92.94 97.65 0.139 Maternal education>8th standard (%) 69.41 70.59 0.500 Birth weight (grams) (mean±SD) 1867±589.85 1799±588.22 0.45 Weight gain during pregnancy (kg) 4.39±2.05 3.96±2.09 0.18 Number of antenatal visits 4.68±1.45 4.49±1.63 0.43 Time since last conception 2.84±1.87 2.92±1.90 0.82 GA (weeks) 37.55 35.72 0.63 Placental weight 360.83 373.81 0.40 The gross placental appearance was similar in both the groups. The average placental weight was similar in both groups. Histopathological examination of placenta was significantly abnormal in stillbirths compared with live births (95.29 vs. 81.18%; p = 0.004). Table 2 shows the prevalence of selected placental findings by type of lesion, comparing stillbirths with live births. Table 2 Selected placental findings for singleton pregnancies, stillbirth compared with live birth Characteristics Stillbirth N = 85 (%) Live birth N = 85 OR (95% CI) p Developmental disorders  Single umbilical artery 6 (7.05) 4 (4.7) 1.54 (0.45–5.27) 0.75  Velamentous insertion 3 (3.52) 1 (1.17) 3.07 (0.43–∞) 0.62  Furcated insertion 0 0 – – Placental membranes  Circummarginate insertion 9 (10.5) 7 (8.23) 1.32 (0.48–3.59) 0.79  Circumvillate insertion 5 (5.88) 1 (3.52) 5.25 (0.79–∞) 0.21  Delayed villous maturity (diffuse) 33 (38.82) 14 (16.47) 3.22 (1.58–6.56) 0.002  Distal villous hypoplasia (diffuse) 44 (51.76) 31 (36.47) 1.87 (1.01–3.44) 0.06 Inflammatory disorders  Acute chorioamnionitis-placental membranes 12 (14.11) 6 (7.05) 2.16 (0.80–5.86) 0.21  Acute chorioamnionitis-chorionic plate 10 (11.76) 8 (9.41) 1.28 (0.49–3.33) 0.80  Acure funisitis 9 (10.58) 2 (2.35) 4.91 (1.15–∞) 0.06  Acute umbilical cord arteritis 6 (7.05) 2 (2.35) 3.15 (0.7–∞) 0.28  Acute umbilical cord phlebitis 11 (12.94) 7 (8.23) 1.66 (0.63–4.36) 0.45  Chorionic plate acute vasculitis 24 (28.23) 12 (14.11) 2.39 (1.12–5.12) 0.04  Chorionic plate vascular degenerative changes 28 (32.94) 20 (23.53) 1.6 (0.82–3.12) 0.23 Villitis  Acute diffuse villitis 26 (30.59) 14 (16.47) 2.23 (1.08–4.62) 0.04  Chronic diffuse villitis 14 (16.47) 4 (4.7) 3.99 (1.39–12.04) 0.02 Circulatory disorders  Retroplacental hematoma 16 (18.82) 7 (8.23) 2.58 (1.02–6.48) 0.07  Parenchymal infarction 28 (32.94) 20 (23.52) 1.59 (0.82–3.12) 0.23   Focal 12 (14.12) 5 (5.88) 2.63 (0.92–7.50) 0.12   Multifocal 12 (14.12) 12 (14.12) 1 (0.43–2.33) 1   Diffuse 4 (4.70) 3 (3.53) 1 (0.43–2.33) 1  Intraparenchymal thrombus 18 (21.17) 10 (11.76) 2.01 (0.88–4.59) 0.15  Perivillous/intervillous fibrin/fibrinoid deposition (diffuse) 47 (55.29) 34 (40.00) 1.85 (1.01–3.4) 0.06  Foetal vascular thrombi in the chorionic plate 26 (30.58) 12 (14.12) 2.68 (1.26–5.7) 0.02  Avascular villi 21 (24.70) 7 (8.23) 3.65 (1.49–8.93) 0.006   Focal 9 (10.59) 2 (2.35) 4.91 (1.15–∞) 0.06   Multifocal 8 (9.41) 4 (4.70) 2.10 (0.64–6.83) 0.37   diffuse 4(4.70) 1 (1.17) 4.15 (0.60–∞) 0.37  Oedema (placental hydrops) 3 (3.53) 1 (1.17) 3.07 (0.43–∞) 0.62  Syncitial knots 12 (14.11) 17 (20.00) 0.66 (0.3–1.46) 0.41 Characteristics Stillbirth N = 85 (%) Live birth N = 85 OR (95% CI) p Developmental disorders  Single umbilical artery 6 (7.05) 4 (4.7) 1.54 (0.45–5.27) 0.75  Velamentous insertion 3 (3.52) 1 (1.17) 3.07 (0.43–∞) 0.62  Furcated insertion 0 0 – – Placental membranes  Circummarginate insertion 9 (10.5) 7 (8.23) 1.32 (0.48–3.59) 0.79  Circumvillate insertion 5 (5.88) 1 (3.52) 5.25 (0.79–∞) 0.21  Delayed villous maturity (diffuse) 33 (38.82) 14 (16.47) 3.22 (1.58–6.56) 0.002  Distal villous hypoplasia (diffuse) 44 (51.76) 31 (36.47) 1.87 (1.01–3.44) 0.06 Inflammatory disorders  Acute chorioamnionitis-placental membranes 12 (14.11) 6 (7.05) 2.16 (0.80–5.86) 0.21  Acute chorioamnionitis-chorionic plate 10 (11.76) 8 (9.41) 1.28 (0.49–3.33) 0.80  Acure funisitis 9 (10.58) 2 (2.35) 4.91 (1.15–∞) 0.06  Acute umbilical cord arteritis 6 (7.05) 2 (2.35) 3.15 (0.7–∞) 0.28  Acute umbilical cord phlebitis 11 (12.94) 7 (8.23) 1.66 (0.63–4.36) 0.45  Chorionic plate acute vasculitis 24 (28.23) 12 (14.11) 2.39 (1.12–5.12) 0.04  Chorionic plate vascular degenerative changes 28 (32.94) 20 (23.53) 1.6 (0.82–3.12) 0.23 Villitis  Acute diffuse villitis 26 (30.59) 14 (16.47) 2.23 (1.08–4.62) 0.04  Chronic diffuse villitis 14 (16.47) 4 (4.7) 3.99 (1.39–12.04) 0.02 Circulatory disorders  Retroplacental hematoma 16 (18.82) 7 (8.23) 2.58 (1.02–6.48) 0.07  Parenchymal infarction 28 (32.94) 20 (23.52) 1.59 (0.82–3.12) 0.23   Focal 12 (14.12) 5 (5.88) 2.63 (0.92–7.50) 0.12   Multifocal 12 (14.12) 12 (14.12) 1 (0.43–2.33) 1   Diffuse 4 (4.70) 3 (3.53) 1 (0.43–2.33) 1  Intraparenchymal thrombus 18 (21.17) 10 (11.76) 2.01 (0.88–4.59) 0.15  Perivillous/intervillous fibrin/fibrinoid deposition (diffuse) 47 (55.29) 34 (40.00) 1.85 (1.01–3.4) 0.06  Foetal vascular thrombi in the chorionic plate 26 (30.58) 12 (14.12) 2.68 (1.26–5.7) 0.02  Avascular villi 21 (24.70) 7 (8.23) 3.65 (1.49–8.93) 0.006   Focal 9 (10.59) 2 (2.35) 4.91 (1.15–∞) 0.06   Multifocal 8 (9.41) 4 (4.70) 2.10 (0.64–6.83) 0.37   diffuse 4(4.70) 1 (1.17) 4.15 (0.60–∞) 0.37  Oedema (placental hydrops) 3 (3.53) 1 (1.17) 3.07 (0.43–∞) 0.62  Syncitial knots 12 (14.11) 17 (20.00) 0.66 (0.3–1.46) 0.41 Table 2 Selected placental findings for singleton pregnancies, stillbirth compared with live birth Characteristics Stillbirth N = 85 (%) Live birth N = 85 OR (95% CI) p Developmental disorders  Single umbilical artery 6 (7.05) 4 (4.7) 1.54 (0.45–5.27) 0.75  Velamentous insertion 3 (3.52) 1 (1.17) 3.07 (0.43–∞) 0.62  Furcated insertion 0 0 – – Placental membranes  Circummarginate insertion 9 (10.5) 7 (8.23) 1.32 (0.48–3.59) 0.79  Circumvillate insertion 5 (5.88) 1 (3.52) 5.25 (0.79–∞) 0.21  Delayed villous maturity (diffuse) 33 (38.82) 14 (16.47) 3.22 (1.58–6.56) 0.002  Distal villous hypoplasia (diffuse) 44 (51.76) 31 (36.47) 1.87 (1.01–3.44) 0.06 Inflammatory disorders  Acute chorioamnionitis-placental membranes 12 (14.11) 6 (7.05) 2.16 (0.80–5.86) 0.21  Acute chorioamnionitis-chorionic plate 10 (11.76) 8 (9.41) 1.28 (0.49–3.33) 0.80  Acure funisitis 9 (10.58) 2 (2.35) 4.91 (1.15–∞) 0.06  Acute umbilical cord arteritis 6 (7.05) 2 (2.35) 3.15 (0.7–∞) 0.28  Acute umbilical cord phlebitis 11 (12.94) 7 (8.23) 1.66 (0.63–4.36) 0.45  Chorionic plate acute vasculitis 24 (28.23) 12 (14.11) 2.39 (1.12–5.12) 0.04  Chorionic plate vascular degenerative changes 28 (32.94) 20 (23.53) 1.6 (0.82–3.12) 0.23 Villitis  Acute diffuse villitis 26 (30.59) 14 (16.47) 2.23 (1.08–4.62) 0.04  Chronic diffuse villitis 14 (16.47) 4 (4.7) 3.99 (1.39–12.04) 0.02 Circulatory disorders  Retroplacental hematoma 16 (18.82) 7 (8.23) 2.58 (1.02–6.48) 0.07  Parenchymal infarction 28 (32.94) 20 (23.52) 1.59 (0.82–3.12) 0.23   Focal 12 (14.12) 5 (5.88) 2.63 (0.92–7.50) 0.12   Multifocal 12 (14.12) 12 (14.12) 1 (0.43–2.33) 1   Diffuse 4 (4.70) 3 (3.53) 1 (0.43–2.33) 1  Intraparenchymal thrombus 18 (21.17) 10 (11.76) 2.01 (0.88–4.59) 0.15  Perivillous/intervillous fibrin/fibrinoid deposition (diffuse) 47 (55.29) 34 (40.00) 1.85 (1.01–3.4) 0.06  Foetal vascular thrombi in the chorionic plate 26 (30.58) 12 (14.12) 2.68 (1.26–5.7) 0.02  Avascular villi 21 (24.70) 7 (8.23) 3.65 (1.49–8.93) 0.006   Focal 9 (10.59) 2 (2.35) 4.91 (1.15–∞) 0.06   Multifocal 8 (9.41) 4 (4.70) 2.10 (0.64–6.83) 0.37   diffuse 4(4.70) 1 (1.17) 4.15 (0.60–∞) 0.37  Oedema (placental hydrops) 3 (3.53) 1 (1.17) 3.07 (0.43–∞) 0.62  Syncitial knots 12 (14.11) 17 (20.00) 0.66 (0.3–1.46) 0.41 Characteristics Stillbirth N = 85 (%) Live birth N = 85 OR (95% CI) p Developmental disorders  Single umbilical artery 6 (7.05) 4 (4.7) 