Placental histopathological abnormalities in adverse obstetric outcomes: a retrospective cross-sectional study at Sultan Qaboos University Hospital

Abstract

Introduction

Placenta is a vital organ with highly specialized functions. According to the Perinatal Section of the Pediatric Pathology Society, placental histopathological abnormalities are typically categorized into maternal vascular hypoperfusion, fetal thrombotic vasculopathy, and inflammatory lesions. This study aims to assess the placental histopathological abnormality results in relation to adverse obstetric outcomes and to investigate whether specific placental abnormalities are associated with particular adverse outcomes.

Methods

A retrospective cross-sectional study was conducted between January 2017 and January 2020 including all women who were admitted to Sultan Qaboos University Hospital with an adverse obstetric outcome who met the inclusion criteria, and whose placentas were sent for histopathological examination.

Results

A total of 191 women were included in the study. The most common adverse obstetric outcomes included preterm labor (25.1%), fetal growth restriction (FGR) (19.4%), preeclampsia and related complications (15%), placental abruption (14.1%), and chorioamnionitis (14%). 74% of women had abnormal placental findings. Among women with preterm labor, inflammatory lesions were present in 56.3% of cases (p = 0.006). Fetal thrombotic vasculopathy lesions were present in 13.5% of FGR cases (p = 0.037). In preeclampsia cases, maternal under perfusion lesions were present in 79% of cases (p = 0.013).

Conclusion

Placental histopathological examination is an important tool for assessing perinatal outcomes. Correlating placental findings with specific obstetrical conditions and adverse outcomes provides valuable information that can assist obstetricians in developing appropriate management plans for future pregnancies.

Introduction

Placenta is a vital organ with highly specialized functions. It supports fetal growth and development throughout pregnancy. It has immunological functions that play an important role in fetal protection from infections and harmful substances [1]. The placental barrier consists of four layers: syncytiotrophoblast, cytotrophoblast, extraembryonic mesoderm (connective tissue) and fetal vascular endothelium in the early stages of pregnancy to increase its protection during early embryonic development. However, its thickness decreases, consisting of only two layers, the outer and inner layers, in the later stages in response to the increasing requirements of the developing fetus for nutrients. This barrier protects the fetus from most microorganisms. However, they can be affected by the pathological lesion with subsequent decreased immune protection of the fetus [2].

An abnormal placenta can lead to a wide range of adverse obstetric events including fetal growth restriction, intrauterine fetal death, pre-eclampsia, preterm labor and placental abruption. These events increase maternal and fetal morbidity and mortality and carries a risk of recurrence in subsequent pregnancies [3].

In cases of adverse obstetric events, histopathological examination of placenta can provide valuable information about the underlying pathological process that led to the event and helps in formulating an appropriate plan of care in subsequent pregnancies to prevent recurrence [3]. The first effort that has been made to classify the abnormalities found in placenta histopathological examination was in 1999 by the Perinatal Section of the Society for Pediatric Pathology in the United States. They have broadly classified the placenta histopathology lesions into maternal vascular hypoperfusion, fetal vascular obstruction, and amniotic fluid infection [4]. The 2016 Amsterdam criteria for categorizing placental lesions, have been established by experts in perinatal pathology worldwide, and agreed on four major patterns of placental injury: maternal vascular malperfusion, fetal vascular malperfusion, acute chorioamnionitis, and villitis of unknown etiology [5].

Recent studies indicate that placental abnormalities such as maternal vascular malperfusion, accelerated villous maturation, and placental infarctions are strongly associated with fetal growth restriction (FGR). These abnormalities result in a compromised blood flow between mother and fetus, limiting the placenta’s ability to support fetal development and often leading to smaller fetal size and potential neonatal complications [6].

A retrospective study by Ogunyemi and others, involving placenta histopathology results of 774 preterm neonates who delivered between 24 and 32 weeks, found that histological chorioamnionitis significantly increased the risk of preterm delivery and neonatal mortality. Moreover, they found that vascular and coagulation placental findings increased the risk of necrotizing enterocolitis of the neonate [7]. In 2013, a prospective study carried out by Ch et al. assessing the placenta in both fetal growth restriction and fetal demise, found that 74.1% of women with fetal demise and 66.7% of women with fetal growth restriction had placenta histopathological abnormalities with uteroplacental insufficiency and acute inflammation being the leading identifiable abnormalities in both groups [8]. Another retrospective study published in 2016 by Man and others, aimed to assess the histopathological placental findings in stillbirth. Their study results showed that abnormalities of the placenta, cord or membranes were the cause of death in 32% of cases while ascending infection was present in 19% of cases [9]. A systematic review and meta-analysis, published by FALCO and others in 2017, found that the incidence of both placental villous and vascular histopathological lesions was four- to seven-fold higher in pre-eclamptic than in normal pregnancies [10].

