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A case-control study of hypoxic-ischemic encephalopathy in newborn infants at >36 weeks gestation

Published:March 25, 2013DOI:https://doi.org/10.1016/j.ajog.2013.03.023

      Objective

      The purpose of this study was to determine risk factors that are associated with hypoxic ischemic encephalopathy (HIE).

      Study Design

      This was a case-control study that included newborn infants with HIE who were admitted to the hospital between January 2001 and December 2008. Two control newborn infants were chosen for each case. Logistic regression and classification and regression tree (CART) analysis that compared control infants and cases with grade 1 HIE and control infants and cases with grades 2 and 3 HIE was performed.

      Results

      Two hundred thirty-seven cases (newborn infants with grade 1 encephalopathy, 155; newborn infants with grade 2 encephalopathy, 61; newborn infants with grade 3 encephalopathy, 21) and 489 control infants were included. Variables that were associated independently with HIE included higher grade meconium, growth restriction, large head circumference, oligohydramnios, male sex, fetal bradycardia, maternal pyrexia and increased uterine contractility. CART analysis ranked high-grade meconium, oligohydramnios, and the presence of obstetric complications as the most discriminating variables and defined distinct risk groups with HIE rates that ranged from 0–86%.

      Conclusion

      CART analysis provides information to help identify the time at which intervention in labor may be of benefit.

      Key words

      For Editors' Commentary, see Contents
      Intrapartum asphyxia in mature newborn infants causes 10-15% of cases of cerebral palsy, and its prevention is a major justification for the hospitalization of low-risk mothers who give birth in developed countries.
      • Himmelmann K.
      • Hagberg G.
      • Wiklund L.M.
      • Eek M.N.
      • Uvebrant P.
      Dyskinetic cerebral palsy: a population-based study of children born between 1991 and 1998.
      • Gurbuz A.
      • Karateke A.
      • Yilmaz U.
      • Kabaca C.
      The role of perinatal and intrapartum risk factors in the etiology of cerebral palsy in term deliveries in a Turkish population.
      • Perlman J.M.
      Intrapartum hypoxic-ischemic cerebral injury and subsequent cerebral palsy: medicolegal issues.
      • Volpe J.J.
      Neurology of the newborn.
      Despite advances in obstetric and neonatal care over the last 4 decades, the rate of cerebral palsy in normally formed newborn infants with a birthweight of >2.5 kg has not declined.
      • Perlman J.M.
      Summary proceedings from the neurology group on hypoxic-ischemic encephalopathy.
      In addition, the seizure rate and the neonatal encephalopathy rate in newborn infants with a birthweight of >2.5 kg (which is often a marker of acute intrapartum neonatal brain injury) show no decline.
      • Foley M.E.
      • Alarab M.
      • Daly L.
      • Keane D.
      • Macquillan K.
      • O'Herlihy C.
      Term neonatal asphyxial seizures and peripartum deaths: lack of correlation with a rising cesarean delivery rate.
      The objective of this study was to determine risk factors that are associated with the development of hypoxic ischemic encephalopathy (HIE).

