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Role of umbilical cord arterial pH and lactate in newborn assessment of term antenatal women with hypertensive disorders of pregnancy

  • Naina Kumar
    Correspondence
    Corresponding author. Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, Mangalagiri, 522503, Guntur, Andhra Pradesh, India.
    Affiliations
    Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, Mangalagiri, Guntur, Andhra Pradesh, India
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  • Ashu Yadav
    Affiliations
    Department of Obstetrics and Gynecology, Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, Ambala, Haryana, India
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Published:March 07, 2020DOI:https://doi.org/10.1016/j.cegh.2020.02.026

      Highlights

      • Significant correlation exists between HDP severity and cord blood lactate and pH.
      • Mode of delivery significantly effects cord blood pH and lactate levels.
      • Neonatal gender and birth weight have no effect on cord blood pH and LDH levels.
      • Cord blood LDH levels increases significantly with severity of HIE.
      • Cord blood LDH is better predictor of neonatal outcome with 100% sensitivity.

      Abstract

      Problem

      To know role of cord arterial blood pH and lactate dehydrogenase levels in neonatal outcome assessment.

      Methods

      Present observational study was conducted in Obstetrics and Gynecology department of a rural tertiary center of Northern India over 6 months (July–January 2019) on 155 term (≥37-≤42 weeks) antenatal women with hypertensive disorders of pregnancy fulfilling inclusion criteria. Immediately after delivery, arterial blood sample was drawn from doubly clamped 10–12 cm long umbilical cord in pre-heparinized insulin syringe, which was sent for pH estimation and 0.5 ml in lithium heparin tube for lactate dehydrogenase levels. One- and 5-min neonatal Apgar score was noted by pediatrician. Cord blood pH and lactate levels were then compared with overall neonatal outcome. Statistical analysis was done using SPSS-22 version.

      Results

      Mean values of umbilical cord arterial pH and LDH was 7.2 ± 0.1 and 449.5 ± 562.9 U/L respectively. Significantly low mean cord blood pH (7.03 ± 0.12) and high LDH levels (939.74 ± 781.75 U/L) were observed in neonates of eclamptic mothers (p = 0.00). Mode of delivery had significant effects on cord blood parameters with significantly low pH and elevated LDH levels seen in neonates delivered by emergency LSCS for fetal distress (p < 0.05). Cord blood LDH levels were more significantly associated with NICU admission, neonatal morbidity and mortality. Cord blood LDH was a better predictor of neonatal outcome with 100% sensitivity and 79.73% specificity.

      Conclusion

      Cord arterial blood lactate dehydrogenase levels were better predictor of overall neonatal outcome.