In Oman, few published studies that assessed the incidence and perinatal outcomes of various adverse obstetric events including preterm labor and stillbirth. Notably, no prior studies have examined the placenta histopathological findings in relation to these adverse events. We aimed to evaluate the placental histopathological abnormalities associated with adverse obstetric outcomes and to investigate the relationship between specific adverse obstetric outcomes and corresponding placental histopathological findings.

Methods

A retrospective cross-sectional study was conducted after obtaining ethical approval from the Medical Research Ethics Committee (MREC), College of Medicine and Health Science in Sultan Qaboos university with MREC# 2184. Informed consent was not sought for the present study because it was a retrospective chart review without declaring any patient identity or information. All pregnant women from 16 to 41 weeks of gestation, who were admitted to Sultan Qaboos University Hospital delivery suit between January 2017 and January 2020 with adverse obstetric outcomes were included in the study. Their placentas were submitted for histopathological examination after delivery in alignment with the hospital’s protocol. The total number of deliveries was around 4000 per year during the study period. The protocol at our institution recommends sending the placenta in all cases where the pregnancy was complicated by an adverse outcome, including fetal growth restriction, intrauterine fetal demise, pregnancy associated hypertensive disorders, preterm labour, etc. Pregnant women with multiple gestations, a history of molar pregnancy, confirmed congenital or chromosomal abnormalities, first trimester pregnancy loss or placenta ultrasonographic abnormalities (except placenta accreta spectrum) were excluded from the study. Ultrasonographic placental abnormalities were excluded due to inconsistencies in assessments across practitioners and sonographers, and the lack of a standardized reporting system at the time. Additionally, some patients underwent their detailed ultrasound evaluation at other institutions, limiting the availability of complete information for those cases. The placenta was delivered spontaneously by controlled cord traction, placed in formalin immediately after delivery and submitted to the pathology lab within 24 h. All placentas were examined macroscopically. This included examining the umbilical cord for number of vessels, insertion, coiling, membranes for their appearance. Following this sectioned placenta weight was taken then the placenta is serially sliced. Maternal and fetal and cut surfaces of placenta were examined for lesions such as infarctions. The sample size was calculated assuming the prevalence of placental abnormalities in adverse obstetric outcomes to be 20% (p = 0.20), and for a 95% confidence level with a 5% margin of error (d = 0.05).

$${\rm{n}} = {{{{\left({1.96} \right)}^2}\left({0.20} \right){\rm{ }}\left({0.80} \right){\rm{ }} = {\rm{ }}3.8416.{\rm{ }}0.16{\rm{ }} = {\rm{ }}{{246.65}^2}} \over {{{\left({0.05} \right)}^{2 }}\,\,\,\,0.0025}}$$

So, approximately 247 participants are needed for this study to detect a prevalence of 20% with 95% confidence and a 5% margin of error.

After applying inclusion and exclusion criteria on a total of 247 pregnant women, 191 were included in our study. Fifty-six cases were excluded, 25 cases of multiple gestations, nine cases with fetal congenital anomalies, five cases with sonographic placenta abnormalities, 11 cases with previous history of molar pregnancy and two cases who had preterm delivery by cesarean section due to purely maternal indications, sickle cell disease and lung cancer. Four cases had missing placenta histopathology report. See flow chart (Fig. 1).

Fig. 1

Flow diagram of patient’s inclusion and exclusion criteria

The patients’ information was obtained from the delivery suite registry and electronic patient records. Data collection sheet was designed to obtain the following information: (1) Maternal demographics (age, gravidity, parity, blood group, past medical and obstetric history), (2) Current pregnancy adverse event (i.e., the indication for placental histopathological examination), (3) Delivery details (gestational age, mode of delivery, baby details, Neonatal Intensive Care Unit (NICU) admission) and (4) Placenta histopathology findings. See Appendix 1 (supplementary material).

Preterm labor was defined as the onset of labor before 37 weeks of gestation. It is characterized by regular contractions leading to cervical changes before the full-term pregnancy [11]. Fetal Growth Restriction (FGR) was defined as a fetal weight below the 10th percentile for gestational age [12]. Intrauterine fetal death (IUFD) is defined as the death of a fetus at or after 20 weeks of gestation but before or during delivery. It is also referred to as stillbirth [13]. Preeclampsia is a pregnancy-specific hypertensive disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation [14].