      Materials and Methods

      Patient selection

      Inclusion criteria were newborn infants who were born at the Rotunda Maternity Hospital in Dublin from January 2001 to December 2008 at ≥36 weeks 0 days' gestation and who required admission to the neonatal intensive care unit at ≤24 hours after delivery with evidence of encephalopathy. Newborn infants who were born between January 2001 and July 2005 were identified retrospectively. Newborn infants who were born between July 2005 and December 2008 were identified prospectively.
      Grade of encephalopathy was assigned as the highest stage of encephalopathy (Sarnat and Sarnat
      • Sarnat H.
      • Sarnat M.
      Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study.
      grading) that had been documented in the clinical notes and/or as noted on serial examination by a member of the research team (B.C.H., M.D.K., or S.M.). Two control newborn infants (the infants who were born before and after each case) were chosen for each case. Exclusion criteria for cases were out-born infants, <36 weeks' gestation, the presence of a major congenital anomaly, or any primary cause for encephalopathy other than hypoxia-ischemia. Exclusion criteria for control infants were out-born infants, <36 weeks' gestation, the presence of a major congenital anomaly, or any signs of encephalopathy in the neonatal period. If an infant was excluded as a control, then the infant who was delivered either before or after this infant was chosen.
      The obstetrics definitions that were used in data acquisition are outlined in Table 1.
      Table 1Obstetrics definitions used in data acquisition
      VariableDefinition
      Antenatal traumaSignificant fall, accident, or abdominal injury in the antenatal period
      Late bookingInitiation of antenatal care at >24 weeks' gestation
      Pregnancy-induced hypertensionMaternal blood pressure ≥140/90 mm Hg on 2 separate occasions >4 hours apart
      PreeclampsiaNew onset hypertension and proteinuria at >20 weeks' gestation
      Proteinuria>0.3 g protein/d in a 24-hour urine collection or, in the absence of a 24-hour urine collection, the presence of 2+ protein on dipstick
      Gestational diabetes mellitusGlucose intolerance with onset or first recognition during pregnancy and a normal glucose tolerance test by 6 weeks after delivery
      Substantial antepartum hemorrhageVaginal blood loss equal to or greater than a menstrual period
      Nonsubstantial antepartum hemorrhageVaginal blood loss less than a menstrual period
      Fetal bradycardiaDecrease in the baseline fetal heart rate <100 beats/min
      Late decelerationsTransient decrease in fetal heart rate that occurs at or after the peak of a uterine contraction
      Fetal tachycardiaIncrease in baseline fetal heart rate to ≥160 beats/min
      Early decelerationsTransient decrease in fetal heart rate that coincides with the onset of a uterine contraction
      Fetal heart rate variabilityThe beat-to-beat changes in fetal heart rate
      Unsatisfactory cardiotocogramThe presence of a fetal bradycardia and/or late decelerations and/or fetal tachycardia and/or early decelerations (transient decrease in fetal heart rate that coincides with the onset of a uterine contraction) and/or fetal heart rate variability <5 beats/min
      Satisfactory cardiotocogramBaseline rate: 110-160 beats/min; moderate variability; absence of any late or variable decelerations; accelerations that may or may not be present
      High-grade meconiumGrade 3 (thick or pea soup consistency) meconium or meconium that requires tracheal suction
      Maternal pyrexiaTemperature ≥38°C measured with a tympanic thermometer
      Duration of first stage of laborThe time from when the cervix was fully effaced and at least 1-cm dilated (in the presence of regular contractions) up to the time of full dilation
      Shoulder dystociaDifficult delivery of the shoulders that required additional obstetric maneuvers to release the shoulders after gentle downward traction failed
      Uterine ruptureA defect that involves the entire uterine wall that was symptomatic and required surgical intervention
      Placental abruptionPresence of retroplacental hematoma and clinical symptoms (as assessed by the clinical team at the time of delivery)
      Hayes. HIE in newborn infants >36 weeks gestation. Am J Obstet Gynecol 2013.
      Further details on data acquisition are available in the Appendix.
      The data were analyzed by logistic regression analysis to identify the variables that were associated independently with HIE and with a classification and regression trees (CART) analysis to help define the distinct clinical groups at higher risk of HIE. CART analysis examines a dataset to find the best variables and associated cutoff points to group the data into those with and without the outcome in question. Splitting stops when the statistical process determines no further discriminating advantage with any of the remaining factors.
      • Hamilton E.F.
      • Smith S.
      • Yang L.
      • Warrick P.
      • Ciampi A.
      Third- and fourth-degree perineal lacerations: defining high-risk clinical clusters.
      Two analyses were carried out: 1 analysis compared control infants and cases with grade 1 HIE; 1 analysis compared control infants and cases with grades 2 and 3 HIE. Criteria for inclusion included reaching statistical significance (P < .25) in the univariate analysis (Table 2, Table 3, Table 4) and clinical importance. Factors of clinical importance were defined as factors that have been associated with asphyxia and/or neonatal encephalopathy from previous published studies or deemed important from clinical practice. Logistic regression analysis was used to produce estimates of the odds ratios.
      Table 2Univariate analysis of preconception, antenatal, peripartum, and neonatal factors
      VariableControl infantsGrade 1Grade 2Grade 3P value
      λ2 test for trend
      Unadjusted odds ratio95% CI
      n%n%n%n%
      Maternal age, y
      The first analysis looks at age ≤20 years and then in 5-year groupings up to ≥38 years. The second analysis simply looks at <25 years or >25 years
       ≤20357.21912.258.2314.3.24Reference
       21-259319.03925.01219.6419.050.750.407–1.36
       26-3013728.13522.41727.929.50.510.28–0.92
       31-3718928.74931.42134.41047.60.550.31–0.96
       ≥38346.9148.969.829.50.840.40–1.74
      Maternal age, y
      The first analysis looks at age ≤20 years and then in 5-year groupings up to ≥38 years. The second analysis simply looks at <25 years or >25 years
       <2510822.15132.71422.95733.3.0840.670.47–0.95
       ≥2538077.910567.34777.051466.7
      Nationality
       Irish/English35572.811875.23659.01257.1< .050.840.60–1.18
       Other13327.33924.82541.0942.9
      Maternal smoking
       038080.511576.23866.71789.5.17Reference
       1-10/D5812.32516.61221.05210.51.510.97–2.36
       11-20/D316.6106.6610.5001.160.61–2.18
       >20/D30.610.711.8001.50.25–9.08
      Maternal smoking
       No38080.511576.23866.71789.5.19Reference
       Yes9219.53623.81933.3210.5.05
      χ2 test
      1.390.95–2.03
      Mother consumed alcohol during pregnancy