      Keywords

      1. Introduction

      Worldwide hypertensive disorder of pregnancy (HDP) is one of major causes of perinatal and maternal morbidity and mortality.
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      • Famurewa A.C.
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      Comparison of serum calcium and magnesium between preeclamptic and normotensive pregnant Nigerian women in abakaliki, Nigeria.
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      and affects approximately 2–10% of all pregnancies.
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      Geneva: WHO; 2005. Make every mother and child count.
      HDP especially eclampsia and pre-eclampsia were found to be strongly associated with increased risk of intrapartum fetal hypoxia, severe birth asphyxia, stillbirth, and intrapartum fetal death.
      • Kongwattanakul K.
      • Saksiriwuttho P.
      • Chaiyarach S.
      • Thepsuthammarat K.
      Incidence, characteristics, maternal complications, and perinatal outcomes associated with preeclampsia with severe features and HELLP syndrome.
      ,
      • Vats K.
      • Paul M.
      Study of fetal outcome in hypertensive disorders of pregnancy in a tertiary care maternity hospital of Delhi.
      Furthermore, fetal hypoxia results whenever there is compromise in maternal oxygenation, placental perfusion, or when the oxygenated blood supply to the fetus is hampered due to any reason. As a result of inadequate oxygenation, there occurs anaerobic metabolism with production of huge amounts of organic acids, especially lactic acid. Accumulation of lactic acid in turn leads to depletion of buffer system resulting in metabolic acidosis with associated low fetal pH, fetal distress and poor Apgar score at birth.
      • Omo-Aghoja L.
      Maternal and fetal Acid-base chemistry: a major determinant of perinatal outcome.
      The resultant fetal acidosis increases the risk of intrapartum- cerebral palsy,
      • Borruto F.
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      Prevention of cerebral palsy during labour: role of foetal lactate.
      ,
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      hypoxic ischemic encephalopathy (HIE).
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      Intrapartum fetal asphyxia: definition, diagnosis, and classification.
      ,
      • Lee A.C.
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      Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990.
      and neonatal death.
      • Patavoukas E.
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      • Wiberg-Itzel E.
      Relationship between various maternal conditions and lactic acid dehydrogenase activity in umbilical cord blood at birth.
      ,
      • Allanson E.R.
      • Waqar T.
      • White C.R.H.
      • Tuncalp O.
      • Dickinson J.E.
      Umbilical lactate as a measure of acidosis and predictor of neonatal € risk: a systematic review.
      There are various ways of detection of fetal hypoxia, of which most commonly used are Apgar score at birth, umbilical cord blood gas analysis and cord blood lactate dehydrogenase levels. Fetal acidosis results in low Apgar score at birth (<7), low umbilical cord pH (umbilical artery cord blood pH < 7.24),
      • Victory R.
      • Penava D.
      • Da Silva O.
      • Natale R.
      • Richardson B.
      Umbilical cord pH and base excess values in relation to adverse outcome events for infants delivering at term.
      high umbilical base deficit or high cord blood lactate dehydrogenase levels (>612U/L).
      • Wiberg-Itzel E.
      • Josephson H.
      • Wiberg N.
      • Olson L.
      • Winbladh B.
      • et al.
      Lactic dehydrogenase in umbilical cord blood in healthy infants after different modes of delivery.
      Umbilical cord blood pH has a significant effect on various fetal organ functions, even a minor change in cord blood pH can severely affect organ systems, especially nervous, and cardiovascular system with resultant fetal distress and poor Apgar score at birth.
      • Omo-Aghoja L.
      Maternal and fetal Acid-base chemistry: a major determinant of perinatal outcome.
      The normal value of umbilical cord arterial blood pH is 7.24 ± 0.07.
      • Victory R.
      • Penava D.
      • Da Silva O.
      • Natale R.
      • Richardson B.
      Umbilical cord pH and base excess values in relation to adverse outcome events for infants delivering at term.
      Neonates with cord blood values lower than one to two standard deviation from mean value were associated with a substantial risk of poor Apgar score, increased neonatal intensive care unit (NICU) admission, and need for assisted neonatal ventilation.
      • Victory R.
      • Penava D.
      • Da Silva O.
      • Natale R.
      • Richardson B.
      Umbilical cord pH and base excess values in relation to adverse outcome events for infants delivering at term.
      Furthermore, neonatal death was found to be more likely at pH < 7.00.
      • Armstrong L.
      • Stenson B.J.
      Use of umbilical cord blood gas analysis in the assessment of the newborn.
      Another important indicator of neonatal birth asphyxia is cord blood arterial lactate dehydrogenase (LDH) levels.
      • Patavoukas E.
      • Åberg-Liesaho J.
      • Halvorsen C.P.
      • Winbladh B.
      • Wiberg-Itzel E.
      Relationship between various maternal conditions and lactic acid dehydrogenase activity in umbilical cord blood at birth.
      LDH activity is significantly linked to severity of neonatal diseases such as birth asphyxia,
      • Patavoukas E.
      • Åberg-Liesaho J.
      • Halvorsen C.P.
      • Winbladh B.
      • Wiberg-Itzel E.
      Relationship between various maternal conditions and lactic acid dehydrogenase activity in umbilical cord blood at birth.
      ,
      • Wiberg-Itzel E.
      • Josephson H.
      • Wiberg N.
      • Olson L.
      • Winbladh B.
      • et al.
      Lactic dehydrogenase in umbilical cord blood in healthy infants after different modes of delivery.
      ,
      • Reddy S.
      • Dutta S.
      • Narang A.
      Evaluation of lactate dehydrogenase, creatine kinase and hepatic enzymes for the retrospective diagnosis of perinatal asphyxia among sick neonates.
      ,
      • Morales P.
      • Bustamante D.
      • Espina-Marchant P.
      • et al.
      Pathophysiology of perinatal asphyxia: can we predict and improve individual outcomes?.
      HIE,
      • Thoresen M.
      • Liu X.
      • Jary S.
      • et al.
      Lactate dehydrogenase in hypothermia-treated newborn infants with hypoxic-ischaemic encephalopathy.
      respiratory distress,
      • Ozkiraz S.
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      • Kilicdag H.
      • Ozel D.
      • Sert A.
      Lactate and lactate dehydrogenase in predicting the severity of transient tachypnea of the newborn.
      necrotizing enterocolitis.
      • Morini F.
      • di Crosta I.
      • Ronchetti M.P.
      Lactate dehydrogenase activity is increased in plasma of infants with advanced necrotizing enterocolitis.
      and NICU admission.
      • Patavoukas E.
      • Åberg-Liesaho J.
      • Halvorsen C.P.
      • Winbladh B.
      • Wiberg-Itzel E.
      Relationship between various maternal conditions and lactic acid dehydrogenase activity in umbilical cord blood at birth.
      ,
      • Karlsson M.
      • Dung K.T.
      • Thi T.L.
      • et al.
      Lactate dehydrogenase as an indicator of severe illness in neonatal intensive care patients: a longitudinal cohort study.
      Hence, the present study was conducted with the aim to know the role of umbilical cord arterial pH and LDH levels in assessment of newborns delivered to term antenatal women with HDP.