1.54 (0.45–5.27) 0.75  Velamentous insertion 3 (3.52) 1 (1.17) 3.07 (0.43–∞) 0.62  Furcated insertion 0 0 – – Placental membranes  Circummarginate insertion 9 (10.5) 7 (8.23) 1.32 (0.48–3.59) 0.79  Circumvillate insertion 5 (5.88) 1 (3.52) 5.25 (0.79–∞) 0.21  Delayed villous maturity (diffuse) 33 (38.82) 14 (16.47) 3.22 (1.58–6.56) 0.002  Distal villous hypoplasia (diffuse) 44 (51.76) 31 (36.47) 1.87 (1.01–3.44) 0.06 Inflammatory disorders  Acute chorioamnionitis-placental membranes 12 (14.11) 6 (7.05) 2.16 (0.80–5.86) 0.21  Acute chorioamnionitis-chorionic plate 10 (11.76) 8 (9.41) 1.28 (0.49–3.33) 0.80  Acure funisitis 9 (10.58) 2 (2.35) 4.91 (1.15–∞) 0.06  Acute umbilical cord arteritis 6 (7.05) 2 (2.35) 3.15 (0.7–∞) 0.28  Acute umbilical cord phlebitis 11 (12.94) 7 (8.23) 1.66 (0.63–4.36) 0.45  Chorionic plate acute vasculitis 24 (28.23) 12 (14.11) 2.39 (1.12–5.12) 0.04  Chorionic plate vascular degenerative changes 28 (32.94) 20 (23.53) 1.6 (0.82–3.12) 0.23 Villitis  Acute diffuse villitis 26 (30.59) 14 (16.47) 2.23 (1.08–4.62) 0.04  Chronic diffuse villitis 14 (16.47) 4 (4.7) 3.99 (1.39–12.04) 0.02 Circulatory disorders  Retroplacental hematoma 16 (18.82) 7 (8.23) 2.58 (1.02–6.48) 0.07  Parenchymal infarction 28 (32.94) 20 (23.52) 1.59 (0.82–3.12) 0.23   Focal 12 (14.12) 5 (5.88) 2.63 (0.92–7.50) 0.12   Multifocal 12 (14.12) 12 (14.12) 1 (0.43–2.33) 1   Diffuse 4 (4.70) 3 (3.53) 1 (0.43–2.33) 1  Intraparenchymal thrombus 18 (21.17) 10 (11.76) 2.01 (0.88–4.59) 0.15  Perivillous/intervillous fibrin/fibrinoid deposition (diffuse) 47 (55.29) 34 (40.00) 1.85 (1.01–3.4) 0.06  Foetal vascular thrombi in the chorionic plate 26 (30.58) 12 (14.12) 2.68 (1.26–5.7) 0.02  Avascular villi 21 (24.70) 7 (8.23) 3.65 (1.49–8.93) 0.006   Focal 9 (10.59) 2 (2.35) 4.91 (1.15–∞) 0.06   Multifocal 8 (9.41) 4 (4.70) 2.10 (0.64–6.83) 0.37   diffuse 4(4.70) 1 (1.17) 4.15 (0.60–∞) 0.37  Oedema (placental hydrops) 3 (3.53) 1 (1.17) 3.07 (0.43–∞) 0.62  Syncitial knots 12 (14.11) 17 (20.00) 0.66 (0.3–1.46) 0.41 The developmental disorders of placenta such as single umbilical artery, placental membrane abnormalities such as circum marginate placenta and circum villate placenta were more prevalent in stillbirths but with no significant difference. Delayed villous maturation (DVM) was significantly more in stillbirths (38.82 vs. 16.47%; p = 0.002), and distal villous hypoplasia (DVH) was more prevalent in stillbirths, showing a trend towards significant difference (51.76 vs. 36.47%; p = 0.06) (Fig. 2). Fig. 2. View largeDownload slide Microphotograph showing delayed villous hypoplasia. Fig. 2. View largeDownload slide Microphotograph showing delayed villous hypoplasia. Acute chorioamnionitis of the placental membranes and chorionic plate was similar in the two groups. Acute umbilical cord arteritis and phlebitis and chorionic plate vascular degenerative changes were comparable between the two groups. Acute funisitis was more prevalent in stillbirths with a trend towards significant change (10.58 vs. 2.35%; p = 0.06). Chorionic plate acute vasculitis was significantly more in stillbirths (28.235 vs. 14.11%; p = 0.04). Acute diffuse (30.59 vs. 16.47%; p = 0.04) and chronic diffuse villitis (16.47 vs. 4.7%; p = 0.02) were significantly more in stillbirths than live births (Fig. 3). Fig. 3. View largeDownload slide Microphotograph showing acute diffuse villitis. Fig. 3. View largeDownload slide Microphotograph showing acute diffuse villitis. Maternal circulatory disorders (parenchymal infarction) were similar in two groups (Fig. 4). Retro placental haematoma (18.82 vs. 8.23%; p = 0.07) and perivillous/intervillous fibrin deposits (55.29 vs. 40%; p = 0.06) were more prevalent in stillbirths with a trend towards significant change (Fig. 