The Association Between Umbilical Cord Abnormalities and the Development of Non-Reassuring Fetal Heart Rate Leading to Emergent Cesarean Deliveries

ORIGINAL ARTICLE The association between umbilical cord abnormalities and the development of non-reassuring fetal heart rate leading to emergent cesarean deliveries

E Weiner1, N Fainstein1, L Schreiber2, R Sagiv1, J Bar1 and M Kovo1

OBJECTIVE: To study the contribution of umbilical cord (UC) abnormalities in emergent cesarean deliveries (ECDs) for non- reassuring fetal heart rate (NRFHR) and to explore their association with placental histopathology and neonatal outcome. STUDY DESIGN: Data from 530 ECDs for NRFHR were reviewed for the occurrence of UC abnormalities. Those included the presence of UC entanglements, the number and location of loops, true knots and short cord (o50 cm). Multiple UC entanglements were defined as ⩾ 2 UC loops. Results were compared with 530 vaginal deliveries (VD group) matched for maternal age, parity and gestational age. Additionally, we compared neonatal outcome and placental histopathology in cases of ECDs with a single vs multiple UC entanglements. Neonatal outcome consisted of low Apgar score (⩽7 at 5 min), cord blood pH ⩽ 7.1 and composite neonatal outcome that was defined as one or more of respiratory distress, necrotizing enterocolitis, sepsis, transfusion, ventilation, seizure, hypoxic-ischemic encephalopathy, phototherapy or death. Placental lesions were classified as: lesions related to maternal vascular supply, lesions related to fetal vascular supply (consistent with fetal thrombo-occlusive disease), and maternal and fetal inflammatory responses. RESULTS: UC entanglements, true knots and short cords were all more common in the ECD group compared with the VD group, Po0.001, P = 0.002, P = 0.004, respectively. The rate of one loop entanglement did not differ between the groups. The rate of multiple UC entanglements was higher in the ECD group compared with the VD group, 20.6% vs 6.4%, respectively, Po0.001. ECDs with multiple compared with single UC entanglement had higher rate of adverse neonatal outcome, P = 0.031, and more placental fetal vascular lesions 19.3% vs 8.1%, P = 0.027, respectively. CONCLUSION: Multiple UC entanglements, true knots and short cords were more common in ECDs for NRFHR, suggesting their role in the development of fetal placental vascular lesions and adverse neonatal outcome. Journal of Perinatology (2015) 35, 919–923; doi:10.1038/jp.2015.102; published online 20 August 2015

INTRODUCTION Most of the studies lack information about the number of Non-reassuring fetal heart rate (NRFHR) monitoring during labor is UC loops entangled, sites of entanglements other than the fetal one of the major indications for immediate delivery by performing neck and other cord abnormalities. We aimed to ﬁll this gap and an emergent cesarean delivery (ECD) worldwide.1,2 to study the association of different UC abnormalities, in particular Several umbilical cord (UC) abnormalities have been associated UC entanglements with respect to site and the number of cord with the development of NRFHR and adverse perinatal outcome. loops in pregnancies complicated with ECD. Additionally, Such UC abnormalities include cord entanglements, hypercoiling, we aimed to study the association between single vs multiple true knots, strictures and short cords.3 Multiple mechanisms may UC entanglements in cases of NRFHR requiring ECD with lead to the development of NRFHR in association with placental pregnancy outcome and placental histopathology. We pathology and UC abnormalities and macroscopic and categorized placental lesions into those that are associated with microscopic changes.4,5 Notably, UC abnormalities occur also in maternal vascular circulation, changes in the fetal vascular supply uneventful normal vaginal deliveries. (thrombo-occlusive disease) and inﬂammatory lesions of maternal The association of nuchal cord (cord around neonatal neck) and and fetal origin.19 pregnancy outcome has been studied thoroughly, suggesting an increased risk for induction of labor, slow progress of labor, fetal distress, shoulder dystocia, meconium, low Apgar scores and MATERIALS AND METHODS higher rate of instrumental and CDs.6–14 On the other hand, others The medical records of all women who underwent ECD for NRFHR between found no association between the presence of nuchal cord and 15–17 37 and 42 weeks of gestation at the labor ward of Edith Wolfson Medical adverse neonatal outcome or labor complications. Center, Holon, Israel from January 2009 to June 2013 were reviewed. Fetal Furthermore, in a very large study including 420 000 pregnancies heart rate monitor tracings were interpreted by the obstetrical staff with nuchal cord, lower rate of CDs and lower perinatal mortality according to the American College of Obstetrics and Gynecology was observed, compared with deliveries without nuchal cord.18 guidelines.20