      2. Material and methods

      Study Design, setting and duration: Present prospective observational study was conducted in the department of Obstetrics and Gynaecology of rural tertiary care centre of Northern India over six months (July 2018 to January 2019).
      Study Sample: All one hundred fifty-five (155) term antenatal women with Hypertensive Disorders of Pregnancy, including Gestational hypertension, Pre-eclampsia, Eclampsia and Chronic hypertension reporting to the labour ward during the study period.
      Inclusion criteria: Gestational age ≥37 to ≤42 weeks, singleton live pregnancy, women with HDP (Gestational hypertension/Chronic hypertension/Pre-eclampsia/Eclampsia).
      Exclusion criteria: Gestation <37 or >42 weeks, normotensive antenatal women, multifetal gestation, intrauterine fetal death, fetus with congenital malformations, maternal drug addiction or smoking or any substance abuse, neonates born to mothers who had received opioids within 4 h prior to delivery (pharmacological depression), hemolytic disease of the newborn, previous cesarean section with scar dehiscence or scar rupture.

      2.1 Definitions

      Hypertension in pregnancy: It is defined as diastolic blood pressure of ≥90 mmHg on two or more occasions more than 4 h apart or a single diastolic blood pressure of >110 mmHg.
      • NICE clinical guideline 107
      Hypertension in pregnancy: the management of hypertensive disorders during pregnancy.
      Gestational hypertension: It is new onset hypertension with systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or both at or after 20 weeks of gestation without proteinuria and or other features of preeclampsia.
      • Magee L.A.
      • Pels A.
      • Helewa M.
      • Rey E.
      • von Dadelszen P.
      Canadian Hypertensive Disorders of Pregnancy Working Group, Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary.
      ,
      • Kintiraki E.
      • Papakatsika S.
      • Kotronis G.
      • Goulis D.G.
      • Kotsis V.
      Pregnancy-Induced hypertension.
      Chronic Hypertension: It is defined as blood pressure ≥140/90 mmHg before pregnancy or before 20 weeks of gestation.
      • Mulrow C.D.
      • Chiquette E.
      • Ferrer R.L.
      • et al.
      Management of chronic hypertension during pregnancy.
      Preeclampsia: It is defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or both with proteinuria and, potentially other end-organ dysfunction.
      • Magee L.A.
      • Pels A.
      • Helewa M.
      • Rey E.
      • von Dadelszen P.
      Canadian Hypertensive Disorders of Pregnancy Working Group, Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary.
      When the systolic blood pressure becomes ≥160 mmHg or diastolic blood pressure ≥110 mmHg, or both, with epigastric pain, cerebral/visual disturbances, decreased urine output, pulmonary edema, thrombocytopenia, deranged liver functions, or intrauterine growth restriction, it is called as severe pre-eclampsia.
      • American College of Obstetricians and Gynecologists
      Emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Committee Opinion No. 623.
      Eclampsia: It is defined as new onset grand-mal seizures in women with preeclampsia.
      • NICE clinical guideline 107
      Hypertension in pregnancy: the management of hypertensive disorders during pregnancy.
      ,
      • Magee L.A.
      • Pels A.
      • Helewa M.
      • Rey E.
      • von Dadelszen P.
      Canadian Hypertensive Disorders of Pregnancy Working Group, Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary.
      Hypoxic Ischemic Encephalopathy: It is defined as deficiency of oxygenation and blood perfusion of brain, leading to brain injury.
      • Chalak L.
      • Kaiser J.
      Neonatal guideline hypoxic-ischemic encephalopathy (HIE).
      It is classified into three stages.
      • Sarnat H.B.
      • Sarnat M.S.
      Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study.
      • Stage I
        Neonates are alert, with normal or hypertonic muscle tone, tendon reflexes are increased, but seizures are absent and the neonates usually remain active and survival is best.
      • Stage II
        Neonates are lethargic with hypotonia, tendon reflexes are increased and seizures are common. All the reflexes of baby are weak and electroencephalography (EEG) shows low voltage, periodic or paroxysmal waves. Mortality ranges between 14 and 17%.
      • Stage III
        The neonates are comatose with flaccid muscle tone; tendon reflexes are depressed or absent with frequent seizures. All neonatal reflexes are absent with EEG showing periodic or isoelectric pattern. Long term morbidity and mortality is usually very high.
      Study Population: One hundred fifty-five (155) term antenatal women with HDP admitted in the labour ward of Obstetrics and Gynaecology department.
      Ethical Issues: The present prospective observational study was carried out after proper Institutional Ethical Committee approval and informed written consent from all the participants.
      Methodology: After obtaining informed written consent from all the randomly selected participants in their vernacular language, demographic features like age, gestation, parity, type of HDP, mode of delivery, etc were recorded on structured data collection sheet. A detailed medical and family history of all participants was taken to ensure that they fulfil the inclusion criteria for study. History of any antepartum convulsions were also recorded in un-booked cases to classify them as eclamptic, if otherwise proved. This was followed by a thorough physical examination of every subject which was recorded. The blood pressure of all the subjects at admission to the labor ward and after 2 h of rest was carefully noted with the woman in sitting position with her arm at the level of heart using an appropriately sized cuff as per the clinical guidelines given by the Society of Obstetricians and Gynecologists of Canada.
      • Magee L.A.
      • Pels A.
      • Helewa M.
      • Rey E.
      • von Dadelszen P.
      Canadian Hypertensive Disorders of Pregnancy Working Group, Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary.
      In order to differentiate between gestational hypertension and pre-eclampsia, around 10 ml of mid-stream urine sample of all the patients was taken in a clean container for urinary protein analysis using dipsticks and it was graded as trace to 4+ (Trace, 0.1 g/L; 1+, 0.3 g/L; 2+, 1 g/L; 3+, 3.0 g/L; 4+, 10 g/L). Furthermore, a detailed history of any pre-pregnancy or early pregnancy (<20 weeks) rise in blood pressure was recorded to confirm chronic hypertension.
      Immediately after delivery by any route (vaginal/cesarean) and before the newborn's first cry umbilical cord arterial blood sample was drawn from the double-clamped 10–12 cm long segment of the cord, as minor changes can occur in umbilical pH within 60 s of delivery,
      • Sarnat H.B.
      • Sarnat M.S.
      Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study.
      and over 60 min it (both arterial or venous pH) can fall by more than 0.2 pH units.
      • Ullrich J.R.
      • Ackerman B.D.
      Changes in umbilical artery blood gas values with the onset of respiration.
      When the cord is doubly clamped immediately after delivery, the pH remains relatively stable at room temperature for an hour.
      • Armstrong L.
      • Stenson B.
      Effect of delayed sampling on umbilical cord arterial and venous lactate and blood gases in clamped and unclamped vessels.
      • Sykes G.S.
      • Molloy P.M.
      Effect of delays in collection or analysis on the results of umbilical cord blood measurements.
      • Armstrong L.
      • Stenson B.J.
      Use of umbilical cord blood gas analysis in the assessment of the newborn.
      The arterial blood sample thus drawn was then collected anaerobically in a pre-heparinized insulin syringe, which was sent immediately for pH estimation by blood gas analyzer at 37° Celsius and around 0.5 ml in a lithium heparin tube for the analysis of LDH levels. Apgar score of the neonates was noted at 1 and 5 min after birth by the pediatrician.
      The data thus obtained included gravidity, parity, gestational age at delivery, mode of delivery, neonatal Apgar score at birth, gender and birth weight of the fetus, umbilical cord arterial blood pH and LDH values, NICU admission, neonatal complications and outcome.

