Clinicopathological audit of the placenta in fetal growth restriction

Clinical details

In our study, the maternal age of the babies born with FGR ranged from 20 to 39 years. The average maternal age was 26.97 ± 4.18. FGR babies were seen more in primigravidas (60.49%) than in multigravidas. The mean POG was 35.76 ± 2.86. More than half of the babies (56.8%) were born pre-term, with 43.2% being born at term. Breech presentation was noted in 6.17% of cases.

On the basis of clinical history, ultrasonography findings, and other hematological investigations, the causes of IUGR were divided into maternal, fetal, placental, and unknown [Tables 1-3]. Of the total, definite underlying causes of FGR could be identified in 64 cases, of which 44 cases showed only maternal causes of FGR, 10 showed only fetal causes, and 31 had only placental causes. Among these, 2 cases showed all three abnormalities, i.e., maternal, fetal, and placental, while 14 cases had maternal and placental causes, 2 had maternal and fetal causes, and 2 had fetal and placental causes simultaneously. In 17 cases, the cause of FGR remained idiopathic.

Overall, and among the maternal causes, pregnancy-induced hypertension (PIH) and bad obstetric history (BOH) were the most common. Absent end diastolic flow (AEDF) on color Doppler evaluation was the most common underlying placental cause, and meconium-stained liquor (MSL) was the most common fetal finding.

Placental histopathological findings

The placental weight ranged from 154 g to 700 g, with the average weight being 367.86 g. Only 3.7% (3/81) of cases had a placental weight <200 g. A single diamniotic dichorionic placenta was received. Eccentric insertion was noted in 52 (64.19%) of the 81 cases. The histopathological findings of the placentae [Figures 1 and 2] observed are summarized in Table 4. The placenta was found to be normal in 15 (18.5%) cases. MVM was seen in 18/81 cases (22.2%), FVM in 12/81 (14.8%) cases, and inflammatory lesions were seen in 14/81 cases (17.3%). None of the cases of gestational diabetes mellitus (GDM), PIH or rhesus incompatibility showed either FVM or MVM.

Close

Figure 1:

Photomicrographs of H&E sections from placenta showing a- prominent syncytial knots (blue arrow) (400x), (b) chorangiosis (200x), (c) decreased number and vascularity of villi (200x), (d) infarct (100x), (e) prominent syncytial knots and intervillous hemorrhage (200x), (f) fibrotic villi and calcification (yellow arrow, black arrow) (200x).

Export to PPT

Close

Figure 2:

Photomicrographs of H&E sections from placenta showing (a and b) fibrotic villi with perivillous fibrin (200x and 400x), (c) infarct (200x), (d)-meconium macrophage (400x) and (e) and f-chorioamnionitis (200x and 400x).

Export to PPT

Six placentas met the early-onset FGR criterion (mean gestational age 29.7 ± 1.2 weeks). Mean trimmed placental weight was 143 ± 77 g. Two-thirds of the cases (4/6; 66.7%) had a recorded maternal clinical factor (e.g., pre-eclampsia or chronic hypertension), one-third (2/6; 33.3 %) showed a coded placental complication (e.g., abruptio placentae), and no fetus-specific complications were documented. Histologically, all early FGR placentas displayed widespread MVP signatures-macro-/micro-infarction, retro-placental hemorrhage, heavy intervillous/perivillous fibrin deposition, and accelerated villous maturation–with universal (>90%) prominence of syncytial knots and distal villous hypoplasia. Seventy-five placentas fell into the late-onset group (mean gestational age 36.3 ± 1.1 weeks). The mean placental weight was slightly higher at 165 ± 102 g. A maternal contributing condition was present in just over half the cohort (41/75; 54.7%), fetus-centered factors in 10/75 (13.3%), and placental complications in 29/75 (38.7%). Histopathology again revealed a high burden of malperfusion lesions– intervillous/perivillous fibrin, infarcts, syncytial knotting–but with greater morphological heterogeneity; inflammatory lesions (villitis/chorioamnionitis) and calcification were more frequently recorded than in the early group.

Placental pathology in maternal causes

A total of 44 of 81 cases showed only a maternal cause for FGR. These included cases in which the same patient had several varying predisposing factors, for example, there was one case of BOH associated with Rh incompatibility, one case of BOH with GDM, and another with BOH with GDM and gestational hypertension (GHTN). Also noted were cases with intrahepatic cholestasis of pregnancy (IHCP) and gestational hypothyroidism, and IHCP with thrombocytopenia and systemic lupus erythematosus. There was also a case of pre-eclampsia with hyperparathyroidism, hypothyroidism, and vitiligo.

Overall, the most common maternal causes included PIH (11/81) and BOH (11/81). Among women with PIH, preeclampsia (9/11) was more common than GHTN (2/11). In these women with PIH, 2 cases were also found to have anhydramnios, and 2 had oligohydramnios. On average, the placentae of women with PIH were smaller in size. Microscopic examination of these placentae revealed the presence of prominent syncytial knots, infarcts, calcification, occasional fibrotic villi, and ectatic blood vessels. These findings are compatible with those described in PIH placentae in previous studies.^[20,21]

Of the 11 women with BOH, 2 cases were associated with GDM (of which one was also associated with GHTN), 1 case with Rh incompatibility, and a single case was also associated with the presence of polyhydramnios. All of these women were at term and were between 25 and 35 years of age. On microscopic examination, similar to previous studies, we found the presence of fibrin deposition and intervillous hemorrhage, with a few cases showing the presence of calcification, distal villous hypoplasia, prominent syncytial knots, avascular and hypovascular villi, infarcts, retroplacental hematoma, and even congested villi.^[22]