1Department of Obstetrics and Gynecology, Edith Wolfson Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Holon, Israel and 2Department of Pathology, Edith Wolfson Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Holon, Israel. Correspondence: Dr E Weiner, Department of Obstetrics and Gynecology, Edith Wolfson Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, P.O. Box 5, Holon 58100, Israel. E-mail: [email protected] Received 24 March 2015; revised 8 July 2015; accepted 9 July 2015; published online 20 August 2015 Contribution of UC abnormalities in ECD for NRFHR E Weiner et al 920 Excluded from the study were patients with additional indications for number of coils by the length of the cord in centimeters. Hypercoiling was ECD such as abnormal progress in labor, patients with evidence of fetal or diagnosed in cases of umbilical coiling index 40.3 coils cm− 1.24 neonatal malformations, multiple pregnancies, preterm labor (o37 weeks of gestation), non-vertex presentation or cases with missing data. The Statistics control group included patients who underwent normal vaginal deliveries at the same time period matched for maternal age, gestational age and Continuous variables were calculated as mean ± s.d. or median and range, parity. as appropriate. Categorical variables were calculated as rate (%). ’ As part of our departmental protocol, documenting UC abnormalities Continuous parameters were analyzed by Student s t-test and categorical observed during cesarean or vaginal deliveries by the obstetrics staff is variables by chi-square test or by Fisher exact test, as appropriate. o fi included in every delivery report. UC abnormalities included: cord A P-value of 0.05 was considered statistically signi cant. Data were entanglements loops around neck (nuchal cord loop), trunk or limb, as analyzed with the SPSS software, version 15.0 (SPSS, Chicago, IL, USA). fi ⩾ well as the number of loops, true knots and short UCs (o50 cm). Multiple Composite neonatal outcome was de ned as 1 of the following ⩽ ⩽ UC entanglements were defined as ⩾ 2 loops of the UC around neonatal complications: Apgar scores 7 in 5 min, cord blood pH 7.1, sepsis, blood neck, trunk or limb. transfusion, phototherapy, respiratory distress syndrome, transient tachypnea of the newborn, mechanical ventilation, intraventricular hemorrhage, seizures, hypoxic–ischemic encephalopathy, necrotizing Data collection enterocolitis, or death. The clinical data for the present study were collected from the patients’ Composite placental maternal vascular supply lesions was defined as the medical and surgical files and included demographic and labor presence of ⩾ 1 maternal vascular supply abnormalities and composite characteristics: age, gravidity and parity, body mass index, pregestational placental fetal vascular supply lesions was defined as the presence of ⩾ 1 diabetes mellitus, gestational diabetes mellitus (A1 and A2), preeclampsia, fetal vascular supply abnormalities. trial of labor after cesarean section (TOLAC) attempt, gestational age at To identify independent risk factors for ECD, a multivariate stepwise delivery, oligohydramnious (amniotic fluid index o5 cm), the presence of forward logistic regression analysis was performed. Preeclampsia, FGR and intrapartum fever 438 °C, and meconium. Gestational age was confirmed TOLAC attempts served as independent variables. by first-trimester ultrasonography. The following information was collected from the neonatal records: Apgar scores, cord blood pH, sepsis (positive blood or cerebrospinal fluid RESULTS culture), need for blood transfusion, need for phototherapy, respiratory During the study time period, 4507 CDs were performed out of distress syndrome, need for mechanical ventilation, necrotizing 20 366 deliveries (CD rate of 22.1%). Of them, 530 ECD (ECD group) enterocolitis, intraventricular hemorrhage, hypoxic ischemic encephalo- were performed owing to NRFHR, as the only indication. Normal pathy, seizures, and death. Birth weight percentile for gestational age was matched VD (VD group) served as controls. assigned using the updated Israeli growth charts.21 Fetal growth restriction (FGR) was defined as actual birth weight o10th% for gestational age. At the time of decision to perform an ECD, 494/530 (93.2%) For the purpose of the study, we compared the prevalence and types of of the FHR tracings were interpreted as category 2 tracings and UC abnormalities between ECD and normal vaginal deliveries (controls). 36/530 (6.8%) as category 3 tracings according to the guidelines of 20 Additionally, we compared pregnancy characteristics, neonatal outcome the American College of Obstetrics and Gynecology. and placental histopathology in cases of ECDs with a single UC Maternal and delivery characteristics are summarized in Table 1. entanglement (nuchal or body or limb) vs multiple UC entanglements. There were no between-group differences in maternal age, Approval for the study was obtained from the Local Ethics Committee. gestational age at delivery, maternal body mass index, rate of diabetes, oligohydramnious, intrapartum fever or meconium. Placental examination Higher rate of preeclampsia, FGR and TOLAC attempts As part of departmental protocol, in every case of ECD placentas are sent were observed in the ECD group compared with controls to histopathology evaluation. Placental pathology examinations were (P = 0.003, Po0.001, Po0.001 respectively). performed using a standard protocol, described by us in previous Table 2 presents the different UC abnormalities observed in the studies.22,23 Briefly, after fixation in formalin and removal of the study groups. UC entanglements were the most common cord membranes and cord, the placentas were weighed. For each placenta, at abnormality observed in both groups. UC entanglements were least five tissue samples were embedded in paraffin blocks for microscopic significantly more common in the ECD group compared with the assessment. All examinations were done by a single pathologist (LS).