      2.2 Laboratory measurements

      The acid-base values were analyzed immediately using Institutional Siemens arterial blood gas Analyzer machine. The normal reference value taken for arterial cord blood pH in term newborn was 7.24±0.07.
      • Victory R.
      • Penava D.
      • Da Silva O.
      • Natale R.
      • Richardson B.
      Umbilical cord pH and base excess values in relation to adverse outcome events for infants delivering at term.
      In addition to this 0.5 ml of arterial cord blood sample collected in a lithium heparin tube for LDH analysis was transported within 5 min to the department of biochemistry, where the analysis was performed within 10 min of sampling.
      Though LDH can be separated into five different isoenzymes, but in this study, we measured the total LDH activity, which is routinely considered in clinical practice. LDH was analyzed in the biochemistry department of our Institute, using the standard procedure (DGKC method), in which the test tubes containing cord blood sample were first centrifuged and then analyzed by the Erba Mannheim XL System (ERBA diagnostics Mannheim GmbH, Germany). Two reagents (R1 and R2) were used, R1 consisted of Tris buffer (pH 7.5) 100 mmol/l and Pyruvate 2.0 mmol/l and R2 was NADH 1.66 mmol/l. The activity of LDH was then detected by using the reaction given as under: Pyruvate + NADH + H+ → Lactate + NAD+.
      • Henry R.J.
      • Chiamori N.
      • Golub O.J.
      • Berkman S.
      Revised spectrophotometric methods for the determination of glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, and lactic acid dehydrogenase.
      in which LDH catalysis the reduction of pyruvate to lactate oxidizing reduced nicotinamide adenine dinucleotide (NADH) to NAD. The rate of oxidation of NADH was found to be directly proportional to LDH activity in the cord blood sample and the activity was determined by rate of decrease in absorbance at 340 nm as NAD was produced. The analytic range for the equipment was 43.8–1200 U/L with a between-days coefficient of variation (CV) of 2.43%. The normal reference value for LDH taken from umbilical cord arterial blood in a term newborn was <612 U/L.
      • Wiberg-Itzel E.
      • Josephson H.
      • Wiberg N.
      • Olson L.
      • Winbladh B.
      • et al.
      Lactic dehydrogenase in umbilical cord blood in healthy infants after different modes of delivery.

