Placental Pathology in Severe Pre-eclampsia and Eclampsia

Introduction: Hypertensive disorders complicating pregnancy contribute significantly to maternal and perinatal morbidity and mortality. Since placenta is the functional unit between the mother and fetus examination of placenta can give an idea about prenatal experience of fetus. The aim is to observe the morphology and histopathology of placenta in pregnancy with severe preeclampsia / eclampsia between 20-42 weeks of gestation.

Hypertensive disorders complicate 5-10% of all pregnancies, and contribute greatly to maternal morbidity and mortality.Of these disorders, the preeclampsia syndrome, either alone or superimposed on chronic hypertension (HTN) is the most dangerous. 1acenta has been described as a "diary of intrauterine life". 2 Pregnancy complications like HTN are reflected in the placenta in a significant way (both macroscopically and microscopically).The inadequate trophoblast invasion of maternal spiral arteries leading to decreased placental perfusion is associated with the changes seen in the placenta of pre-eclamptic women. 3Foetal growth is essentially dependent on formation and full development of the placenta.As placenta is a mirror which reflects the intrauterine status of the foetus, examination of placenta gives a clear idea of what had happened with it, when it was in the mother's womb and what is going to happen with the foetus in future. 4,5w pregnancy incites or aggravates HTN remains unsolved despite decades of intensive research.As there is relationship between abnormal placentation and preeclampsia (PE) a thorough study of placenta is indispensible to evaluate possible etiological factor.Despite observed link between placenta and newborn health, examination of placenta is seldom performed in institutions, so the present study was carried out to analyze and study the morphometric features, gross and histological changes of placenta in severe preeclampsia and eclampsia.

MATERIALS AND METHODS
The study was a prospective, descriptive study, conducted in the Department of Obstetrics and Gynaecology and Department of Pathology, Tribhuwan University Teaching Hospital, TUTH in Kathmandu, Nepal for one year from 15 th May 2015 -14 th May 2016.Permission was obtained from institutional review board to conduct the study.All singleton pregnancies ( live or IUFD) between 20-42 weeks with severe preeclampsia/eclampsia were included in the study, exclusion criteria being multiple pregnancies, pregnancies with GDM, vascular disorders, renal disease, connective tissue disease, chronic HTN, heart disease and congenital malformations.The placentas from both vaginal and cesarean deliveries were included.Immediately after the delivery, weight (wt) of the baby was taken.Once the placenta was delivered, it was washed in the running tap water.Any abnormality of the placenta and cord was noted.Umbilical cord was cut at its placental site of insertion and placental wt was measured in grams.As the shape of placenta is not always circular, diameter was taken along two axes perpendicular to each other and average diameter was taken.Placental area was calculated using the following formula: Area = πr 2 .Placental volume was measured by using the water displacement technique.Gross examination of placenta was done for the presence of infarction, calcification, retroplacental hematoma and chorangioma.These findings were confirmed by the pathologist once the placenta was delivered to pathology department.Placenta was preserved in 10 % formalin solution and then transported to Department of Pathology.Samples were taken from the insertion of umbilical cord, margins 3, 6, 9, 12 O' clock positions, centre of the placenta, fibrotic, calcified and infracted area and histopathological examination was done.

RESULTS
There were 4276 deliveries during the study period of which 62 were severe preeclampsia (prevalence 1.45%) and 7 were eclampsia (prevalence 0.16%).Out of 62 PE cases, only 48 meeting the inclusion criteria and all 7 cases of eclampsia were included in the study.
The placental changes were studied under the headingsplacental morphometry (Table 1).gross anatomy (Table 2) and histopathology which included villous pathology (Table 3) and stromal pathology (Table 4).Average weight of placenta was 386 gm ranging from 150 gm to 500 gm.Similarly there was a wide range of placental area ranging from 92.4 cm 2 to 240.4 cm 2 Grossly various findings were found in the placenta.Among them, infarction was seen in 12 cases (21.82%) followed by calcified area comprising of 11 (20.00%)cases (table 2).Microscopically syncytial knots were the most common findings (n=53; 96.36%) followed by fibrinoid necrosis (n=18; 3272% table 3).
In the stroma of the placenta, calcification was the most common pathology (n=52; 94.54%) followed by hyalinised areas (n=9; 16.36%).Endothelial proliferation was seen in 6(10.91%)cases.(Table 4) There was wide variation in birth weight ranging from 0.8-3.5 kg with mean birth weight of 2.37 kg.The mean fetoplacental ratio was 6.1.(Table 5) Similarly effect of anti hypertensive drugs on placental change was studied.Out of 55 patients included in the study, 45 were on anti hypertensive drugs and all 45 placentas showed histopathological changes significant to PE despite the duration and type of drug.There was also no difference in the placental changes of patients taking 500 mg or 1000 mg of calcium/day.Similarly 4 patients were on Aspirin 75 mg/day in addition to anti hypertensive drugs, who still showed placental changes.