Placental lesions Table 1. Categorization of placental lesions was described by us in previous Maternal and delivery characteristics in the ECD group studies,22,23 and it is based according to the criteria that were adopted by compared with the normal VD (control) group the Society for Pediatric Pathology.19 Briefly, maternal vascular supply abnormalities included: lesions resulting from loss of integrity of the Characteristic ECD group VD group P-value maternal circulation, that is, placental, marginal and retro-placental hemorrhages, vascular lesions related to maternal underperfusion (acute n = 530 n = 530 atherosis and mural hypertrophy), and villous changes related to maternal underperfusion (increased syncytial knots, villous agglutination, increased Maternal age (years) 29.7 ± 5.1 30.1 ± 5.2 0.206 intervillous fibrin deposition and villous infarcts). Fetal vascular supply Gestational age (weeks) 39.0 ± 2.4 39.1 ± 2.5 0.506 − abnormalities included findings consistent with fetal thrombo-occlusive BMI (kg m 2) 24.7 ± 5.4 24.1 ± 4.8 0.056 disease: vascular lesions (thrombosis of the chorionic plate and stem Diabetes mellitus 28 (5.3) 22 (4.2) 0.469 villous vessels) and villous changes (hypovascular, fibrotic and avascular Preeclampsia 43 (8.1) 20 (3.8) 0.003 villi). Placental findings consistent with chorioamnionitis were defined by Oligohydramnious 32 (6.0) 19 (3.6) 0.084 the presence of an inflammatory neutrophil infiltrate at ⩾ 2 sites on the TOLAC attempts 42 (7.9) 14 (2.6) o0.001 chorionic plate and extraplacental membrane. The maternal inflammatory FGRo10th percentile 99 (18.6) 48 (9.1) o0.001 response was divided into three stages: early, acute subchorionitis Intrapartum fever 438 °C 22 (4.2) 13 (2.5) 0.168 (stage 1); intermediate acute chorioamnionitis (stage 2); and late, severe Meconium 107 (20.1) 89 (16.8) 0.178 chorioamnionitis (stage 3). The fetal inflammatory response was also Abbreviations: BMI, body mass index; ECD, emergent cesarean delivery; divided into three stages: early, umbilical phlebitis (stage 1); intermediate, FGR, fetal growth restriction; TOLAC, trial of labor after cesarean delivery; umbilical arteritis (stage 2); and concentric umbilical perivasculitis VD, normal vaginal delivery. All data are shown as number (%) or (necrotizing funisitis, stage 3). ± fi mean s.d. Diabetes mellitus: include pregestational and gestational Abnormal cord insertion was de ned as either velamentous or marginal diabetes (GDMA1 and A2). insertion. Umbilical coiling index was calculated by dividing the total