      2.3 Statistical analysis

      Statistical analysis of data was performed using software SPSS version 22.0. Unpaired t-test/Mann-Whitney U- test was used for comparison of two continuous variables and for comparison between more than two groups, ANOVA/Kruskal Wallis test was used. The qualitative variables were correlated using Chi-Square test or Fisher's exact test and a p value of <0.05 was considered statistically significant.

      3. Result

      Of total 155 term antenatal women, 96 (61.9%), had Gestational hypertension, 34 (21.9%) Pre-eclampsia, 17 (11%) Eclampsia and eight (5.2%) had Chronic hypertension. The mean ± SD age of all the patients was 25.6 ± 3.1 years with a minimum of 20 years and maximum of 35 years. The mean ± SD for gestation was 38.48 ± 1.113 weeks, with a minimum of 37 weeks and maximum of 41 weeks. The various demographic features including age, gestation, gravidity, parity, type of HDP, mode of delivery and neonatal birth weight are depicted in Table 1. The comparison of type of HDP with neonatal Apgar score at 1, 5 min, umbilical cord blood arterial pH and LDH levels is depicted in Table 2. Of total 155 term antenatal women with HDP, 85 (54.8%) had normal delivery, 66 (42.6%) lower segment cesarean section (LSCS) [59 (89.4%) emergency LSCS and 7 (10.6%) elective LSCS], three (1.9%) instrumental delivery and one (0.6%) assisted breech delivery. Of 59 emergency LSCS, 40 (67.8%) were done for fetal distress and 19 (32.2%) for reasons other than fetal distress like non-progress of labor, breech in labor and previous cesarean section scar in labor, etc. Neonates born to mothers who underwent emergency LSCS for fetal distress had higher cord blood LDH levels (mean ± SD:673.98 ± 463.34 U/L vs 538.56 ± 869.31U/L) and lower arterial pH (7.12 ± 0.14 vs 7.21 ± 0.12) as compared to the neonates delivered to mothers who underwent LSCS for indications other than fetal distress. Furthermore, of all the delivered neonates 118 (76.13%) had cord blood LDH<612 U/L and 37 (23.9%) had >612U/L. Of these 37 neonates, 27 (73%) were delivered by emergency LSCS, two (5.4%) had instrumental delivery, one (2.7%) by elective LSCS and one (2.7%) by breech assisted vaginal delivery. Hence, neonatal umbilical cord arterial blood LDH levels were significantly associated with the mode of delivery (p = 0.000).
      Table 1Demographic features.
      ParameternPercentage (%)
      Age (Years)
      18–20053.2% (05/155)
      21–257045.2% (70/155)
      26–307246.5% (72/155)
      31–35085.2% (08/155)
      Gestation (weeks)
      ≥37-<399863.2% (98/155)
      ≥39-<415132.9% (51/155)
      ≥41-≤42063.9% (06/155)
      Gravidity
      G16038.7% (60/155)
      G25132.9% (51/155)
      G32818.1% (28/155)
      G4149.0% (14/155)
      ≥G5021.3% (02/155)
      Parity
      Nulliparous7548.4% (75/155)
      Multiparous8051.6% (80/155)
      Type of Hypertensive Disorder of Pregnancy
      Gestational Hypertension9661.9% (96/155)
      Pre-eclampsia3421.9% (34/155)
      Eclampsia1711.0% (17/155)
      Chronic Hypertension085.2% (08/155)
      Mode of delivery
      Normal Delivery8554.8% (85/155)
      Lower segment cesarean section6642.6% (66/155)
      Emergency LSCS5989.4% (59/66)
      Elective LSCS0710.6% (07/66)
      Instrumental delivery031.9% (03/155)
      Breech assisted delivery010.6% (01/155)
      Neonatal Birth Weight (kg)
      ≥1.5-<2.53723.9% (37/155)
      ≥2.5-<3.511272.3% (112/155)
      ≥3.5063.9% (06/155)
      Table 2Comparison of Type of HDP with neonatal Apgar score at 1, 5 min, umbilical cord blood arterial pH and Lactate dehydrogenase levels.
      ParametersGestational HypertensionChronic HypertensionPre-eclampsiaEclampsiaFp-value
      Mean ± SDMean ± SDMean ± SDMean ± SD
      Apgar at 1min6.92 ± 0.876.63 ± 0.746.50 ± 1.165.71 ± 1.217.950.000
      Apgar at 5min8.81 ± 0.678.75 ± 0.718.38 ± 1.107.35 ± 1.2214.750.000
      Cord blood pH7.22 ± 0.107.19 ± 0.107.15 ± 0.127.03 ± 0.1217.840.000
      Cord blood Lactate Dehydrogenase (U/L)349.61 ± 525.09238.26 ± 309.30536.22 ± 443.59939.74 ± 781.756.600.000
      Three eclamptic and one pre-eclamptic antenatal women required ventilatory support for severe hypertension with pulmonary edema, of which one could not be survived and succumbed to death, but the neonates of all four survived.
      Of total 155 delivered neonates, 78 (50.3%) were females and 77 (49.7%) were males. Around 78.1% and 93.5% neonates had Apgar score >7 at one and 5 min respectively, whereas only 21.9% and 6.5% had Apgar score <7 at one and 5 min respectively. The mean ± SD of birth weight of all the neonates was 2.7 ± 0.4 Kg with a minimum of 1.7 Kg and maximum of 3.8 Kg. The mean ± SD values of umbilical cord arterial pH and LDH was 7.2 ± 0.1 and 449.5 ± 562.9 U/L respectively. No significant correlation was observed between neonatal gender, birth weight, and cord blood arterial LDH and pH values. Of total 155 neonates, 112 (72.3%) were born healthy, 22 (14.2%) suffered from HIE I, 14 (9%) HIE II and the remaining 7 (4.5%) had HIE III. The correlation of severity of HIE with mean umbilical cord blood arterial pH and LDH levels is shown in Table 3. Of all the neonates, 112 (72.3%) required resuscitation at birth with 54 (34.8%) requiring NICU admission. There was a total of seven (4.5%) neonatal deaths. The correlation of NICU admission and neonatal death with mean umbilical cord blood arterial pH and LDH levels is depicted in Table 4. It was observed that cord blood LDH was a better predictor of overall neonatal outcome with high sensitivity and negative predictive value for neonatal morbidity and mortality as compared to pH and Apgar score at birth. The sensitivity (100% vs 85.71%), specificity (79.73% vs 59.46%) and Negative predictive value (100% vs 98.88%) of cord blood LDH levels was higher as compared to cord blood arterial pH in prediction of neonatal outcome, as shown in Table 5. The Receiver Operating Characteristic (ROC) curves for umbilical cord arterial blood pH and LDH levels with neonatal death and complications is depicted in Fig. 1, Fig. 2.
      Table 3Correlation of severity of Hypoxic Ischemic Encephalopathy with mean umbilical cord blood arterial pH and LDH levels.
      Severity of Hypoxic Ischemic EncephalopathyHypoxic Ischemic Encephalopathy-IHypoxic Ischemic Encephalopathy-IIHypoxic Ischemic Encephalopathy-IIIFp-value
      Mean ± SDMean ± SDMean ± SD
      Cord blood arterial pH7.10 ± 0.106.99 ± 0.127.00 ± 0.173.7450.032
      Cord blood arterial LDH (U/L)793.25 ± 630.891055.45 ± 732.621770.25 ± 896.345.0360.011
      Table 4Correlation of NICU admission and neonatal death with mean umbilical cord Blood arterial pH and LDH levels.
      ParametersNo