5). Fig. 4. View largeDownload slide Microphotograph showing parenchymal infarction. Fig. 4. View largeDownload slide Microphotograph showing parenchymal infarction. Fig. 5. View largeDownload slide Microphotograph showing intervillous fibrin deposits. Fig. 5. View largeDownload slide Microphotograph showing intervillous fibrin deposits. Foetal vascular thrombi in the chorionic plate (30.58 vs. 14.12%; p = 0.02) and avascular villi (24.7 vs. 8.23%; p = 0.006) were significantly more in stillbirths than live births. The prevalence of focal avascular villi (10.59 vs. 2.35%; p = 0.06) showed a trend towards significant difference in the stillbirths. DISCUSSION The most common placental findings in stillbirths were abnormalities of the foetal villous capillaries, inflammatory lesions, villitis and foetal circulatory disorders. These included terminal villous immaturity, chorionic plate acute vasculitis, acute and chronic diffuse villitis, foetal vascular thrombi in chorionic plate and avascular villi. Notably, the prevalence of terminal villous immaturity and hypoplasia, acute diffuse villitis and fibrin deposition was >30% in this study reflecting the causality associated with stillbirth. Similarly maternal complications such as placental abruption and gestational diabetes were significantly associated with stillbirths. The common findings in both stillbirths and live births were developmental disorders, placental membrane abnormalities, inflammation and maternal circulatory disorders (retro placental haematoma, parenchymal infarction and thrombus, fibrin). Our results provide valuable insight into the causality and possible associations of stillbirths. DVM and DVH are characteristically associated with abnormal uterine artery Doppler secondary to poor perfusion in villous vessels [20]. They are more common with maternal glucose intolerance, anaemia, smoking, air pollution, pregnancy at high altitudes and genetic abnormalities (aneuploidy, Beckwith–Wiedemann syndrome) [20, 21]. This study showed a strong association of DVM with placental insufficiency. Given the fact that DVM has significant association with stillbirths, and placental insufficiency was strongly associated with DVM, strict monitoring of pregnancy for causes related to placental insufficiency should be recommended. Acute villitis of placenta, which is usually of infectious aetiology, is commonly associated with premature rupture of membranes, prolonged labour, repeated vaginal examination and women belonging to lower socio-economic status with poor access to healthcare [22, 23]. The significant association of acute villitis, which is a preventable condition, stresses the need for strict vigilance during the pregnancy period and timely management to avoid stillbirths. Similarly, chorionic plate vasculitis caused by infection of the chorionic vessels is preventable if timely interventions are taken. Acute chorioamnionitis were common in both stillbirths and live births placentas. Placental inflammation because of infection is an important cause for both stillbirth and preterm birth and likely precipitates labour leading to preterm delivery [24, 25]. The most likely mechanism for placental inflammation leading to stillbirth is the inability to tolerate infection-precipitated labour by some foetuses [26]. The results in this study were similar to previous studies, which proved strong association between foetal vascular thrombi and avascular villi with conditions causing compromised umbilical blood flow such as PIH [27]. Several findings had greater prevalence among stillbirths than live births such as increased fibrin deposits, distal villous hypoplasia and funisitis with a trend towards significant difference, which demands further evaluation with