Following the 2016 Amsterdam criteria [5], placenta histopathological abnormalities were divided into three groups: (1) Maternal vascular under-perfusion, (2) Fetal thrombotic vasculopathy and (3) Inflammation. Maternal vascular under-perfusion lesions were consisted of small chorionic villi, villous hypoplasia, hypermature villi, infarction, ischemia, hemorrhage, necrosis, congestion, increased syncytial knots, fibrin deposition and chorangiosis [15]. The lesions kept under the fetal thrombotic vasculopathy group were fibromuscular sclerosis, chorionic vessel thrombi, avascular villi, intramural vascular fibrin deposition, hemorrhagic endovasculitis, villous stromal-vascular karyorrhexis and villous edema. Lastly, the inflammatory group composed of chorionic plate inflammation, villitis or intervillitis, vasculitis, chorioamnionitis, subchorionitis, deciduitis and funisitis. See Appendix 2 (supplementary material) [16].

Data analysis was performed using Statistical Package for the Social Sciences (SPSS), version 28 and Microsoft Excel. Fisher Exact test was used for measuring the statistically significant relationship between a placenta histopathological abnormality and adverse obstetric outcome. A p value of < 0.05 was determined to be statistically significant.

Results

We included 191 women in our analysis, The median maternal age was 31 years (range: 17–47 years), while the median gravidity and parity were three (range: 1–15) and one (0–9) respectively. The median gestational age at delivery was 34 weeks (range: 17–41 weeks), while the median birth weight of the neonates was 1820 g (range: 140–4435 g) (Table 1).

Table 1 Maternal demographics

Total of 10 different adverse obstetric events were recorded in our study that indicated placental histopathological examination. The most common adverse events were: preterm labour (25.1%), fetal growth restriction (FGR) with or without abnormal Doppler studies or oligohydramnios (19.4%), gestational hypertension, which included pre-eclampsia, eclampsia and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (15%), placental abruption (14.1%) and chorioamnionitis (14%). Intrauterine fetal death (IUFD), second trimester pregnancy loss, which is pregnancy loss before 24 weeks of gestation and fetal bradycardia requiring admission to NICU, were noted in 18 (9.4%) of cases each. Other less frequent indications were adherent placenta and placenta previa (5% and 4% respectively). (Table 2).

Table 2 List of adverse obstetric outcomes reported and percentage of abnormal placenta histopathology

Placenta histopathology was abnormal in 141 (74%) cases. Further details of the abnormal placenta histopathology for each adverse obstetric outcome are shown in Table 2. Of note, abnormal placenta was found in 56 to 88.5% for the various adverse obstetric outcomes, the lowest being the adherent placenta and the highest for chorioamnionitis cases.

The type of placenta histopathology abnormality in relation to each adverse obstetric outcome is shown in Table 3. Among women with preterm labor, inflammatory lesions were present in 56.3% of the cases and it was statistically significant (p = 0.006) while maternal vascular under-perfusion lesions were present in 35.4% of the cases and it was also statistically significant (p = < 0.001). For FGR cases, maternal vascular under-perfusion lesions were present in 59.5% while fetal thrombotic vasculopathy lesions were present in 13.5%. Both were statistically significant with p values of 0.002 and 0.037 respectively. Inflammatory lesions were present in 8.3% of FGR cases. For pre-eclampsia, eclampsia and HELLP syndrome cases, maternal vascular under-perfusion lesions were present in 78.6% of them and it was statistically significant (p = 0.013) while 14.3% of the cases had inflammatory lesions (p = 0.003). Fetal thrombotic vasculopathy lesions were noted in 7.4% of placental abruption cases (p = 0.019) while maternal vascular under-perfusion and inflammatory lesions were present in 59.3% and 18.5% of cases respectively. Cases with suspected chorioamnionitis were confirmed histopathologically by presence of inflammatory lesions in 73.1. % (p < 0.001). Maternal vascular under-perfusion lesions were present in 53.8% of chorioamnionitis cases. 72% of IUFD cases had maternal vascular under-perfusion lesions and 56% of the cases had inflammatory lesions. Moreover, inflammatory lesions were present in 61.1% of cases with second trimester pregnancy loss (p = 0.012). Maternal vascular under-perfusion lesions were present in 72.2% of cases with second trimester pregnancy and fetal bradycardia, 33.3% with adherent placenta and 57.1% with placenta previa.

Table 3 Types of placental histopathology lesions in each adverse obstetric outcome

For the mode of delivery, 52% delivered vaginally while 48.2% delivered by cesarean section. One hundred fifty-one were live born babies. Among those, 101 (67%) required NICU admission. Further details about mode of delivery and percentage of neonates requiring NICU admission in relation to each adverse obstetric outcome is shown in Table 4.