       No71.542.5611.6714.76NANANA
       Yes7214.93119.871016.67523.8NANANA
       Missing40483.621277.54981.671571.4NANANA
      Weekly units of alcohol consumed by mother during pregnancy
       1-24259.2
       3-41419.72167.7250.0360.0.83
       5-71115.5619.4330.0240.0
       ≥845.626.50000
       Regular weekly intake of alcohol (any amount)9219.526.5220.000
      Family history of seizures
       No46696.914894.95998.31995.0.33Reference
       Yes153.185.111.715.01.380.61–3.12
      Obstetric history
       No30864.011171.03051.01467.0.64Reference
       Yes17336.04529.02949.0733.0< .05
      χ2 test
      0.930.67–1.30
      Medical/surgical history
       No21845.76642.33049.2525.0.33Reference
       Yes25954.39057.73150.81575.01.141.57
      Maternal history of respiratory problems
       No44292.714592.955996.71785.0Reference
       Yes357.3117.0523.3315.0.980.920.49–1.70
      Maternal history of cardiovascular problems
       No45695.614794.26098.41995.0.79Reference
       Yes214.495.811.615.01.060.50–2.44
      Maternal history of gastrointestinal problems
       No44593.314291.05691.81785.0.17Reference
       Yes326.7148.9758.2315.01.430.81–2.52
      Maternal history of neurologic problems
       No44593.314391.75793.41785.0.31Reference
       Yes326.7138.346.6315.01.290.72–2.30
      Maternal history of hematologic problems
       No42789.514190.45590.21575.0.34Reference
       Yes5010.5159.669.8525.01.060.64–1.75
      Maternal history of muscular problems
       No43791.613787.85691.81785.0.29Reference
       Yes408.41912.258.23151.410.84–2.36
      Maternal history of depression
       No44392.914794.25895.11575.0.27Reference
       Yes347.195.834.9525.0< .05
      χ2 test
      1.010.55–1.85
      Maternal history of infertility
       No46497.314794.26098.41785.0.05Reference
       Yes132.795.811.6315.0< .05
      χ2 test
      2.080.95–4.57
      Maternal history of hypothyroidism
       No46998.315498.761100.020100.0.26Reference
       Yes81.721.300000.500.105–2.38
      Maternal history of problems (other)
       No36977.411875.64675.41260.0.17Reference
       Yes10822.63824.41524.6840.01.190.93–1.71
      Primiparity
       No26154.25132.72643.3838.1< .001Reference
       Yes22145.910567.33456.71361.92.081.51–2.87
      Parity
       035072.611976.34066.71571.4.485Reference
       19419.52717.31118.329.50.860.57–1.30
       2326.685.1813.3001.010.54–1.89
       361.221.311.7419.12.360.78–7.15
      Gestational age at time of booking
       <12 wk7214.92113.5813.3314.3.06
       13-15 wk22346.27347.12338.3628.6
       16-18 wk8216.93019.41118.3314.3
       19-23 wk469.51610.358.3419.0
       24-30 wk265.485.258.3314.3
       31-37 wk214.442.635.000
       38-42 wk102.110.746.714.8
       Not booked30.6221.311.714.8
      Gestation age at time of booking ≥24 wk
       No42387.614090.34778.31676.2.08Reference
       Yes6012.4159.71321.7523.81.060.66–1.72
      Serology
       Negative46396.915298.15795.02095.2.66Reference
       Positive153.131.935.014.80.950.38–2.36
      Trauma in pregnancy
       No47197.714896.15493.11890.0.01Reference
       Yes112.363.946.9210.02.351.02–5.41
      Medications (any) during pregnancy
       No42590.414091.54581.81583.3.11Reference
       Yes459.6138.51018.2316.71.230.74–2.06
      Substantial antepartum hemorrhage
       No43690.613186.24677.971260.0< .001Reference
       Yes459.42113.81322.03840.02.161.37–3.41
      Growth scans
       No12926.72415.51016.9515.0< .001Reference
       Intrauterine growth restriction81.763.900002.760.89–8.49
       Normal34571.412580.74881.41995.02.031.34–3.07
       Large for dates10.20011.7003.680.22–60.42
      Abnormal growth
       No34594.512595.44898.019100.0.93Reference
       Yes92.564.612.0001.40.52–3.84
      Biophysical profile
       8/831393.711891.54595.719100.0.51Reference
       6/8185.486.224.3000.960.43–2.13
       Other30.932.300001.730.34–8.68
      ARM
       No15732.56239.51525.91257.1.18Reference
       Yes32667.59560.54374.1942.9< .05
      χ2 test
      0.780.56–1.09
      Amniotic fluid volume
       Normal44792.613284.64984.51990.5< .05
       Oligohydramnios285.82113.5813.829.5
       Polyhydramninos81.731.911.700
      Oligohydramnios
       No45594.213586.55086.21990.5.01Reference
       Yes285.82113.5813.829.52.481.45–4.25
      Induction of labor
       No36375.311473.14779.71885.7.39Reference
       Yes11924.74226.91220.3314.30.980.68–1.40
      Method of induction of labor
       No induction36276.011674.04779.71885.7.38Reference
       Prostin, ARM, or syntocinon326.7138.335.1114.81.070.57–1.98
       Combination of 2 methods459.51610.358.529.51.030.60–1.75
       Combination of 3 methods377.8117.146.8000.810.44–1.52
      Stage 1: duration in hours
       09220.52215.61325.0844.4.08
       1-210623.72618.4815.415.6
       3-481.853.6611.500
       5-69521.21712.147.715.6
       7-86815.22215.6815.415.6
       9-12429.41812.735.8211.1
       >12204.52014.2611.5211.1
       Not fully dilated173.8117.847.7316.7
      Syntocinon
       Stage 1
      No31066.07248.33054.61473.7< .05Reference
      Yes16034.07751.72545.5526.31.751.27–2.43
       Stage 2
      None30766.06546.82549.01575.0.01Reference
      In progress12426.75942.51631.4420.01.821.27–2.61
      Stopped347.31510.81019.615.02.231.28–3.90
       Stage 2
      No30766.06546.82549.01575.0< .05Reference
      Yes15834.07453.32651.0525.01.911.37–2.66
      Maximum no. of pains per 15 minutes
       On partogram
      04410.185.71019.6320.0< .05
      2-4368.296.423.916.7
      5-617239.43524.81529.4426.7
      7-814533.25740.41325.5426.7
      >9409.23222.71121.6320.0
       >9
      No39790.810977.34078.41280.0< .001Reference
      Yes409.23222.71121.6320.02.861.80–4.53
       >7
      No33777.17553.23466.71173.3< .01Reference
      Yes10022.96646.81733.3426.72.391.67–3.41
      Analgesia (any)
       No7515.7117.158.829.5.02Reference
       Yes40484.314392.95291.21990.52.191.27–3.76
      Entonox
       No34572.010870.14578.91676.2.46Reference
       Yes13428.04629.91221.1523.80.960.68–1.37
      Pethidine
       No42989.612782.55291.21885.7.33Reference
       Yes5010.42717.558.8314.31.530.96–2.44
      Epidural
       No20843.45837.72950.91257.1.37Reference
       Yes27156.69662.32849.1942.91.010.74–1.39
      General anesthesia
       No48599.413586.05183.61466.7< .001Reference
       Yes30.62214.01016.4733.331.749.69–103.92
      Spinal anesthesia
       No44192.213993.34986.02095.2.57Reference
       Yes377.7106.781414.81.090.61–1.95
      Other analgesia (paracetamol, TENS, fentanyl, remifentanil, solpadeine)
       No47098.114497.355100.021100.0.48
       Yes91.942.70000
      Dilation
       Fully dilated43196.213092.24892.31583.3.01Reference
       Never fully dilated173.8117.847.7316.72.381.20–4.72
      Analgesia given
       None7515.7117.1458.829.5< .001Reference
       Epidural only19841.35133.12035.1628.61.590.89–2.84
       Epidural plus other analgesia7315.24529.2814314.33.191.71–5.98
       Other analgesia, excluding epidural13327.84730.52442.11047.62.531.41–4.54
      Mode of delivery
       Spontaneous vaginal29160.04528.71525.4733.3< .001Reference