Shinde et al., however, reported anemia to be the most common cause in their study; though they also found PIH to be a common cause (12%), which is similar to the 13.5% incidence in our study.^[20] Furthermore, other studies conducted in India and surrounding countries have reported a higher incidence of PIH in IUGR cases.^[18,23]

Of the remaining causes, GDM was the most common (6/81). Apart from the cases associated with BOH, a single case of GDM also showed the presence of placenta accreta with a bilobed placenta. Two of these cases were preterm, and the rest were term. Microscopically, they showed evidence of fibrin deposition, calcification, prominent syncytial villi, chorioamnionitis, and occasionally, congested villi with stromal edema. These findings are compatible with those reported previously.^[22]

Rh incompatibility was noted in 4/81 cases, of which one case also showed the presence of oligohydramnios. In these cases, only fibrin deposition in the villi and at the membranes was noted.

Amongst cases with hypothyroidism (4/81), microscopic examination revealed fibrotic villi with prominent syncytial knots and calcification. In the single case that was associated with pre-eclampsia, fewer villi and ectatic blood vessels was also noted. Kumari et al. have reported similar findings in the placenta of mothers with hypothyroidism.^[24]

Placental pathology in placental and fetal causes

AEDF was noted in 9 cases (11.1%) and was associated with fibrotic villi, intervillous hemorrhage, decreased number of villi, calcification, chorionitis, and vascular luminal narrowing. Abnormal ultrasound Doppler indices, especially AEDF, have been reported in conditions with fetal hypoxia and often lead to perinatal mortality. The histological findings associated with AEDF, as also seen in our study, could be due to a defect in terminal villous development and response to chronic vasoconstriction.^[25]

Of the 81 cases with FGR, 7 cases (8.6%) showed oligohydramnios. The major microscopic features noted in these cases include fibrotic villi with focal calcification, chorioamnionitis, vascular luminal narrowing, and ischemia.

Cases with anhydramnios (6/81, 7.4%) were all at term, except for a single case, which was associated with premature rupture of membranes (PROM) and hence, also leakage per vaginum. Microscopically, they showed the presence of fibrotic villi, calcification, prominent syncytial knots, chorangiosis with congested villi, and subchorionic fibrin plaque deposition.

The incidence of oligohydramnios and anhydramnios reported by Thekkedathu was higher than that observed in our study, even though they had a smaller sample size.^[18] This could be due to regional variations and other causes related to individual pregnancies, for example, the presence of PROM and leakage.

MSL was the most common fetal condition associated with these IUGR cases. MSL may occur due to placental insufficiency, maternal hypertension (including preeclampsia), oligohydramnios, maternal drug abuse, and fetal hypoxia. In our study, one case showed MSL due to bladder rupture in the fetus, and another case was associated with the presence of a low-lying placenta. Microscopically, these showed the presence of meconium macrophages in the membranes. They also showed the presence of fibrotic villi, calcification, and intervillous hemorrhage. Occasional cases showing deciduitis, chorionitis, and decreased vascularity of villi were also noted. These findings are suggestive of longstanding fetal hypoxia, which could be due to a variety of causes, including anhydramnios.

The overall histological features found in FGR placentae in our study included fibrin deposition, calcification, prominent syncytial knots, villous infarctions, inflammation, and vascular abnormalities, depending upon the underlying cause. These findings are similar to those described in previous studies.^[18-20]

Most of our cases showed MVM, which is also reflective of the fact that the majority of our cases had maternal causes leading to FGR, and that PIH, which is known to cause vascular abnormalities, was a major contributor in our cases. Idiopathic cases (20.9%) formed the second largest group, indicating the need for further workup, evaluation, and research into the possible causes of FGR. Our 22% rate of MVM aligns with the 20–30% spectrum summarized by Sun et al. in their systematic overview of placental findings in FGR.^[11] Shinde et al. also reported 24.6% cases in whom no identifiable cause was found, which is similar to our findings.^[20] Inflammatory lesions were another leading finding; however, these were usually seen in term cases, where the FGR was not as severe as compared to those with MVM and FVM. Further, 18.5% of our cases had normal placentae, which has also been seen in previous studies. We did not find comparable studies that categorized histological lesions on the basis of FVM, MVM, inflammatory, and idiopathic in FGR cases.

In our study, placentas from early-onset FGR showed a uniform pattern of diffuse MVM, i.e., lower weight, widespread infarction, and dense intervillous fibrin. This high-MVM profile is similar to the description by Sun et al.^[11] The high rate of pre-eclampsia and chronic hypertension in these mothers points to a primary maternal vasculopathy. Taken together, the data support severe placental under-perfusion – not inflammation – as the main driver when growth restriction presents before 32 weeks.

Beyond 32 weeks, the pathology broadens. MVM persists, but villitis, calcification, and focal abruptions appear more often, and placental weight rises modestly–signs of partial compensation. Only half of the mothers had hypertensive disease, suggesting that sub-clinical placental ageing and low-grade inflammation, rather than overt vasculopathy, precipitate late-onset growth restriction. Sun et al. reached a comparable conclusion.^[11] Clinically, early FGR warrants intensive Doppler surveillance, whereas late-onset disease may need a combined Doppler-plus-biomarker approach.

The major limitation of our study was the lack of clinical details in a few patients due to incomplete filling of the histopathological requisition form, and the lack of follow-up of these patients due to the outbreak of the COVID-19 pandemic during the study. Our sample size was also limited due to the restriction of the patient population at our center, as it was converted into a partially dedicated COVID-19 center.