Table 2. Umbilical cord abnormalities in the ECD group and in the Table 3. Maternal and delivery characteristics in ECDs with single vs control group multiple umbilical cord entanglements

Umbilical cord abnormalities ECD group VD group P-value Single UC Multiple UC P-value entanglement entanglements n = 530 n = 530 n =99 n = 109 Umbilical cord entanglements 208 (39.2) 117 (22.1) o0.001 Maternal age (years) 29.6 ± 5.2 29.7 ± 5.2 0.89 Single UC entanglement 99 (18.7) 83 (15.7) 0.221 Gestational age 39.6 ± 1.32 39.9 ± 1.12 0.077 Nuchal loop 65 (12.3) 68 (12.8) 0.853 (weeks) UC around limb 16 (3) 6 (1.1) 0.051 Nulliparity 58 (58.6) 64 (58.7) 1 UC around trunk 18 (3.4) 9 (1.7) 0.117 BMI (kg m −2) 24.6 ± 5.2 24.8 ± 5.3 0.784 Diabetes mellitus 6 (6.1) 3 (2.8) 0.314 Multiple UC entanglements 109 (20.6) 34 (6.4) o0.001 Preeclampsia 10 (10.1) 6 (5.5) 0.298 Nuchal loops 81 (15.3) 31 (5.8) o0.001 Oligohydramnions 9 (9.1) 3 (2.8) 0.072 UC loops around limb 16 (3) 1 (0.2) o0.001 TOLAC attempts 12 (12.1) 12 (11.0) 0.831 UC loops around trunk 12 (2.3) 2 (0.4) 0.01 Active labor 45 (45.5) 57 (52.2) 0.334 FGRo10th percentile 21 (21.2) 19 (17.4) 0.597 True knot 18 (3.4) 4 (0.8) 0.004 Intrapartum fever 3 (3.0) 5 (4.6) 0.502 Short cord o50 cm 17 (3.2) 4 (0.8) 0.006 438 °C Meconium 33 (33.3) 36 (33.0) 1 Abbreviations: ECD, emergent cesarean delivery; UC, umbilical cord; VD, normal vaginal delivery. All data are shown as number (%). Abbreviations: BMI, body mass index; ECD, emergent cesarean delivery; FGR, fetal growth restriction; TOLAC, trial of labor after cesarean delivery; UC, umbilical cord. Diabetes mellitus: include pre-gestational and gestational diabetes (GDMA1 and A2). All data are shown as number (%) or VD group, 39.2% vs 22.1%, respectively, Po0.001. The rate of mean ± s.d. single UC entanglement did not differ between the ECD and the VD groups, 18.7% vs 15.7%, respectively, P = 0.221. The most common site of single UC entanglement was neonatal neck (12.3% vs 12.8% in the ECD compared with the VD group, Table 4. Immediate neonatal outcome in ECDs with single vs multiple respectively, P = 0.853). The rate of single UC loop at other umbilical cord entanglements neonatal sites, such as neonatal limb or trunk, did not differ between the groups. Single UC Multiple UC P-value The rate of multiple UC entanglements was significantly higher entanglement entanglements in the ECD group compared with the VD group, 20.6% vs 6.4%, o respectively, P 0.001. n =99 n = 109 Multiple UC entanglements around neonatal neck, limb or trunk were all more common in the ECD group compared with the Neonatal weight (g) 3158 ± 484 3272 ± 411 0.067 VD group, Po0.001, Po0.001, P = 0.01, respectively. With respect Neonatal 5.34 ± 1.9 5.91 ± 2.2 0.047 to other UC abnormalities: ECD group compared with the VD