DISCUSSION
Placenta is a vital organ maintaining pregnancy and promoting fetal development.A fetus derives its nutritional substances and obtains its metabolic and immunological requirements from the placenta.The impaired placental function in terms of abnormal placental morphology or histology accounts for the fetal and neonatal complications seen in pregnancies complicated by severe preeclampsia and eclampsia.
Incidence of severe PE was 1.45% and that of eclampsia was 0.16% which is higher than that reported by Gautam SK et al in a study conducted at the same institute in 2012. 6Higher incidence of eclampsia was noted in studies conducted at Paropakar Maternity and Women's Hospital and Patan Hospital (0.29%and 0.24% respectively). 7,8

Placental Morphometry
Placental weight: In our study the mean wt of the placenta was 386.36 gm similar to that observed by Kartha et al 5 .All the placentae from severe pre-eclampsia weighed < 500gm, the least wt recorded being 150 gm similar to a study done by Narasimha and Vasudeva. 9From all these results it can be inferred that the placental weight is reduced in pregnancies complicated by hypertension which could be due to reduced uteroplacental blood flow.

Volume of Placenta:
We found average placental volume of 353cc. 18Slightly higher value was noted in studies done by Majumdar et al 3 Vaibhav et al 11 and Kartha et al 5 This may be because these three studies included all PIH cases in contrast to our study which included only severe PE and eclampsia cases.

Gross Anatomy of Placenta
Site of Umbilical cord insertion: Abnormal cord insertion seems to be associated with impaired development and function of the placenta, and has been linked to PIH. 13 We found marginal cord insertion in 5.45 % of cases similar to a study done by Vijayalaxmi et al. 14 This finding was much less than that found by Majumdar et al in which incidence was 20%. 3 Infarction: Extensive placental infarction is usually seen in placentae from preeclamptic mothers when there is a vascular abnormality which predisposes to thrombosis. 15Infarction was the most common gross anatomical abnormality, found in our study (21.82%) similar to that by Kartha et al. 5 Incidence was 48% and 53.1 % in studies by Vijayalaxmi et al 14 and Salgadho et al. 16 Calcification: Calcification is regarded as evidence of placental senescence or degeneration.We found calcification in 20% cases.Slightly higher incidence was noted by Vassiliki et al (32.32%) 17 and Vijayalaxmi et al (35%). 14This higher incidence could be because these two studies included only late preterm and term cases in contrast to our study which included early preterm cases as well.
Retro-placental Hematoma: Retroplacental hematoma was observed in 5.45% of cases which was low compared to the study by Narasimha and Vasudeva. 9Incidence was quite high i.e. 38.88% in severe PE cases in a study by Tangirala et al. 18 Chorangioma: Chorangioma is the hemangioma of placenta and was observed in only 1 case of severe PE (1.82%) which was less than that noted by Kartha et al. 5 In a study by Ogino and Redline incidence was 0.51% and it was more commonly associated with PE, multiple gestation and prematurity. 19llous Pathology Syncytial Knots: Increased syncytial knots are associated with conditions of uteroplacental malperfusion.We found syncytial knots in 96.36% of cases, which is quite higher than that noted by Majumdar et al 3 and Kartha et al 5 Masodkar et al 20 and Avasthi et al 21 found this finding in 69% and 80% cases of PIH respectively.Syncytial knot formation being an indication of severity of PE could have been seen more in our study due to inclusion of cases of severe PE and eclampsia only.
Fibrinoid Necrosis: Fibrinoid necrosis of placental villi is a highly characteristic lesion, which is due to replacement of the villus by fibrin. 22In the present study incidence was 32.72% which is higher than that noted by Narasimha and Vasudeva9 and Kartha et al. 5 Acute Atherosis: Acute atherosis is associated with severe and early PE.The frequency of acute atherosis was 10.2% in PE in the study by Kim YM et al 23 Kartha et al noted slightly high incidence (16%) of acute atherosis. 5However none of the cases showed acute atherosis in the index study probably due to very small sample size as compared to these studies.
Hyalinised Villi: Hyalinization is villous hypovascularity, mechanism of which is not fully understood.Hyalinised villi was observed in 12.72% cases.Similar finding was reported by Majumdar et al 3 In contrast Kartha et al noted hyalinised villi in significantly high number of cases (27%). 5