       Ventouse8417.44528.71016.9514.72.941.91–4.53
       Forceps71.531.946.8314.36.322.32–17.21
       Elective cesarean418.510.611.7000.2150.05–0.91
       Emergency cesarean489.95233.12542.4942.97.925.09–12.34
       Ventouse and forceps112.374.500002.811.05–7.53
       Instrument delivery/emergency cesarean20.442.646.814.819.94.20–94.29
       Other19339.811271.34474.61466.73.892.78–5.46
       Spontaneous vaginal/elective cesarean332638.64629.31627.1733.3< .001Reference
       Intervention (any)15231.411170.74672.91466.75.423.84–7.61
      Emergency cesarean delivery
       No43489.710164.33050.91152.4< .001Reference
       Yes5010.35635.72949.21047.65.863.96–8.67
      Maternal pyrexia
       No46496.312982.35288.11781.0< .001Reference
       Yes183.72616.8711.9419.04.852.69–8.73
      Maternal antibiotics
       No45794.613688.95191.11785.0.01Reference
       Yes265.41711.158.9315.02.161.22–3.84
      Presentation
      The first category of presentation looks at cephalic, breech and “other” (grouping all other types of presentation) as 3 separate groups. The second analysis groups breech with all other types of presentation
       Cephalic46696.915196.25594.821100.0.83Reference
       Breech102.0810.6423.5000.6190.16–2.27
       Other51.0453.211.7002.470.74–8.21
      Presentation
      The first category of presentation looks at cephalic, breech and “other” (grouping all other types of presentation) as 3 separate groups. The second analysis groups breech with all other types of presentation
       Cephalic46696.915196.25594.821100.0.84Reference
       Breech/other153.1263.835.2001.230.53–2.87
      Complications
      The first analysis studies shoulder dystocia as a separate group, the second combines it with all other complications.
       None46897.112278.74881.41571.4< .001Reference
       Shoulder dystocia112.32012.9711.929.56.723.28–13.73
       Other30.6138.446.8419.0517.845.25–60.53
      Complications
      The first analysis studies shoulder dystocia as a separate group, the second combines it with all other complications.
       No46897.112278.74881.41571.4< .001Reference
       Yes142.93321.31118.6628.69.14.91–16.86
      Fetal heart rate tracing
       Deemed satisfactory13331.11811.8610.700< .001Reference
       Unsatisfactory29568.913588.25089.317100.03.762.35–6.02
      Meconium
       Low grade44391.911070.063559.31676.2< .001Reference
       High grade398.14729.92430.7523.85.403.53–8.28
      Resuscitation
       No34592.763.946.600< .001Reference
       Yes277.314796.15793.421100.0287.5136–605.4
      Birthweight percentile for gestational age
       ≤3rd316.41710.81016.400.53Reference
       3rd-97th42287.613284.14574.01990.5< .05
      χ2 test
      0.530.307–0.911
       ≥97th296.085.169.829.50.630.28–1.40
      Occipitofrontal head circumference percentile for gestational age
       ≤3rd224.753.3711.900.26Reference
       3rd-97th42490.614093.34271.21794.4< .001
      χ2 test
      0.850.41–1.76
       ≥97th224.753.31016.915.61.330.51–3.46
      Occipitofrontal head circumference percentile for gestational age ≥97th percentile
       No44695.314596.74983.11794.4< .05Reference
       Yes224.753.31016.9515.61.550.79–3.00
      Birth order
       Singleton48699.615397.56098.421100.0.18Reference
       Twin20.442.611.6005.221.00–27.13
      Sex
       Female24149.47547.82236.1942.9.10Reference
       Male24750.68252.23963.91257.11.240.90–1.69
      36-37 wks' gestation
       No45294.014391.75591.71365.0.001Reference
       Yes296.0138.358.3735.01.861.06–3.25
      ARM, artificial rupture of membranes; CI, confidence interval; NA, not available because of missing numbers; TENS, transcutaneous electrical nerve stimulation.
      Hayes. HIE in newborn infants >36 weeks gestation. Am J Obstet Gynecol 2013.
      a λ2 test for trend
      b The first analysis looks at age ≤20 years and then in 5-year groupings up to ≥38 years. The second analysis simply looks at <25 years or >25 years
      c χ2 test
      d The first category of presentation looks at cephalic, breech and “other” (grouping all other types of presentation) as 3 separate groups. The second analysis groups breech with all other types of presentation
      e The first analysis studies shoulder dystocia as a separate group, the second combines it with all other complications.
      Table 3Maternal socioeconomic grouping
      Socioeconomic grouping (SEG) classification: 1 = higher managerial, professional; 2 = intermediate managerial, administrative, professional; 3 = skilled manual workers; 4 = semiskilled manual workers; 5 = unskilled manual workers; 6 = casual laborers; 7 = unemployed; 10 = unclassified
      Grade of HIESocioeconomic grouping as per maternal occupation at booking, n (%)
      Pearson χ2 (21) = 31.1671; P = .071
      Socioeconomic grouping, n (%)
      The combined classifications: 0 = SEG 1-5; 1 = SEG 6,7; 10 = SEG 10
      Pearson χ2 (3) = 2.2547 reflects no significant difference using Pearson χ2 between socioeconomic groups for grade of HIE; P = .521.
      123456710Total0110Total
      032 (6.61)72 (14.88)87 (17.98)25 (5.17)37 (7.64)20 (4.13)186 (38.43)25 (5.17)484 (100.00)253 (52.27)206 (42.56)25 (5.17)484 (100.00)
      14 (2.58)38 (24.52)28 (18.06)8 (5.16)15 (9.68)4 (2.58)48 (30.97)10 (6.45)155 (100.00)93 (60.00)52 (33.55)10 (6.45)155 (100.00)
      22 (3.28)7 (11.48)8 (13.11)8 (13.11)4 (6.56)026 (42.62)6 (9.84)61 (100.00)29 (47.54)26 (42.62)6 (9.84)61 (100.00)
      32 (10.00)4 (20.00)2 (10.00)2 (10.00)1 (5.00)09 (45.00)020 (100.00)11 (55.00)9 (45.00)020 (100.00)
      Total40 (5.56)121 (16.81)125 (17.36)43 (5.97)57 (7.92)24 (3.33)269 (37.36)41 (5.69)720 (100.00)386 (53.61)293 (40.69)41 (5.69)720 (100.00)
      HIE, hypoxic ischemic encephalopathy.
      Hayes. HIE in newborn infants >36 weeks gestation. Am J Obstet Gynecol 2013.
      a Socioeconomic grouping (SEG) classification: 1 = higher managerial, professional; 2 = intermediate managerial, administrative, professional; 3 = skilled manual workers; 4 = semiskilled manual workers; 5 = unskilled manual workers; 6 = casual laborers; 7 = unemployed; 10 = unclassified
      b Pearson χ2 (21) = 31.1671; P = .071
      c The combined classifications: 0 = SEG 1-5; 1 = SEG 6,7; 10 = SEG 10
      d Pearson χ2 (3) = 2.2547 reflects no significant difference using Pearson χ2 between socioeconomic groups for grade of HIE; P = .521.
      Table 4Payment status and grade of encephalopathy
      Grade of encephalopathyHealth insurance, n (%)Medical card, n (%)Cash, n (%)Public, n (%)Total, n (%)
      0165 (33.88)115 (23.61)7 (1.44)200 (41.07)487 (100.00)
      150 (32.05)34 (21.79)2 (1.28)70 (44.87)156 (100.00)
      219 (31.15)14 (22.95)2 (3.28)26 (42.62)61 (100.00)
      38 (38.10)5 (23.81)08 (38.10)21 (100.00)
      Total242 (33.38)168 (23.17)11 (1.52)304 (41.93)725 (100.00)
      Pearson χ2 test (9) = 2.6561 reflects no significant difference found between grades of HIE using Pearson χ2 when looking at payment method; P = .976.
      HIE, hypoxic ischemic encephalopathy.
      Hayes. HIE in newborn infants >36 weeks gestation. Am J Obstet Gynecol 2013.
      Ethical approval was obtained from the research ethics committee at The Rotunda Hospital.