hospitalization (days) group had higher rate of true knots, 3.4% vs 0.8%, respectively, Umbilical cord 3 (3) 6 (5.5) 0.502 ⩽ P = 0.004, and short cords, 3.2% vs 0.8%, respectively, P = 0.006. pH 7.1 By using multivariate stepwise forward logistic regression 5-min Apgar 1 (1) 2 (1.8) 1 score ⩽ 7 analysis, ECD was found to be independently associated with Respiratory 4 (4) 8 (7.3) 0.38 total UC entanglements (odds ratio (OR) = 1.6, 95% confidence morbiditya interval (CI) = 1.2 to 1.8, P = 0.008), multiple UC entanglements Cerebral morbidityb 001 (OR = 2.9, 95% CI = 2.1 to 3.9, P = 0.012), true knot (OR = 2.7, 95% Neonatal sepsis 0 1 (0.9) 1 CI = 1.4 to 3.2, P = 0.007) and short cord (OR = 2.6, 95% CI = 1.9 to Necrotizing 001 3.6, P = 0.004). enterocolitis Out of the 530 ECDs, UC entanglements were observed in 208 Blood transfusions 0 1 (0.9) 1 cases (39.2%). Cases were divided into those with single vs Phototherapy 3 (3) 6 (5.5) 0.502 Neonatal death 0 0 1 multiple UC entanglements. Table 3 presents maternal and Composite adverse 9 (9.1) 22 (29.3) 0.031 delivery characteristics in ECDs with single UC entanglement vs neonatal outcome multiple UC entanglements. There were no between-group differences in maternal age, gestational age at delivery, maternal Abbreviations: ECD, emergent cesarean delivery; UC, umbilical cord. All data a body mass index, nulliparity, rate of pregnancy complications as are shown as number (%) or mean ± s.d. Respiratory morbidity included diabetes, preeclampsia and FGR, rate of oligohydramnions, the presence of respiratory distress syndrome or transient tachypnea of the newborn or mechanical ventilation or need for respiratory support. intrapartum fever or meconium. Neonatal outcome parameters b Cerebral morbidity included the presence of intraventricular hemorrhage of cases with single loop vs multiple UC loops are summarized in or seizures or hypoxic–ischemic encephalopathy. Table 4. Neonatal hospitalization was longer in the multiple UC entanglements vs single UC entanglement group, 5.91 ± 2.2 days vs 5.34 ± 1.9 days, respectively, P = 0.047. Compo- site adverse neonatal outcome was higher in the multiple UC UC entanglements vs single UC loop group, 438 ± 104 vs entanglements vs single UC entanglement group, 29.3% vs 9.1%, 468 ± 102 g, respectively, P = 0.037. Higher rate of fetal vascular respectively, P = 0.031. supply lesions (composite) was observed in the multiple UC Table 5 presents the rate of different placental lesions in the entanglements group compared with the single UC entanglement group with single UC entanglement vs multiple UC entanglements group, 19.3% vs 8.1%, respectively, P = 0.027. There was no group. Placenta weights were significantly lower in the multiple difference in the rate of abnormal cord insertion, hypercoiling