Table 4 Perinatal outcomes and adverse obstetric event

Discussion

Histopathological examination of the placenta in cases of adverse obstetric outcome is crucial. It provides valuable information to obstetricians, neonatologists, and pediatricians. Sending the placenta to histopathology laboratory for evaluation should align with and be interpreted in the context of the patient’s clinical condition. This correlation helps ensure that findings from placental analysis are meaningfully integrated into the overall assessment, aiding in understanding potential impacts on maternal and fetal health [3]. There are specific clinical situations and conditions that are suggested by experts that require placental examination [17, 18]. In our study, placenta histopathology was abnormal in 74% of women with various obstetric outcomes. Studies have shown that presence of severe features of maternal vascular malperfusion lesions can carry 10–25% risk of recurrence in subsequent pregnancies [19]. Same risk of recurrence is also found in spontaneous preterm birth with histological chorioamnionitis [20]. This valuable information can assist the clinician to formulate appropriate plan of care in subsequent pregnancies. A retrospective cohort study by Romero and others, looked at the placental histopathologic lesions in a normal pregnancy outcome. Histopathological features of inflammatory or vascular lesions were present in 77.8% of cases. However, severe form of lesions was infrequent. The presence of these lesions in pregnancies with normal outcome were contributed to two possible reasons: (1) It could have been associated with parturition process or (2) It didn’t affect the course of pregnancy as it was mild and subclinical to cause any effect [21].

Our study has shown that in cases of preterm labor, half of them had placental inflammatory lesions and this was statistically significant. This is in the line with multiple previous studies including Ogunyemi et al. study that found a significant increase risk of preterm delivery and neonatal mortality in the presence of histological chorioamnionitis [7]. Their study had shown also increased risk of different prematurity complications including intraventricular hemorrhage, bronchopulmonary dysplasia, retinopathy and neonatal sepsis in comparison to preterm delivery cases without chorioamnionitis (OR: 2.2, 2, 1.8 and 2.5 respectively). Other two previous studies, that assessed placental pathology in cases with recurrent preterm delivery, had shown that inflammatory lesions were more associated with recurrent preterm deliveries [20, 22]. This could be contributed to pre-pregnancy endometrial infection rather that ascending infection during pregnancy [22].

With regards to FGR cases, our study found that placenta histopathology was abnormal in 65% of cases with statistically significant presence of maternal vascular under-perfusion and fetal thrombotic vasculopathy lesions. Ch et al., reported a similar figure of abnormal placental histopathology in FGR cases (66.7%).⁸ In a prospective case-control study, evaluating placental findings in small for gestation (birth weight below the 10th percentile), who delivered after 34 weeks of gestation and without Doppler signs of placental insufficiency, found that 21.8% of placentas were normal histologically. Maternal and fetal hypo-perfusion lesions were found in 64% and 15.5% of cases respectively [23]. Placenta weight in FGR cases was not evaluated in our study. However, multiple previous studies had shown that placenta weight was less than 10th percentile in at least half of those cases [8, 23]. A study by Günyeli and others, identified two types of lesions that were present and statistically significant in FGR cases: placental infarction and chorionic intravascular thrombi [24]. Placental infarction should be more than 10–20% of the placental volume to cause an effect [25]. These lesions represent features of defective extravillous trophoblast invasion which could lead to insufficiency in uteroplacental blood supply [26, 27].

Presence of maternal vascular hypo-perfusion lesions in cases of pre-eclampsia and its complications, eclampsia and HELLP syndrome, was statistically significant. Falco and others published a systematic review and meta-analysis assessing placental histopathological lesions in pregnancies complicated by pre-eclampsia [10]. They found that both placental villous and vascular histopathological lesions were four to seven-fold higher in pre-eclamptic than in normal pregnancies. They questioned whether these lesions are the cause of pre-eclampsia or it’s the effect of the disease itself. However, these placental lesions are not specific to the diagnosis of pre-eclampsia and it could have been overestimated. They explained this by the unblinded methodology used in the studies included, and in fact that these placental lesions can also occur in other pregnancy complications like FGR and recurrent pregnancy loss. Orabona et al., in their retrospective cohort study, evaluated the placenta histopathology in early-onset (< 34 weeks) and late-onset (> 34 weeks) pre-eclampsia cases [28]. The incidence of abnormalities was more in early-onset group in comparison to late-onset group. Interestingly, they found a significant relationship between uterine artery (UtA) Doppler velocimetry and different placenta histopathology lesions which were under maternal vascular malperfusion category, i.e., distal villous hypoplasia, decidual arteriolopathy, villous infarcts, syncytiotrophoblast knots, microcalcifications, perivillous fibrin deposition and placental hemorrhage, in which p value was < 0.05 [28, 29]. This suggests that placenta pathology can be a strong contributor to pre-eclampsia cases.