      Results

      Two hundred forty-five cases and 490 control infants were included. Maternal records of 8 case newborn infants and 1 control newborn infant could not be located within the timeframe of data collection. Thus, results for 237 case newborn infants (155 newborn infants with grade 1 encephalopathy, 61 newborn infants with grade 2 encephalopathy, and 21 newborn infants with grade 3 encephalopathy) and 489 control newborn infants are described. An Apgar score of ≤5 at 10 minutes, a continued need for resuscitation (including endotracheal or mask ventilation) at 10 minutes after birth, and/or acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord, arterial, or capillary pH ≤7.10) was present in 93 of 155 of newborn infants (60%) with grade 1 HIE; 47 of 61 newborn infants (77%) with grade 2 HIE, and 21 of 21 newborn infants (100%) with grade 3 HIE. Demographic characteristics of case newborn infants and control newborn infants are presented in Table 5.
      Table 5Demographic characteristics of cases and control infants
      VariableControl infants, n (%)Cases, n (%)Grade 1, n (%)Grade 2/3, n (%)P value
      χ2 analysis of trend
      Preconception characteristics
       Nationality< .05
      Irish/English355 (72.8)166 (69.5)118 (75.2)48 (58.5)
      Other133 (27.2)73 (30.5)39 (24.8)34 (41.5)
       Socioeconomic grouping
      Socioeconomic classification 1 = higher managerial, professional; 2 = intermediate managerial, administrative, professional; 3 = skilled manual workers; 4 = semiskilled manual workers; 5 = unskilled manual workers; 6 = casual laborers; 7 = unemployed; 10 = unclassified
      .07
      1-5253 (52.3)133 (51.6)93 (60.0)40 (49.4)
      6-7206 (42.6)87 (33.7)52 (33.6)35 (43.2)
      1025 (5.7)16 (6.2)10 (6.5)6 (7.4)
      Maternal age, y.24
       ≤2035 (7.2)27 (11.3)19 (12.2)8 (9.8)
       21-2593 (19)55 (23.1)39 (25)16 (19.5)
       26-30137 (28.1)54 (22.7)35 (22.4)19 (27.9)
       31-37189 (28.7)80 (33.6)49 (31.4)31 (23.2)
       ≥3834 (6.9)22 (9.2)14 (8.9)8 (9.8)
      Maternal hypothyroidism8 (1.6)2 (0.8)2 (1.3)0.26
      Significant obstetric history
      Defined as infertility and/or preterm labor and/or recurrent miscarriage and/or previous cesarean delivery.
      173 (35.3)81 (33.1)45 (29.0)36 (43.9)< .05
      Infertility13 (2.7)13 (5.3)9 (5.8)4 (4.9).05
      Family history of seizures15 (3.1)10 (4.1)8 (5.1)2 (2.4).33
      Infant characteristics
       Male sex247 (50.6)133 (54.2)82 (52.2)51 (62.2).10
       36-37 wks' gestation7 (2)12 (4.9)6 (3.9)6 (7.3)< .001
       Singleton486 (99.6)234 (95.5)153 (97.5)81 (98.8).18
      Birthweight percentile for gestational age
       ≤3rd31 (6.4)27 (11.0)17 (10.8)10 (12.2)< .05
       3-97th422 (87.6)196 (80)132 (84.1)64 (78.0)
       ≥97th29 (5.9)16 (6.5)8 (5.1)8 (9.8)
      Occipitofrontal head circumference >97th percentile for gestational age22 (4.7)16 (6.5)5 (3.3)11 (13.4)< .05
      Hayes. HIE in newborn infants >36 weeks gestation. Am J Obstet Gynecol 2013.
      a χ2 analysis of trend
      b Socioeconomic classification 1 = higher managerial, professional; 2 = intermediate managerial, administrative, professional; 3 = skilled manual workers; 4 = semiskilled manual workers; 5 = unskilled manual workers; 6 = casual laborers; 7 = unemployed; 10 = unclassified
      c Defined as infertility and/or preterm labor and/or recurrent miscarriage and/or previous cesarean delivery.
      Among the cases, 7 women (3%) did not have electronic fetal heart rate monitoring (2 women who underwent elective cesarean delivery and 5 women who proceeded to emergency cesarean delivery or spontaneous vaginal delivery without time for electronic fetal heart rate monitoring); intermittent electronic fetal heart rate monitoring was applied in a further 19 women (8%). All remaining cases had continuous fetal heart rate monitoring.
      Among control infants, 50 women (10.2%) did not have electronic fetal heart rate monitoring (37 women who underwent elective cesarean delivery and 13 women who proceeded to emergency cesarean delivery or spontaneous vaginal delivery without time for electronic fetal heart rate monitoring); intermittent electronic fetal heart rate monitoring was applied in a further 84 women (17.2%). All remaining control infants had continuous fetal heart rate monitoring.
      Results of univariate analysis are available (Table 2). The following factors reached statistical significance (P < .25) and were included in the multivariate analysis: maternal age, nationality, maternal smoking, history of infertility, primiparity, gestational age at booking, late booking, antenatal trauma, medication use in pregnancy, substantial antepartum hemorrhage, abnormal growth scans, artificial rupture of membranes, oligohydramnios, duration of first stage of labor, oxytocin use, maximum number of pains per 15 minutes, use of analgesia, general anesthesia, failure to reach full dilation, mode of delivery, maternal pyrexia, maternal antibiotics, obstetric complications (defined as the presence of shoulder dystocia, placental abruption, or uterine rupture), fetal heart rate abnormalities, high-grade meconium, birthweight, head circumference >97th percentile for gestational age, male sex, and gestation at delivery. Given that the decision to deliver by emergency cesarean delivery represents a number of factors, mode of delivery was not included in the CART analysis. Mode of delivery was included in logistic regression analysis.