Table 5. Placental histopathology lesions in emergent cesarean delivery group with single vs multiple umbilical cord entanglements

Single UC entanglement Multiple UC entanglements P-value

n =99 n = 109

Placental weight (g) 468 ± 102 438 ± 104 0.037 Placental weight o10% 11 (11.1) 16 (14.7) 0.537 Hypercoiled cord 12 (12.1) 16 (14.7) 0.686 Abnormal cord insertion 13 (13.1) 19 (17.4) 0.444

Maternal vascular supply lesions Placental hemorrhage 2 (2) 5 (4.6) 0.449 Vascular lesions related to maternal under-perfusion 3 (3) 8 (7.3) 0.220 Villous changes related to maternal under-perfusion 36 (36.3) 30 (27.5) 0.182 Composite maternal vascular supply lesions 41 (41.4) 43 (39.4) 0.779

Fetal vascular supply lesions Vascular lesions consistent with FTOD 2 (2) 8 (7.3) 0.105 Villous lesions consistent with FTOD 6 (6.1) 13 (11.9) 0.156 Composite fetal vascular supply lesions 8 (8.1) 21 (19.3) 0.027

Inflammatory lesions MIR stages 1–3 24 (24.2) 21 (19.5) 0.404 FIR stages 1–3 7 (7.1) 6 (5.5) 0.776 Abbreviations: ECD, emergent cesarean delivery; FIR, fetal inflammatory response; FTOD, fetal thrombo-occlusive disease; MIR, maternal inflammatory response; UC, umbilical cord. Continuous variables are presented as mean ± s.d. and categorical variables as n (%).

cord, maternal vascular supply lesions and placental inflammatory lesions in 125 neurological impaired infants, demonstrating that lesions between the groups. UC entanglements and cord abnormalities are significantly increased in placentas with fetal thrombotic vasculopathy, thus directly contributing to the development of this placental lesion. DISCUSSION Saleemuddin et al.5 demonstrated that placentas with fetal The present study demonstrates a significant high rate of UC thrombotic vasculopathy were associated with higher rate of abnormalities in patients who underwent emergent CD owing to pregnancy complications, such as stillbirth, FGR, oligohydram- NRFHR, compared with normal vaginal deliveries. The most nious and fetal cardiac abnormalities. Our findings point to the common UC abnormality was nuchal cord entanglements. association between multiple cord entanglements and the However, we found that only multiple UC entanglements and development of fetal vascular supply lesions, suggesting an not a single loop entanglement were associated with ECD. These indirect evidence for the presence of compromised UC blood flow, findings are in concordance with previous studies demonstrating leading to NRFHR and impaired neonatal outcome. Still, despite an association of gross cord abnormalities with intrapartum these observations, the impact of screening for UC entanglements – – complications, FGR and stillbirth.6 10,25 27 However, the exact prior to labor, by Doppler ultrasound on pregnancy and neonatal relation between cord abnormalities or entanglements and their outcome, is contradictive.8,30,31 effect on delivery and pregnancy outcome is still controversial.18 The present study is unique in several aspects; there are other Multiple cord loops are reported in 0.3% to 3.8% of deliveries;4 publications on the association of UC abnormalities and NRFHR. nevertheless, the current study demonstrate a much higher Yet, to the best of our knowledge, we are the first to compare rate of multiple UC entanglements in patients who undergo ECD neonatal outcome and placental histopathology in cases of single (20.6%), suggesting its role in the development of NRFHR. UC vs multiple UC entanglements. Second, we applied placental entanglements can cause alterations in cord blood flow.28 These histopathology criteria that were validated and adopted by the alterations can be caused either from direct compression or from Society of Pediatrics Pathology19 and analyze placentas in terms of stretch during fetal descent, which lead to transient cessation of maternal and fetal vascular supply and maternal and fetal cord blood flow, which will be expressed as NRFHR monitor. Other inflammatory responses. possible mechanism by which multiple UC entanglements could We are aware of the limitations of our study: (1) Because of its affect neonatal outcome is through their influence on the retrospective design, clinical follow-up was limited. Only early placenta. neonatal complications could be recorded and analyzed; (2) Following the same line, we found that, in pregnancies Histological evaluation of the cord and placentas were available complicated with ECD, owing to NRFHR, the presence of multiple only for the ECD. Placentas from normal VD are not routinely sent UC entanglements was associated with higher rate of composite to histology evaluation; (3) The term NRFHR monitor is subject to adverse neonatal outcome, as compared with those with a single considerable variations of interpretation among maternal–fetal UC loop. Additionally, we evaluated placental histology findings in medicine specialists. There is a wide spectrum of abnormal FHR all ECD owing to NRFHR and demonstrated that cases with patterns, especially in category 2 tracings, not necessarily multiple UC entanglements had lower placental weights and suggesting fetal compromise;32–34 (4) Unintended bias by the higher rate of fetal vascular supply lesions, specifically, lesions obstetrician attempting to identify an etiology for NRFHR may consistent with fetal thrombo-occlusive disease. Fetal vascular have occurred, leading to a more detailed documentation of UC obstructive lesions are probably the result of stasis, hyper- gross abnormalities in the ECD group compared with cases of coagulability and vascular damage within the fetal circulation of normal deliveries; (5) Antenatal management probably cannot be the placenta.29 Redline4 studied UC abnormalities and placental directly deduced from the present study.

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