      Mean ± SD
      Yes

      Mean ± SD
      tp-value95% Confidence Interval of Difference
      LowerUpper
      NICU Admission
      Cord arterial blood pH7.24 ± 0.077.08 ± 0.149.4840.0000.1240.19
      Cord arterial blood LDH (U/L)204.68 ± 144.76907.46 ± 743.74−9.200.000−853.687−551.873
      Neonatal Death
      Cord arterial blood pH7.19 ± 0.117.00 ± 0.174.2220.0000.1020.281
      Cord arterial blood LDH (U/L)387.05 ± 460.571770.25 ± 896.34−7.3720.000−1753.890−1012.513
      Table 5Comparison of umbilical cord arterial pH and LDH in predictions of neonatal deaths.
      StatisticsLDH Value (95% CI)pH value (95% CI)
      Sensitivity100.00% (59.04%–100%)85.71% (42.13%–99.64%)
      Specificity79.73% (72.34%–85.89%)59.46% (51.09%–67.44%)
      Positive Likelihood Ratio4.93 (3.58–6.79)2.11 (1.48–3.03)
      Negative Likelihood Ratio00.24 (0.04–1.48)
      Disease prevalence4.52% (1.83%–9.08%)4.52% (1.83%–9.08%)
      Positive Predictive Value18.92% (14.49%–24.31%)9.09% (6.52%–12.54%)
      Negative Predictive Value100.00%98.88% (93.45%–99.82%)
      Accuracy80.65% (73.54%–86.54%)60.65% (52.49%–68.39%)
      Fig. 1
      Fig. 1Depicts Receiver Operating Characteristic curve for cord arterial blood pH and Lactate for neonatal death. The Area under curve (AUC) for cord blood lactate was 0.951 and cord blood pH was 0.815, indicating that cord arterial blood lactate is a better predictor of neonatal death.
      Fig. 2
      Fig. 2Depicts Receiver Operating Characteristic curve for cord arterial blood pH and Lactate of neonates with complications. The Area under curve (AUC) for cord blood lactate was 0.749 and cord blood pH was 0.704, indicating that cord arterial blood lactate is a better predictor of neonatal complications.