      Multivariate analysis

      Comparison of control infants with cases of grade 1 HIE

      Table 6 provides a summary of the logistic regression analysis. Seven factors (artificial rupture of membranes, oligohydramnios, >7 pains documented in any 15 minutes, maternal pyrexia, obstetric complications, high-grade meconium, and emergency cesarean and/or instrumental delivery) reached statistical significance for independent association with grade 1 HIE. Recognition of oligohydramnios and the presence of increased uterine contractility represent variables that may be recognized in early labor. Figure 1 shows the results from the CART analysis.
      Table 6Logistic regression analysis of case control data
      VariableUnadjusted odds ratio95% CIP valueCases vs control infants (all grades)Grade 1 HIE vs control infantsGrades 2 and 3 HIE vs control infants
      Adjusted odds ratio95% CIP valueAdjusted odds ratio95% CIP valueAdjusted odds ratio95% CIP value
      Maternal age (<25 y)0.670.47–0.95.0250.920.61–1.60.9820.910.44–1.30.3160.920.33–2.65.886
      Maternal smoking (yes)1.390.95–2.03.0821.750.97–3.15.0651.620.80–3.29.1762.460.94–6.41.065
      Primigravid2.081.51–2.87.0001.010.55–1.82.9671.110.37–3.25.8514.380.86–22.36.075
      Trauma in pregnancy2.351.02–5.41.0440.740.20–2.64.6440.520.11–2.43.4102.130.33–13.45.419
      Significant antepartum hemorrhage2.161.37–3.41.0011.750.89–4.40.1011.120.49–2.56.2808.242.58–26.33.000
      Artificial rupture of membranes0.780.56–1.09.1500.620.37–1.01.0540.480.27–0.85.0111.150.44–2.99.772
      Oligohydramnios2.481.45–4.25.0011.940.82–4.55.1283.402.12–8.23.0000.940.15–5.82.951
      Stage 2 oxytocin1.911.37–2.66.0000.990.57–1.72.9901.210.41–3.57.7241.290.40–4.17.668
      Maximum no. of pains per 15 min >72.391.67–3.41.0002.071.13–3.81.0182.261.14–4.49.0191.230.41–3.68.701
      Analgesia (any)2.191.27–3.76.0041.020.38–2.72.9651.070.28–4.08.9110.620.14–2.63.520
      Emergency section/instrument delivery5.423.84–7.61.0003.031.75–5.24.0006.141.94–19.45.0025.871.42–24.12.014
      Maternal pyrexia4.852.69–8.73.0004.452.02–9.78.0006.071.13–32.45.03515.931.91–132.45.010
      Maternal antibiotics2.161.22–3.84.0080.670.24–1.81.4333.250.37–28.51.2861.220.25–5.99.802
      Complications9.14.91–16.86.00013.612.67–69.26.00210.441.51–72.1.0178.910.59–133.24.113
      Bradycardia3.272.18–4.92.0002.631.44–4.79.0021.430.41–4.93.56511.042.23–54.75.003
      High-grade meconium5.403.53–8.28.0005.132.86–9.19.0004.192.12–8.27.00013.824.59–41.64.000
      Birthweight ≤3rd percentile1.861.08–3.20.0241.850.75–4.54.1771.270.41–3.92.6715.311.39–20.18.014
      Head circumference ≥97th percentile1.550.79–3.00.1972.651.01–6.93.0431.290.32–5.19.7119.322.57–33.90.001
      Sex (male)1.240.90–1.69.1740.990.62–1.60.9820.750.44–1.30.3161.930.78–4.77.151
      Weeks gestation–continuous variable
      Included in the multivariate analysis to control for birthweight.
      1.050.93–1.17.4490.980.82–1.18.3871.040.83–1.30.7020.820.603–1.10.194
      The following interactions were included in the multivariate analysis: primigravid × intervention at delivery; primigravid × bradycardia; stage 2 oxytocin × intervention at delivery; maternal pyrexia × intervention at delivery; maternal antibiotics × intervention at delivery; complications × intervention at delivery; complications × max number of pains per 15 minutes >7.
      CI, confidence interval; HIE, hypoxic ischemic encephalopathy.
      Hayes. HIE in newborn infants >36 weeks gestation. Am J Obstet Gynecol 2013.
      a Included in the multivariate analysis to control for birthweight.
      Figure thumbnail gr1
      Figure 1CART analysis: comparison of control infants with cases with grade 1 disease
      Analysis shows the hierarchy of factors, the percentage of HIE, and the number of records at each node. A, All subjects with grade 1 HIE and controls. B shows that the presence of an obstetric complication was the single most discriminating factor. The presence of C, high-grade meconium, D, oligohydramnios, and E, birthweight <2720 g helped to further discriminate between cases with grade 1 HIE and control infants.
      CART, classification and regression tree; HIE, hypoxic ischemic encephalopathy.
      Hayes. HIE in newborn infants >36 weeks gestation. Am J Obstet Gynecol 2013.

      Comparison of control infants to grades 2 and 3 cases

      Seven variables (significant antepartum hemorrhage, maternal pyrexia, fetal bradycardia, high-grade meconium, birthweight <3rd percentile for gestational age, head circumference >97th percentile for gestational age, and emergency cesarean/instrument delivery) reached statistical significance for independent association with grade 2 and 3 HIE on logistic regression analysis. Recognition of possible growth restriction and/or large fetal head size represents possible modifiable variables. Figure 2 shows the results from CART analysis. Some variables (maternal pyrexia, large head circumference) that have been found to be significant on logistic regression were not identified to form nodes with the tree approach. In CART analysis, the role of these factors may be buried within others because there is no attempt to identify independence, rather the goal is to define and rank the most predictive clinical groupings.
      Figure thumbnail gr2
      Figure 2CART analysis: comparison of control infants with cases with grade 2 and 3 disease
      Analysis shows the hierarchy of factors, the percentage of hypoxic-ischemic encephalopathy, and the number of records at each node. A, All subjects with grade 2/3 HIE and controls. B shows that the presence of high-grade meconium was the single most discriminating factor. The presence of C, obstetric complications or D, oligohydramnios were the next most discriminating factors, followed by E, fetal bradycardia, F and J, male sex, G and I, birthweight, H, gestation <38 weeks, and K, maximum number of pains documented in any 15 minutes on partogram. Three terminal nodes show extreme rates of HIE. These are positions D, (high-grade meconium with oligohydramnios), F, (presence of obstetric complications and male sex), and K, (high-grade meconium, absence of oligohydramnios, birthweight >3590 g with >7 pains documented in any 15 minutes).
      CART, classification and regression tree; HIE, hypoxic ischemic encephalopathy.
      Hayes. HIE in newborn infants >36 weeks gestation. Am J Obstet Gynecol 2013.