Placenta histopathology was abnormal in 83.3% of our cases with placental abruption. Maternal vascular hypo-perfusion lesions presented in nearly third of our cases while inflammatory lesions presented in 11.1% of cases. Gonen et al., assessed placenta histopathology in early-onset (< 34 weeks) and late-onset (> 34 weeks) placental abruption cases. They found that maternal vascular malperfusion lesions, inflammatory lesions and placental hemorrhage were more frequent in early-onset group [30]. Chen and others found that 58% of placental abruption cases was confirmed by placenta histopathological examination [31]. Maternal surface indentation and intravillous hemorrhage were the most frequent lesions found, both are features of maternal vascular malperfusion. These findings confirm the causative association between uteroplacental insufficiency and placental abruption. Moreover, presence of inflammatory lesions noticed to be more in acute cases of placental abruption in compared to chronic cases [32].

The etiopathogenesis of fetal thrombotic vasculopathy lesions in placenta is still not fully understood. Mostly explained because of what is called Virchow’s triad, which includes: hypercoagulable state, endothelial cell injury and blood flow stasis [3]. An interesting finding in our study, was the presence of fetal thrombotic vasculopathy lesions in FGR and placenta abruption cases with small percentage not exceeding 10% (8.3% and 7.4%. respectively) but it was of statistical significance. A similar pattern of results was demonstrated by Lepais et al., where they found higher frequency of fetal thrombotic vasculopathy lesions in obstetric complications, including FGR (OR 5.440), in compared to normal pregnancy [33]. Leistra et al., also found an association between fetal thrombotic vasculopathy lesions in the placenta and neonatal thrombosis, beside its association with adverse obstetric outcome like pre-eclampsia and FGR [34].

For IUFD, only 18 cases were included in our study. Placenta histopathology was abnormal in 83.3% of cases. A close figure was reported by a prospective study examining 27 placentas with fetal demise (74.1%).⁸ However, a systematic review by Ptacek and others, found a wide range of reported percentages of abnormal placenta in IUFD cases, 11 to 60%. This was interpreted by the variety of classification system used to describe placental lesions in which an ideal international consensus on terminology and criteria to classify placental lesions is suggested by authors [27]. In another study, the cause of IUFD was primarily contributed to placenta pathology in 32% of cases [9]. Maternal vascular malperfusion was the dominant placental abnormalities found especially massive perivillous fibrin deposition, which is similar to our results. Many IUFD cases remained unexplained despite the presence of different lesions in the placenta histopathological examination, as these lesions were of uncertain significance, and it can overlap in cases with normal pregnancy outcome [8, 9].

In our study, inflammatory lesions were present in almost two-third of second trimester pregnancy loss cases while one-third had maternal vascular hypo-perfusion abnormalities. Srinivas et al., reported presence of stage 2–3 inflammatory response in 67% of cases with second trimester pregnancy loss [35]. Similarly, Heller and others reported the presence of histologic acute chorioamnionitis in 56.7% of cases with second trimester loss [36]. Odendaal et al., assessed the placenta histopathology abnormalities in pregnancy losses before 22 weeks of gestation. Maternal vascular malperfusion came as the second most prevalent finding, after histologic abruption, followed by acute chorioamnionitis [37, 38]. The similarity in the results of various studies confirms that placental inflammation and defective placentation plays an important role in the pathogenesis of second trimester pregnancy loss.

Limitations

Our study included some limitations. As it was conducted retrospectively, few data were missed such as gross placental examination and placental weight. Small numbers were included for some of the adverse events. Moreover, placenta histopathology reporting was carried out by different pathologists, in which different terminologies were found and needed to be classified into the three groups of placental lesions.

For future studies, we recommend conducting a case-control study with a larger sample size including multiple centers.

Conclusions

Histopathological examination of the placenta revealed abnormalities in 74.0% of women with adverse obstetrical outcomes, underscoring its importance as a tool for evaluating perinatal outcomes. Correlating histopathological findings with clinical conditions and adverse outcomes is essential, as these insights can guide obstetricians in managing future pregnancies.

Establishing hospital protocols for when to conduct placental histopathological examination can further enhance patient care and improve outcomes.