      4. Discussion

      The present prospective observational study was conducted to compare the role of umbilical cord arterial blood pH and lactate dehydrogenase levels at birth in assessment of overall neonatal outcome in term antenatal women with HDP. Of total 155 subjects, 96 (61.9%), had gestational hypertension, 34 (21.9%) pre-eclampsia, 17 (11%) eclampsia and eight (5.2%) had chronic hypertension. The mean ± SD for age and gestation of all the patients was 25.6 ± 3.1 years and 38.48 ± 1.113 weeks respectively. In our study we observed a significant derangement of all the neonatal parameters including Apgar score at one and 5 min, cord blood arterial pH and LDH levels with severity of disease. The mean ± SD values Apgar score at one and 5 min, cord blood pH and LDH in neonates delivered to eclamptic women were 5.71 ± 1.21, 7.35 ± 1.22, 7.03 ± 0.12, 939.74 ± 781.75 U/L respectively, which was highly significant (p = 0.000). A similar study observed no significant difference in cord blood arterial LDH levels in neonates born to women with pregnancy-related disorders as compared to those delivered to healthy women (p = 0.95).
      • Patavoukas E.
      • Åberg-Liesaho J.
      • Halvorsen C.P.
      • Winbladh B.
      • Wiberg-Itzel E.
      Relationship between various maternal conditions and lactic acid dehydrogenase activity in umbilical cord blood at birth.
      In our study we observed a significant correlation between the mode of delivery and umbilical cord arterial blood pH and LDH levels. Neonates delivered by emergency LSCS, especially for fetal distress had significantly lower cord blood pH and high LDH levels (p < 0.05). Similar results were reported by another study which observed that maximum levels of mean arterial cord lactate were observed in neonates delivered instrumentally (5.1 mmol/L) followed by those delivered vaginally (4.3 mmol/L), emergency cesarean section (3.9 mmol/L) and minimum in neonates delivered by elective cesarean section (3.2 mmol/L).
      • Khoshnow Q.
      • Mongelli M.
      Cord blood lactate and pH values at term and perinatal outcome: a retrospective cohort study.
      Similarly, another study reported that significantly higher cord arterial blood LDH levels were found in neonates delivered by emergency caesarian section as compared to those delivered vaginally. Moreover, neonates delivered by vacuum extraction had both arterial and venous elevated cord blood LDH levels, same as with emergency cesarean section, as compared to those delivered by spontaneous vaginal delivery and elective cesarean section.
      • Wiberg-Itzel E.
      • Josephson H.
      • Wiberg N.
      • Olson L.
      • Winbladh B.
      • et al.
      Lactic dehydrogenase in umbilical cord blood in healthy infants after different modes of delivery.
      Furthermore, in our study we observed a significant correlation between low cord blood pH and high LDH levels with NICU admission and neonatal death, more so with cord blood LDH levels. The mean ± SD for cord blood pH and LDH for neonates requiring NICU admission was 7.08 ± 0.14 and 907.46 ± 743.74 U/L respectively and for neonates who expired was 7.00 ± 0.17 and 1770.25 ± 896.34 U/L respectively (p = 0.000). A similar study also reported that cord blood lactate levels were significantly better predictor than pH for neonatal morbidity and mortality (ROC curve area: 0.84 vs 0.78, p = 0.03).
      • Tuuli M.G.
      • Stout M.J.
      • Shanks A.
      • Odibo A.O.
      • Macones G.A.
      • Cahill A.G.
      Umbilical cord arterial lactate compared with pH for predicting neonatal morbidity at term.
      Another similar study observed that cord arterial blood lactate level was more strongly associated with admission to NICU (OR 2.91, P < 0.0001) as compared to cord blood pH (OR 2.72, P < 0.0001).
      • Khoshnow Q.
      • Mongelli M.
      Cord blood lactate and pH values at term and perinatal outcome: a retrospective cohort study.
      Similar results were reported by another study which observed that cord blood lactate is better predictor of neonatal morbidity and mortality as compared to umbilical artery pH.
      • Patil S.S.
      • Sukanya Rath S.
      • George C.E.
      Study on umbilical cord arterial blood gas analysis and cord blood lactate levels as predictors for adverse neonatal outcome: an observational study.
      A recent study has also reported that elevated cord blood LDH levels were significantly associated with increased risk of neonatal mortality.
      • Prithviraj D.