      Comment

      This study identifies a number of important factors that place newborn infants at a significantly increased risk of not tolerating labor. These include higher grade meconium, growth restriction, a large head circumference, oligohydramnios, male sex, fetal bradycardia, and maternal pyrexia. A novel factor that was identified is increased uterine contractility. Defining terminal nodes and their associated complication rates demonstrates how CART analysis can provide useful information to help guide the time that intervention in labor may be of benefit.
      The significant preconception/antenatal factors that were associated with encephalopathy that were found in this study differ from those in the Western Australian study.
      • Badawi N.
      • Kurinczuk J.J.
      • Keogh J.M.
      • et al.
      Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study.
      • Badawi N.
      • Kurinczuk J.J.
      • Keogh J.M.
      • et al.
      Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study.
      This study did not find an association with a family history of seizures, maternal hypothyroidism, or neurologic problems. The broad definition of encephalopathy that was used in the study by Badawi et al
      • Badawi N.
      • Kurinczuk J.J.
      • Keogh J.M.
      • et al.
      Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study.
      may have included newborn infants with encephalopathy of genetic or metabolic origin.
      The lack of any association with socioeconomic status (ie, public/private booking, medical card status, and maternal employment) was surprising. This is in contrast to the findings of other studies.
      • Himmelmann K.
      • Hagberg G.
      • Wiklund L.M.
      • Eek M.N.
      • Uvebrant P.
      Dyskinetic cerebral palsy: a population-based study of children born between 1991 and 1998.
      • Badawi N.
      • Kurinczuk J.J.
      • Keogh J.M.
      • et al.
      Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study.
      • Wu Y.W.
      • Colford Jr., J.M.
      Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis.
      • Wu Y.W.
      • Backstrand K.H.
      • Zhao S.
      • Fullerton H.J.
      • Johnston S.C.
      Declining diagnosis of birth asphyxia in California: 1991-2000.
      To date, there are few studies on the role of induction/augmentation of labor in the causation of HIE.
      • Caughey A.B.
      • Sundaram V.
      • Kaimal A.J.
      • et al.
      Maternal and neonatal outcomes of elective induction of labor.
      Most studies, even if combined in metaanalysis, have limited statistical power for the assessment of a difference in perinatal mortality rate.
      • Sanchez-Ramos L.
      • Olivier F.
      • Delke I.
      • Kaunitz A.M.
      Labor induction versus expectant management for postterm pregnancies: a systematic review with meta-analysis.
      In this study, the induction of labor by any method did not increase the odds of encephalopathy.
      Frequency of contractions was a highly significant risk factor when there were >7 contractions during any 15-minute period. There are few studies on the influence of uterine activity on fetal status, despite awareness that increased uterine activity is associated with higher incidence of an umbilical artery pH of ≤7.11.
      • Bakker P.C.
      • Kurver P.H.
      • Kuik D.J.
      • Van Geijn H.P.
      Elevated uterine activity increases the risk of fetal acidosis at birth.
      • Simpson K.R.
      • James D.C.
      Effects of oxytocin-induced uterine hyperstimulation during labor on fetal oxygen status and fetal heart rate patterns.
      This study identified increased uterine contractions as an independent risk factor for asphyxia. In addition to frequency, the duration and amplitude of contractions are important
      • Impey L.W.
      • Greenwood C.E.
      • Black R.S.
      • Yeh P.S.
      • Sheil O.
      • Doyle P.
      The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy.
      but were not available retrospectively. Uterine contraction rate over a 15-minute period was chosen because this information was easily available on the maternal partogram.
      There is huge reliance on the cardiotocogram, despite poor specificity.
      • Nelson K.B.
      • Dambrosia J.M.
      • Ting T.Y.
      • Grether J.K.
      Uncertain value of electronic fetal monitoring in predicting cerebral palsy.
      This study confirms the high false-positive rate with some abnormality noted on cardiotocogram in 68.9% of control newborn infants. In this study, fetal bradycardia was the only fetal heart rate abnormality that reached statistical significance for independent association with HIE. Although fetal heart rate trace is relied on heavily in the management of labor, uterine contractions (particularly if not associated with fetal heart rate changes) are often ignored. This study highlighted the limitations and usefulness of cardiotocogram and found that here is over reliance on fetal heart rate but less recognition of the importance of increased uterine activity.
      In keeping with previous studies, maternal pyrexia in labor
      • Impey L.W.
      • Greenwood C.E.
      • Black R.S.
      • Yeh P.S.
      • Sheil O.
      • Doyle P.
      The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy.
      • Peebles D.M.
      • Wyatt J.S.
      Synergy between antenatal exposure to infection and intrapartum events in causation of perinatal brain injury at term.
      and higher grade meconium
      • Ojha R.K.
      • Singh S.K.
      • Batra S.
      • Sreenivas V.
      • Puliyel J.M.
      Lactate: creatinine ratio in babies with thin meconium staining of amniotic fluid.
      • Gupta V.
      • Bhatia B.D.
      • Mishra O.P.
      Meconium stained amniotic fluid: antenatal, intrapartum and neonatal attributes.
      were independent risk factors for the development of encephalopathy. It is suggested that hypoxia-ischemia and infection/inflammation share common inflammatory and molecular pathways and therefore have synergistic effects. Cerebral concentrations of proinflammatory cytokines have been shown to be elevated after exposure to either hypoxia-ischemia or infection/inflammation.
      • Peebles D.M.
      • Wyatt J.S.
      Synergy between antenatal exposure to infection and intrapartum events in causation of perinatal brain injury at term.
      In this study, 57 of 724 women (7.9%) had pyrexia in labor, but positive cultures were identified in only 2 cases. Twenty of 57 women (35%) received antibiotics, which may have led to false-negative cultures, although these figures suggest that maternal pyrexia may be inflammatory rather than infective.
      The association between fetal growth restriction and neonatal encephalopathy is well recognized.
      • Yager J.Y.
      Animal models of hypoxic-ischemic brain damage in the newborn.
      • Hankins G.D.
      The long journey: defining the true pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy.
      In CART analysis, birthweight appeared in multiple branches, but with different thresholds. There are many different causes of fetal growth restriction, and each may differ in its potential to contribute to the development of encephalopathy.
      • Badawi N.
      • Kurinczuk J.J.
      • Keogh J.M.
      • et al.
      Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study.
      A head circumference >97th percentile was associated independently with grade 2 and 3 HIE and remained so after adjustment for birthweight and gestation, which suggests that head size rather than overall size of the newborn infant may be the important factor. A previous study in rural Nepal found larger newborn infant head circumference carried a higher risk of neonatal asphyxia.
      • Lee A.C.
      • Darmstadt G.L.
      • Khatry S.K.
      • LeClerq S.C.
      • Shrestha S.R.
      • Christian P.
      Maternal-fetal disproportion and birth asphyxia in rural Sarlahi, Nepal.
      There was no independent association with higher newborn birthweight, which was similar to the findings of this study. A recent study examined the accuracy of sonographic estimation of fetal head circumference up to 3 days before delivery and noted that sonographic measurements consistently underestimated postnatal head circumference by an average of 13.5 mm or 4%.
      • Melamed N.
      • Yogev Y.
      • Danon D.
      • Mashiach R.
      • Meizner I.
      • Ben-Haroush A.
      Sonographic estimation of fetal head circumference: how accurate are we?.
      This may be explained by the fact that sonographic measurements include only the bony calvaria of the fetal skull. In view of the high correlation between sonographic and postnatal measurements (r = 0.845; P < .001), fetal sonographic head circumference measurement before delivery may be of value.
      • Hadlock F.P.
      • Deter R.L.
      • Harrist R.B.
      • Park S.K.
      Fetal head circumference: relation to menstrual age.
      Areas of interest for future studies include the impact of a large head circumference relative to maternal pelvic capacity and absolute head circumference measurement.
      It is acknowledged that cause and effect are difficult to demonstrate in a case-control study. In addition, the retrospective component of this study was a limitation. Different datasets (intensive care admission records, ward journals, and radiology records) were cross-referenced, and it is unlikely that a significant number of newborn infants with encephalopathy during this period were missed. Labor and delivery data may be subject to bias because they were obtained from the maternal chart rather than prospectively. Data on maternal weight/pregnancy weight gain were not available, and labor information on the small number of women in the later stages of labor was limited. Fetal heart rate recordings on newborn infants with grades 2 and 3 encephalopathy (2001-2008) and with grade 1 encephalopathy (2004-2008) and 1 set of control recordings were reviewed independently by a blinded obstetrician (J.K.). Unfortunately, because a large proportion of fetal heart rate tracings were not located or had faded with time, only 102 fetal heart tracings were available. Because of the relatively small number of fetal heart rate recordings that were available, information on fetal heart rate tracings as documented in the medical chart at the time of delivery were used in the analyses. This may have limited the data that were available on fetal heart rate patterns.
      All newborn infants with HIE were included regardless of demographic characteristics. Therefore, our results are applicable to any health care setting with similar demographics and health care systems.
      The findings of this study may serve to identify infants who are at risk of not tolerating the labor process and assist in the decision-making process regarding the need for cesarean delivery.