Stromal Pathology
Fibrosis: Fibrosis was not seen in any of the cases in the present study.However various other studies have shown presence of fibrosis in PIH.Kartha et al found 38% cases of stromal fibrosis 5 whereas it was observed in 92% cases of toxemia in the study by Narasimha and Vasudeva. 9 Calcification: Incidence of stromal calcification was high in the present study (94.54%) whereas Kartha et al and Vijaylaxmi et al reported quite low incidence of 25% and 35% respectively. 5,24yalinised Areas: Hyalinised areas was observed in 7 cases (12.72%).This finding is consistent with the study by Majumdar et al 3 In contrast Kartha et al noted hyalinised areas in 28% of cases which was more than double the index study, which could be attributed to the larger sample size of the study.5 Endothelial Proliferation: In the present study endothelial proliferation was found in 10.91% of cases which is similar to that noted by Kartha et al. 5 Fetal Weight and Feto-Placental Ratio Fetal Weight: Mean birth wt was noted to be 2.37 kg.This finding corroborates with the studies by Madhu L et al 25 and Udaina and Jain26 with average neonatal wt of 2.1 and 2.2 kg respectively.With reference to these values it is inferred that the wt of a newborn baby is significantly low in pregnancy induced HTN due to placental insufficiency.
Feto-Placental Ratio: Also known as placental co-efficient, fetoplacental weight ratio is often used an index of placental nutritional efficacy and is related to adverse perinatal outcomes.We found mean feto-placental ratio of 6.1 which was in concordance with the study by Nag U et al 27 and Gugapriya et al 28  Kartha et al 5 So it can be concluded that the foeto-placental wt ratio is increased in PIH and that the placental wt is more severely affected than that of the foetal wt.

Antihypertensive Drugs
Although 45 patients out of 55 were on anti hypertensive drugs, all 45 placentas showed histopathological changes significant to preeclampsia.
Aspirin/Calcium: Four patients who had history of preeclampsia in previous pregnancy were kept on Aspirin 75 mg/day, who still showed placental changes.Similarly all patients took calcium, 40 took 500 mg/day and 15 took 1000 mg/day, however the histological changes were more or less similar in both groups.

Table 1 : Placental Morphometric StudyTable 2 : Gross Anatomy of Placenta
12acenta: Mean placental area was 148.57cm 2 similar to that noted by Udaina A et al.10 Unlike our study Vaibhav et al11and Ghodke S.P. et al12noted higher values, 182.84+/-56.71cm 2 and 185.04 +/-33.72 cm 2 respectively.The lower placental area in our study compared to these studies could be due to the big difference in gestational age at delivery, ranging from 28 weeks to 40 weeks 2 days.
Placental Pathology in Severe Pre-eclampsia and Eclampsia Jha A et al

Table 3 : Villous PathologyTable 4 : Stromal Pathology
Increased mean feto-placental ratio in hypertensive pregnancies compared to normotensive cases was also observed by Majumdar et al3 and

Table 5 : Fetal weight and Feto-Placental Ratio Placental
Pathology in Severe Pre-eclampsia and Eclampsia Jha A et al