Preterm Neonatal Outcomes in Pregnancy With and Without Preeclampsia

Preterm Neonatal Outcomes in Pregnancy With and Without Preeclampsia Sri Pamungkas1, Noroyono Wibowo1, Rima Irwinda1 1Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia Disclaimer : Address for correspondence : dr. Sri Pamungkas Departemen Medik Kebidanan dan Kandungan FKUI-RSCM, Fakultas Kedokteran Universitas Indonesia, Jalan Salemba Raya No. 6, Jakarta, 10430, Indonesia Phone number: +62-812-8855-2508 E-mail: drsripamungkas@gmail.com Running text : Prenatal Outcomes in Preeclampsia Word counts : 1851 Number of figures : 0 Number of tables : 2 Synopsis : Preterm neonatal borne from mother with preeclampsia is more prone to various complications   ABSTRACT Background: Preeclampsia is one of major causes of both maternal and infant morbidity and mortality in the world. Various complications due to preeclampsia are fetal growth restriction, thrombocytopenia, nervous system disorder, respiratory disorder, and digestive tract disorder. This study aims to investigate whether there are differences of preterm neonatal outcomes in cases with and without preeclampsia. Methods: This study is an observational analytic study using case-control method. A total of 2,750 subjects were included using consecutive sampling. The subject of this study was preterm neonatal with gestational age of <37 weeks in Cipto Mangunkusumo National General Hospital. The data were analyzed in order to determine the relationship between preeclampsia and hypoxic ischemic encephalopathy (HIE), bronchopulmonary dysplasia (BPD), respiratory distress syndrome (RDS) and necrotizing enterocolitis (NEC) on various perinatal periods. Results: Among 2,750 subjects studied, preterm infants with preeclampsia mother were 455 subjects (16.5%) and without preeclampsia were 2,295 subjects (82.4%). There were significant relationship between preeclampsia with hypoxic ischemic encephalopathy ( p = 0,002, OR 3,84, CI95% 1,61-9,17) bronchopulmonary syndrome (p = 0,04, OR 1,87, CI95% 1,03-3,42), respiratory distress syndrome (p < 0,0001, OR 5,51 CI95% 4,35-6,98) and necrotizing enterocolitis (p< 0,001, OR 2,22 CI95% 1,5-3,17). Conclusion: There were significant relationship between preeclampsia with hypoxic ischemic encephalopathy (HIE), bronchopulmonary dysplasia (BPD), respiratory distress syndrome (RDS) and necrotizing enterocolitis (NEC). Keywords: Preeclampsia, Necrotizing Enterocolitis, Hypoxic ischemic encephalopathy, Bronchopulmonary dysplasia, Respiratory distress syndrome   Preeclampsia is a multi-system organ disorder that is unique to pregnancy. Preeclampsia is one of the leading causes of maternal death worldwide, even ranked as the number one cause of maternal death in India in 2016.1 Preeclampsia incidence rates range from 5-15% in all pregnancies worldwide.2 Preeclampsia has both high maternal and neonatal morbidity and mortality. The prevalence of preterm birth, LBW and asphyxia of birth is significantly higher in women with preeclampsia.2 In fetus, various complications of preeclampsia might cause uteroplacental circulation disruption, resulting in disruption of fetal growth, hypoxemia, and even fetal death.3 The only definitive therapy for preeclampsia is delivery of the fetus and placenta. Given the progressive nature of the disorder of preeclampsia, termination of pregnancy is often necessary to minimize both maternal dan fetal morbidity and mortality.4 However, obstetrician must balance the needs between adequate fetal maturation and the risks of the mother and fetus when continuing pregnancy with complications of preeclampsia. Currently termination is usually recommended for pregnancy at gestational age of > 37 weeks with preeclampsia regardless of the severity of the disease. However, the minimum requirement for gestational age can be further compromised to > 34 weeks for preeclampsia with severe manifestations.5 Problems with preterm neonatal occur due to inadequate organ maturation. Neonatal preterm is more susceptible to infection and its various complications. Problems with neonatal preterm often occurring during early life are disorders of the respiratory system, central nervous system, cardiovascular, hematological, and gastrointestinal system. Likewise, labor preeclampsia is associated with worse neonatal outcomes, namely preterm birth, stillbirth, stunted fetal growth, blood disorders (thrombocytopenia), impaired respiratory organ development (bronchopulmonary dysplasia), disorders of the development of the central nervous system (cerebral palsy, hypoxic ischemic encephalopathy), disorders of respiratory organ development (bronchopulmonary dysplasia), disorders of the development of the central nervous system (cerebral palsy, hypoxic ischemic encephalopathy) digestive tract (NEC).2,6,7 This study will review preterm neonatal outcomes in cases of severe preeclampsia so that the results of this study can be useful to improve potential strategies in optimizing outcomes of preterm neonatal outcomes with complications of preeclampsia. METHODS This study is an analytic observational study using case control method conducted in Obstetric and Gynecologic Department of Cipto Mangunkusumo General Hospital. The subjects of this study were all preterm neonates with preeclampsia mother. Preterm in this study was defined as having gestational age of less than 37 weeks during birth. Preterm infants born with mothers having complication such as cardiovascular events, hyperthyroid, or SLE, infants with congenital anomalies, and mother with eclampsia were excluded from the study. Subjects from both study groups were measured for gestational age, preeclampsia status, and complications status.The data were then analyzed using SPSS 21.0. The study was approved by ethical committee of Faculty of Medicine, Universitas Indonesia and Cipto Mangunkusumo Hospital. This study was not sponsored by any third party. All the funding was obtained from main researcher.   RESULTS There were 4,178 patients recruited in this study. Among those patients, 1,268 subjects were not preterm infants, while 160 subjects had incomplete medical record. A total of 2,750 subjects were included in this study. Clinical characteristics of subjects can be found on Table 1. Table 1. Clinical Characteristics of Subjects Variables Preeclampsia N=455 Control Group N=2295 Gestational Age Extremely preterm 33 (7,2%) 718 (92,8%) Very preterm 127 (27,9%) 451 (72,1%) Moderate to late preterm 295 (64,8%) 1126 (35,2%) Neonatal complications Necrotizing enterocolitis 47 (29,3%) 113 (70,6%) Hypoxic ischemic encephalopathy 9 (42,8%) 12 (57,1%) Respiratory Distress Syndrome 354 (28,4%) 892 (71,6%) Bronchopulmonary Dysplasia 15 (26,8%) 41 (73,2%) In order to determine the difference in outcome of preterm infants with preeclampsia mother, bivariate analysis was done between various gestational age, preeclampsia, and various neonatal complications. Bivariate analysis results can be found on Table 2. Table 2. Bivariate Analysis Results NEC p OR, CI 95% HIE P OR, CI 95% RDS P OR, CI 95% Yes No Yes No Yes No EXTREMELY PRETERM (N=751) *survival rate 31% 0,09 3,79, 0,81-17,70 < 0,05 71,7 7,2-709,8 < 0,05 130, 9,30,7-557,9 PE (+) ( N=33) 2 (6.1%) 31 (93.9%) 3 (9,1%) 30 (90,9%) 31 (93,9%) 2 (6,1%) PE (-) (N=718) 12 (1.7%) 706 (98.3%) 1 (0,1%) 717 (99,9%) 76 (10,6%) 642 (89,4%) VERY PRETERM (N=578) 0,06 2,00 0,21-3,29 0,78 0,78 0,16-3,68 < 0,05 6,85 3,27-14,40 PE (+) ( N=127) 29 (22.8%) 98 (77.2%) 2 (1,6%) 125 (98,44%) 119 (93,7%) 8 (6,3%) PE (-) ( 451) 58 (12.9%) 393 (87.1%) 9 (2%) 442 (98%) 315 (69,9%) 136 (30,1%) MODERATE TO LATE PRETERM (N=1421) 0,22 1,44 0,80-2,60 < 0,05 7,72 1,41-42,38 < 0,05 2,80 2,13-3,68 PE (+) (N=295) 16 (5.4%) 279 (94.6%) 4 (1,4%) 291 (98,6%) 204 (69,2%) 91 (30,8%) PE (-) (N=1126) 43 (3.8%) 1083 (96.2%) 2 (0,2%) 1124 (99,8%) 501 (42,3%) 625 (57,7%) Total (N=2750) < 0,05 2,22 1,5-3,17 < 0,05 3,84 1,61-9,17 < 0,05 5,51 4,35-6,98 PE (+) (N=455) 47 (10.3%) 408 (89.7%) 9 (2%) 446 (98%) 354 (77,8%) 101 (22,2%) PE (-) (N=2295) 113 (4.9%) 2182 (95.1%) 12 (0,5%) 2283 (99,5%) 892 (38,9%) 1403 (61,1%) DISCUSSION During the study period, there were 2,750 included in the study subjects who had met the inclusion and exclusion criteria. From 2,750 research subjects obtained over 4 years, it was found that 160 subjects with NEC disorders, 21 subjects with HIE disorders, 1,246 subjects with RDS disorders and 56 subjects with BPD disorders. Among 2,750 study subjects, 455 subjects were born from mothers suffering from preeclampsia. From the data obtained in this study, there were significant differences in the number of HIE events between the preeclampsia group and control group in the extremely preterm group (p <0.05, OR = 71.7, CI95% 7.2-709.8), moderate to late preterm (p <0.05, OR = 9.14, CI95% 1.02 - 82.14), and overall neonatal preterm (p <0.05 OR 3.84, 95% CI 1.61-9,17). One theory put forward in the National Institutes of Health journal stated that there is a relationship between HIE at moderate to late preterm gestational age with clinical manifestations of abnormal fetal heart rate and decreased pH in the placental cord.8,9 According to a journal published by the National Institution of Health, pathophysiology of HIE is divided into two phases. The first phase is decrease in blood flow to the brain followed by a decrease in oxygen and glucose to the nervous system in the brain, causing decreased ATP reserves and lactate accumulation in the brain. The second phase is the onset of inflammation, oxidative stress and excitotoxicity which can cause severe hypoxic-ischemic.10 In the total sample of patients with preeclampsia, a higher percentage of respiratory distress syndrome (RDS) was obtained (77.8% vs. 22.2%). In this study, the results of data analysis obtained using the chi-square test showed that there was a statistically significant relationship in all gestational age groups in preeclampsia to the incidence of RDS (p <0.05). According to a previous study in 2015, about 50% of extremely preterm neonates experienced RDS in preeclampsia mothers which caused vasospasm so that the uteroplacental circulation was interrupted causing reduced fetal perfusion.11 There is a study concluding that neonatal RDS is obtained from mothers suffering from preeclampsia with preterm infants in the third trimester of pregnancy, due to an inflammatory response to cytokines and lack of pulmonary surfactants.11 However, other studies stated that not only preeclampsia causing infants preterm suffers from RDS, but also gestational diabetes due to hormonal changes marked by increased hormone estrogen and progestin, resulting in a state of dysfunctional maternal insulin function and changes in insulin kinetics.12 The incidence of BPD in preterm neonates from mothers who suffer from preeclampsia is 38.5%, significantly higher than preterm babies born to mothers who do not suffer from preeclampsia. A cohort study in the United States of Boston stated that the risk of having BPD is increased by the presence of preeclampsia with an OR 2.96 (CI 95% 1.17-7.51, P = 0.013) The pathophysiology of preeclampsia is not yet known the exact cause, some studies say placental abnormalities that occur have the characteristics of decreased arterial invasion from the mother and decreased blood flow so that it inhibits the development of the placenta and fetus so that hypoxia and ischemia will interfere with fetal angiogenesis. It will also affect lung development in fetus. Impaired pulmonary development due to impaired vascularization is considered to be a risk factor for BPD in preterm infants.13 In this study, it was found that subjects with preeclampsia had more NEC (10.3%) than subjects without preeclampsia (4.9%) at very preterm gestational age. Significant overall results were obtained between preeclampsia and NEC events (p <0.05, OR 2.22, CI95% 1.5-3.17). The presence of NEC was found in 242 babies born to preeclampsia mothers at <34 weeks' gestation. According to a study conducted in Turkey, the incidence of NEC in babies born to mothers suffering from preeclampsia was 13.7%, higher than babies born to mothers without preeclampsia of about 5.5%. Preeclampsia is an important risk factor NEC in neonates with preterm birth at gestational age <30 weeks.14 According to consensus data the International Pediatric Research Foundation, NEC might occur more frequently on preterm babies due to immature digestive tract susceptible to damage from pathogenic bacteria which increase the inflammatory cascade, causing long destruction or perforation of the digestive tract and may further escalated to systemic infections.15 CONCLUSION It is concluded that infants born from preeclampsia mother are more prone to have Hypoxic Ischemic Encephalopathy (HIE), Bronchopulmonary Dysplasia (BPD), Respiratory distress syndrome (RDS), Necrotizing Enterocolitis (NEC) ACKNOWLEDGEMENTS Authors would like to express sincere gratitude to all participating patients who willingly support this study. Authors would also like to extend special thanks to our parents and family for academical guidance and psychological supports. 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