      Acknowledgments

      We thank Myra O'Regan, Associate Professor of Statistics, Trinity College Dublin, for the statistical support and the children and their families who participated in this project.

      Appendix.

      Data acquisition

      Preconception variables

      Maternal age, nationality, family history, medical history (including thyroid and seizure history), obstetric history, parity, tobacco, alcohol, or medication exposure as recorded in the maternal chart was noted. Documented histories of infertility, in vitro fertilization, or clomiphene citrate use were used as markers of infertility. Parental occupations registered on booking and whether the mother held private health insurance, paid cash, or was publically funded were recorded as markers of socioeconomic status. With publically funded subjects, those who qualified for a medical card (awarded on the basis of income below a certain threshold or ongoing medical costs that would lead to undue hardship) were identified separately.

      Antenatal variables

      Apart from late bookers, all women had a dating ultrasound scan. When the menstrual cycle was regular and the last menstrual period was certain and crown-rump length was equivalent to the gestational age ±7 days, the expected date of delivery was calculated from the last menstrual period. In situations in which the menstrual cycle was irregular or the last menstrual period was uncertain or the crown-rump length differed from the gestational age at last menstrual period by >7 days, gestation was calculated by ultrasound scanning. The gestation at booking and any history of antenatal trauma in pregnancy were noted. Late booking and complications of pregnancy (in particular, pregnancy-induced hypertension, preeclampsia, gestational diabetes mellitus, or hypothyroidism) were recorded. Antepartum hemorrhage was graded as substantial or nonsubstantial, and the gestation at which it occurred was documented. Results of growth scans and biophysical profiles that had been performed antenatally were recorded.

      Intrapartum and delivery variables

      The intrapartum cardiotocogram features (if labor had been established) or the characteristics of the cardiotocogram that had been performed before delivery (if labor did not occur), as noted in the maternal chart by either the attending physician or midwife at the time of labor and/or delivery, were recorded. The amniotic fluid volume during the intrapartum period either on rupture of the membranes or by ultrasound assessment was recorded. The grade of meconium that had been noted at delivery was recorded; when this was not stated clearly, the level that had been noted before delivery was documented. The presence of maternal pyrexia and the use of maternal antibiotics in labor were noted. All analgesia that had been administered in the intrapartum period was documented. Use of spinal, epidural, and/or general anesthesia was recorded. The method of membrane rupture (spontaneous or artificial) and duration of rupture of membranes before delivery were noted.
      The type of labor (spontaneous/induced/augmented) and the method used for induction or augmentation were recorded. The maximum rate of infusion of oxytocin at any period in the intrapartum period was noted; if the infusion had been discontinued, the reason for doing so was noted. The maximum number of contractions in any 15-minute interval on each partogram was documented.
      For a subset of infants with grade 1 encephalopathy (those delivered in 2007 and 2008) and for all case infants with grades 2 and 3 encephalopathy, the total number of contractions as documented on the partogram was noted. For this variable, the total number of contractions as documented on the partogram for 1 set of control infants was recorded. The duration of first and second stages of labor (as recorded on maternal partogram) and whether a full 10 cm of dilation was reached was determined from maternal notes that included the maternal partogram. Patients with no labor were coded as length of first stage labor equal to zero. In addition, the mode of delivery for nonlaboring patients who had an elective cesarean delivery was coded with spontaneous vaginal delivery (0 = spontaneous vaginal delivery or elective section); those patients with an emergency cesarean delivery were coded with instrument deliveries (1 = forceps, ventouse, or emergency cesarean delivery). Details of any intervention during labor and delivery, the presentation of the infant in labor, details of complications that were encountered (shoulder dystocia, placental abruption, uterine rupture), and the mode of delivery were also recorded.

      Infant factors

      Infant gestation, birthweight, head circumference, Apgar score, cord pH, resuscitation details, and time to regular respirations were documented from the infant medical record. Neurologic signs on day 1 and 2 of life were recorded from the medical chart.

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