Intrauterine growth restriction (IUGR) is a condition in which a fetus fails to reach its normal growth potential (1). IUGR is one of the most common pregnancy complications in developing countries, increasing neonatal morbidity and mortality (2). Its prevalence is 7%-15% globally and 30% in developing countries (including Iran) (3, 4). One of the most important causes of IUGR is early-onset pre-eclampsia (PE). Still, IUGR with normal blood pressure and without any obvious reason (i.e., idiopathic IUGR [I-IUGR]) is also common (5). IUGR in PE is 3 to 4 times more than normal. Even in some studies, PE is considered as a factor for the occurrence of IUGR (6).
PE is defined as blood pressure above 140/90 and the occurrence of proteinuria in the second half of pregnancy (7, 8). In other words, PE is a syndrome characterized by the onset of hypertension and proteinuria; or hypertension and end-organ damage that happens with or without proteinuria after 20 weeks of gestation (9). The pathophysiology of PE includes maternal, fetal, and placental factors. Placental dysfunction is generally considered to be one of the leading causes of severe cases of IUGR. PE is divided into two categories: early- and late-onset PEs. Late-onset PE is occurred at 34 weeks of gestation and is accompanied by normal fetal development. Early-onset PE occurs before the 34^th week of gestation and is characterized by IUGR (10).
The term PE/IUGR is associated with either normal or minimal pathological findings and described as maternal––and not placental––disease (11). PE and IUGR are the main reasons for perinatal mortality and morbidity (11).
PE/IUGR leads to preterm delivery before 34 weeks of gestation. Placental pathology (such as thrombotic villous) is a common finding in early-onset PE/IUGR (12).
Both early-onset IUGR and early-onset PE are indicators of placental pathology, which is associated with hypoxia and circulatory damage due to placental dysfunction and obstruction of spiral arteries. Some common injuries include infarction, inflammation, and lesions such as chronic ischemia. Maternal Hyper-tension can be associated with early-onset IUGR, which leads to abnormal Doppler (8, 13, 14).
Maternal hypertension and/or abnormal placental Doppler can be associated with early-onset IUGR, which both are associated with poor perinatal outcomes (15, 16).
Doppler studies have also illustrated that early-onset PE/IUGR is associated with affected of the spiral arteries, as these arteries’ defects can play a much lesser role near the term  (17). Motawea et al found a compelling association between high levels of α₂-adrenergic receptors (α₂-ARs) and pregnancy-related pathologies of severe PE and IUGR. Besides, Motawea claimed that human placenta-expressed α₂-ARs might be implicated in the pathogenesis of PE and IUGR (18). Hypoxia of the placenta in PE is a powerful stimulus for the vascular endothelial growth factor (VEGF).
It has been proved that the increased secretion of VEGF proteins affects hypoxia and atherosis of the placental (19). PE-induced IUGR (PE-IUGR) and I-IUGR share common histological changes, suggesting similar pathogenesis. Maternal malperfusion lesions predominated in PE-IUGR with fetal vascular malperfusion were higher in I-IUGR than in PE-IUGR. Hofbauer cells (HBCs) increased in both PE-IUGR and I-IUGR (20). Thus, it seems that PE-IUGR can be accompanied by a normal trophoblastic transformation in the first trimester and atherosclerotic changes in spiral arterioles later. Late changes lead to increased mass in placental, especially in diabetic and twin pregnancies; indeed, placental changes can be found in prolonged pregnancies, placental edema, and fetal hydrops necrosis (21, 22).  Awamleh et al. found placental microRNA (miRNA) as an effective potential factor on gene expression and pathophysiology of early-onset PE and IUGR (23).
This study was designed to compare the pregnancy outcomes and placental pathological findings in IUGR of two groups with and without PE in patients referred to Alzahra Hospital in Rasht (Iran) between 2018 and 2019.

 

IUGR was examined in pregnant women referred to Alzahra Hospital in Rasht (Iran) in this cohort study. Based on Doppler sonography, which is defined as birth weight under 10% percentile of birthweight curves for gestational age, pregnant women with IUGR were divided into two groups of high blood pressure (PE-IUGR, exposed) and normal hypertension (I-IUGR, unexposed) during pregnancy. PE was defined based on the American College of Obstetricians and Gynecologists (ACOG).
This study was confirmed/approved by the Research Council/Ethics Committee of Guilan University of Medical Sciences (IR.GUMS.REC.1397.453). Before being enrolled in the study, pregnant women and their husbands gave their informed consent. Patients with known structural or chromosomal anomalies or intrau-terine infections were excluded from the study. Informations such as maternal characteristics and neonatal outcomes were obtained from all patients through a questionnaire.