      • Reddy B.
      • Deepthi Abhijit
      Laboratory findings and clinical correlation in assessing the severity of perinatal asphyxia.
      Another similar study found that both cord blood Lactate and pH values help in distinguishing between asphyxiated and non-asphyxiated neonates, but lactate levels were observed to be have a better discriminating power.
      • Borruto F.
      • Comparetto C.
      • Wegher E.
      • Treisser A.
      Screening of foetal distress by assessment of umbilical cord lactate.
      In addition to this in our study we found that the cord blood LDH levels were a better predictor of severity of HIE. The mean ± SD of cord blood LDH levels in neonates with HIE I, II and III was 793.25 ± 630.89 U/L, 1055.45 ± 732.62 U/L and 1770.25 ± 896.34 U/L respectively (p = 0.011). Similar results were reported by another study which observed that LDH was not only the best predictor of HIE (sensitivity 100% and specificity 97%) but also its long-term effects on neonates. Furthermore, they observed that poor neonatal condition in first week of birth is strongly associated with elevated cord blood LDH levels.
      • Karlsson M.
      • Dung K.T.
      • Thi T.L.
      • et al.
      Lactate dehydrogenase as an indicator of severe illness in neonatal intensive care patients: a longitudinal cohort study.
      Another similar study reported a significant rise in umbilical cord arterial blood LDH and cardiac enzyme levels (CK-MB and CK-BB) in neonates having stage 3 HIE as compared to neonates with stage 1 and 2 HIE.
      • Prithviraj D.
      • Reddy B.
      • Deepthi Abhijit
      Laboratory findings and clinical correlation in assessing the severity of perinatal asphyxia.
      In our study on comparison of accuracy of umbilical cord arterial blood pH and LDH in prediction of overall neonatal outcome it was observed that LDH is a better predictor with a sensitivity of 100%, specificity of 79.73%, negative predictive value of 100% and a positive predictive value of 18.92%. The overall accuracy of cord blood LDH in prediction of neonatal death was 80.65% as compared to 60.65% for cord blood pH. Similar results were reported by another study which observed that raised cord blood LDH levels had 100% sensitivity, while CK-MB had 100% specificity for neonatal birth asphyxia. Also, they concluded that LDH levels at first 72 h of life are most accurate in differentiating asphyxiated from non-asphyxiated symptomatic neonates.
      • Reddy S.
      • Dutta S.
      • Narang A.
      Evaluation of lactate dehydrogenase, creatine kinase and hepatic enzymes for the retrospective diagnosis of perinatal asphyxia among sick neonates.
      Another similar study observed that cord blood LDH levels are one of the best predictors of prolonged oxygen and respiratory support requirement in newborns with transient tachypnea and has a positive predictive value (PPV) of 88.9%.
      • Ozkiraz S.
      • Gokmen Z.
      • Boke S.B.
      • Kilicdag H.
      • Ozel D.
      • Sert A.
      Lactate and lactate dehydrogenase in predicting the severity of transient tachypnea of the newborn.
      Similar results were reported by another study which observed the sensitivities and specificities of cord blood LDH and pH as 83.9% and 74.1% vs 75.0% and 70.6%, respectively.
      • Tuuli M.G.
      • Stout M.J.
      • Shanks A.
      • Odibo A.O.
      • Macones G.A.
      • Cahill A.G.
      Umbilical cord arterial lactate compared with pH for predicting neonatal morbidity at term.
      Many similar studies have observed that both cord blood lactate and pH had almost equal significance in prediction of overall neonatal outcome.
      • Khoshnow Q.
      • Mongelli M.
      Cord blood lactate and pH values at term and perinatal outcome: a retrospective cohort study.
      ,
      • Einikyte R.
      • Snieckuviene V.
      • Ramasauskaite D.
      • et al.
      The comparison of umbilical cord arterial blood lactate and pH values for predicting short-term neonatal outcomes.
      Hence, Umbilical cord arterial blood pH and LDH levels were significantly associated with poor Apgar score of newborns at birth and correlates well with NICU admission, neonatal complications and deaths in women with hypertensive disorders of pregnancy.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of competing interest

      There are no conflicts of interest.

      Acknowledgement

      I thank Dr. Namit Kant Singh for his expert advice and support.

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