larger sample size. The major strength of this study was the inclusion of live birth age-matched controls and use of standardized placental pathology protocol to allow comparison of lesions between stillbirths and live births prospectively. The use of population-based design increases the strength of the study. This is the first study that compared prospectively the various maternal and infant characteristics of stillbirths and live births, which had similar birth weight and GA. This study confirms a significant relationship between placental histopathological abnormalities and stillbirths. The study further points to the occurrence of preventable and treatable causes of stillbirths in a given study population based on a geographical area. Exclusion of stillbirths and live births who weigh <1 kg was the major limitation in our study. Pathologists could not be blinded to stillbirth/live birth status because of the need to perform both clinical and research placental examinations, which was yet another limitation. The placental findings associated with stillbirth have been well evaluated [10, 15–18, 28–30]. However, these studies could not determine the true association of placental pathology to stillbirth because of the lack of control group. A few studies lacked standardized placental examination protocols and failed to consider the GA of the stillbirth. Moreover, the study group did not reflect the general population of stillbirths and live births. Our study attempted to address these weaknesses. The data we found will allow clinicians to interpret placental findings of stillbirths. This can provide meaningful explanations to parents. Though we could find no placental lesion, which was exclusively found in stillbirths, the clinician can comment about the frequency of a finding by describing about the lesion prevalence. The strength of association between a placental lesion and stillbirths could be explained using the ORs and associated maternal and infant characteristics described previously. In conclusion, our study compares a population of stillbirths with live births who weighed >1 kg, analysing the differences in placental characteristics. We confirm that stillbirths do have significant placental histopathological abnormalities compared with age-matched live births. The identification of these abnormal placental patterns could provide information about the etiopathogenisis in stillbirths of unknown aetiology. ACKNOWLEDGEMENTS The authors thank the Dean, Seth GS Medical College and KEM hospital, Mumbai for permitting them to publish the manuscript. The authors also acknowledge the Department of Obstetrics and Gynaecology, KEM hospital for helping in the participant enrolment. REFERENCES 1 Facts about still birth . Prevention Cfdca, ed. Vol CDC 24/7; saving lives, protecting people, 2015 . 2 Cousens S , Blencowe H , Stanton C , et al. National, regional, and worldwide estimates of stillbirth rates in 2009 with trends since 1995: a systematic analysis . Lancet 2011 ; 377 : 1319 – 30 . Google Scholar CrossRef Search ADS PubMed 3 Reddy UM. Prediction and prevention of recurrent stillbirth . 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J Obstet Gynaecol 2009 ; 29 : 225 – 8 . Google Scholar CrossRef Search ADS PubMed 30 Helgadottir LB , Turowski G , Skjeldestad FE , et al. Classification of stillbirths and risk factors by cause of death–a case-control study . Acta Obstet Gynecol Scand 2013 ; 92 : 325 – 33 . Google Scholar CrossRef Search ADS PubMed © The Author(s) [2018]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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Journal of Tropical PediatricsOxford University Press

Published: Feb 6, 2018

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