Maternal characteristics were age, gestational age, gravidity, parity, body mass index (BMI), number of cigarettes smoked per day, type of delivery, and known diseases (including diabetes, chronic hypertension, thrombophilia, seizure, and asthma). 
Neonatal outcomes were Apgar scores of less than 7 in 5 min, hospitalization duration, and neonatal intensive care unit (NICU) hospitalization. Early neonatal complications are usually as follows: blood transfusion, sepsis, respiratory distress, mechanical ventilation, seizure, phototherapy, intraventricular hemorrhage, respiratory support, hypoxic-ischemic encephalopathy, or death.
In this study, all the pathological assessments of the placenta were performed in the laboratory of Alzahra Hospital by the same pathologist who was not aware of the outcomes of pregnancies and randomization. Sample groups were based on the standard protocol presented in previous studies (24).
After removing membranes and the umbilical cord, the placenta was fixed in formalin and weighed. For each placenta, a minimum of eight tissue samples from areas with abnormal appearance were obtained, including one sample from the entrance of the umbilical cord, one from the middle of the placenta tissue with abnormal macroscopic appearance, two grossly abnormal samples from the center of the tissue, one sample from an abnormal placental margin, an extra-sample of membranes, and two samples from the umbilical cord. Paraffin block was prepared and evaluated microscopically. The fetoplacental weight ratio (neonatal birth weight to placental weight ratio) was also measured.
Maternal- or fetal-originated placental lesions were defined based on the Pediatric Pathology Society. Lesions were divided into three pathophysiological groups: lesions with abnormal maternal blood flow, lesions with abnormal fetal vascular support, and inflammatory lesions. Maternal circulatory lesions are divided into several categories; in the first category, the continuity of maternal blood circulation is reduced by retro placental hemorrhage. The second category of vascular injuries is associated with insufficient maternal perfusion (acute atherosclerosis and mural hypertrophy). The third category of villi changes is associated with maternal under-perfusion (increased syncytial knots, agglutination of villi, increase in fibrin deposition of villi, and infarction of villi). Fetal vascular support lesions were thrombo-occlusive vascular lesions (including chorionic vascular throm-bosis and primary villi vessels) and vascular lesions associated with vascular occlusive diseases (fibrotic, hypovascular, and avascular villi).
Placental findings, including chorioamnionitis, are defined as infiltration of neutrophil inflammatory cells at more than two spots on the chorionic surface and extracellular membrane. The maternal inflammatory response is divided into three stages: early and subacute chorioamnionitis (stage 1), acute chorioamnionitis (stage 2), and late and severe chorioamnionitis (stage 3). The fetal inflammatory response is also divided into three stages, including early (stage 1), moderate arthritis of the umbilical arteries (stage 2), and concentrated umbilical vacuities (necrotizing funisitis; stage 3). In addition, when the lymphocyte (inflammatory cells) are infiltrated in the stroma or terminal of the villi, inflammation of the villi with unknown cause or chronic villitis is generated, which usually spreads to small vessels.
The current study included placental features reported according to the latest pathology criteria in the cases mentioned above.
In order to compare pregnancy outcomes and placental findings in PE-IUGR and I-IUGR groups with 95% CI and 80% test power, the sample size was determined based on the study by Kovo et al. (24). The mean placental weight in neonates born in the PE-IUGR and I-IUGR groups was 314±106 and 348±74, respectively, and, according to the sampling formula, at least 108 subjects in each group were evaluated.
In this study, data were collected, coded, and entered into SPSS 21 (SPSS Inc., Chicago, Ill., USA) Mean and SDs (95% CI) were used to describe quantitative variables with normal distribution, and interquartile ranges were used for quantitative variables with abnormally-distributed. Qualitative variables were also described based on number and percentage.   Normal distributions of the study variables were measured using the Kolmogorov-Smirnov Test.
Analytical evaluation and comparison of pregnancy outcomes and placental findings in the PE-IUGR and I-IUGR groups were performed based on t (or Mann-Whitney non-parametric equivalent) and chi-square tests (when Fisher’s exact test was not valid) in order to identify the effect of independent risk factors (maternal age, BMI, gestational age, birth weight, etc.). A logistic regression model was used for neonatal outcomes in the presence of one or more complications, such as blood transfusion, sepsis, respiratory distress, mechanical ventilation, seizure, phototherapy, intra-ventricular hemorrhage, respiratory support, hypoxic-ischemic enceph-alopathy, or death. The level of statistical significance of the tests was considered as a P-value<0.05.