Strength of association between umbilical cord pH and perinatal and long term outcomes: systematic review and meta-analysis.

OBJECTIVE: To evaluate the association between umbilical cord pH at birth and long term outcomes.
DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline (1966-August 2008), Embase (1980-August 2008), the Cochrane Library (2008 issue 8), and Medion, without language restrictions; reference lists of selected articles; and contact with authors. STUDY SELECTION: Studies in which cord pH at birth was compared with any neonatal or long term outcome. Cohort and case-control designs were included.
RESULTS: 51 articles totalling 481 753 infants met the selection criteria. Studies varied in design, quality, outcome definition, and results. Meta-analysis carried out within predefined groups showed that low arterial cord pH was significantly associated with neonatal mortality (odds ratio 16.9, 95% confidence interval 9.7 to 29.5, I(2)=0%), hypoxic ischaemic encephalopathy (13.8, 6.6 to 28.9, I(2)=0%), intraventricular haemorrhage or periventricular leucomalacia (2.9, 2.1 to 4.1, I(2)=0%), and cerebral palsy (2.3, 1.3 to 4.2, I(2)=0%).
CONCLUSIONS: Low arterial cord pH showed strong, consistent, and temporal associations with clinically important neonatal outcomes that are biologically plausible. These data can be used to inform clinical management and justify the use of arterial cord pH as an important outcome measure alongside neonatal morbidity and mortality in obstetric trials.

Introduction

Perinatal asphyxia is a major cause of neonatal and childhood morbidity and mortality and has been associated with neonatal death1; hypoxic ischaemic encephalopathy and seizures2 3; intraventricular haemorrhage4; cerebral palsy5; and delayed development.5 Perinatal asphyxia is predicated by fetal acidosis, determined by umbilical cord pH at birth.6 Cerebral palsy is thought to occur more frequently at an arterial cord pH of <7.00 and a base deficit of ≥12 mmol/l.7 These criteria, however, have been derived through consensus, not through evaluation of collated summaries of evidence,7 leading to clinical uncertainty.8 This is because existing observational studies of the association between cord pH and outcomes have drawn inconsistent inferences, partly as a result of the different thresholds used to define abnormality, the variety of outcomes evaluated, and the different variables measured (arterial cord pH, venous cord pH, or base excess).9 10 11 It has been suggested that neonatal complications are associated with metabolic rather than respiratory acidosis.12 13 Respiratory acidosis arises in the early stages of impaired blood supply to the fetus; hypoxaemia and hypercapnia occur, leading to a reduction in pH with a normal base excess.6 If hypoxia is prolonged, anaerobic metabolism results and base excess rises secondary to the presence of lactic acidosis.

On the basis of nine studies, a review14 claimed an association between fetal acidosis and neonatal death and cerebral palsy. This review was, however, carried out in the late 1990s, during which time new studies on the subject have been published and guidelines produced on the methodology and reporting of systematic reviews, including quality assessment of included studies, which were not in widespread use at the time of the review’s publication.15 Substantial uncertainty therefore remains about the value clinicians may attach to acidosis in the clinical management of neonates and the long term implications of a low arterial cord pH. However, cord pH is also commonly used as an outcome measure in obstetric clinical trials16 17 18 and it is one of the bench marks by which obstetricians judge their performance on the labour ward.19 A documented low cord pH is a factor that may be used to support medico-legal claims of harm during intrapartum events resulting in long term disability.20 It is therefore imperative that the validity of this association is supported with high quality evidence. We carried out a comprehensive systematic review of the literature to quantitatively establish the strength of association of acidosis at birth with neonatal mortality, morbidity, and long term outcomes and to assess if causal criteria were met.21

Methods

This systematic review was protocol driven using widely recommended methods for reviews22 23 24 and evaluation of causal associations.21 25 26 27 28 The review was carried out and has been reported according to MOOSE guidance.15

We searched Medline (1966-August 2008), Embase (1980-August 2008), the Cochrane Library (2008 issue 8), and Medion for relevant published articles. To identify “grey” literature we also searched SIGLE, Web of Science, the national research register, and medical conferences register. For the Medline search (also see web extra on bmj.com) we used a combination of MeSH headings, such as umbilical cord, hydrogen-ion concentration, or asphyxia neonatorum; keywords, such as umbilical artery pH and cord pH; and word variants using “OR” for capturing citations of the relevant text. To capture relevant outcomes we combined these using “AND” with a combination of MeSH headings, such as human development and infant mortality; keywords, such as developmental delay and handicap; and word variants. We restricted the search to human studies but applied no language restrictions. We adapted the Medline search strategy for use in other databases. We also hand searched recent major journals. Two investigators (RKM and GLM) carried out the search. Using Reference Manager 11.0, we constructed a comprehensive database collating all citations.

Study selection and data extraction

Two reviewers (RKM or GLM, partly in duplicate) scrutinised the database and obtained full articles of all citations potentially meeting the predefined selection criteria. Translations of articles in languages other than English were obtained. Two reviewers (GLM and RKM or ZL) included or excluded studies in accordance with the most recent guidance,23 using strict adherence to the following criteria: population—infants with cord blood obtained at birth; index test—cord blood examined for arterial or venous pH or base excess; outcome—any measure of compromise of neonatal or childhood wellbeing, such as mortality; neonatal morbidity, including hypoxic ischaemic encephalopathy, seizures, intraventricular haemorrhage, periventricular leucomalacia, and long term outcomes, including cerebral palsy; and study design—observational studies that allowed generation of a 2×2 table (true positives, false positives, false negatives, and true negatives) to compute an estimate of the association between test result and outcomes. We excluded studies with five or fewer cases, because of unreliability.

The manuscripts were examined for duplicated populations. If any were found we selected the most recent and complete version. No language restrictions were applied in study selection. We scrutinised the reference lists of selected studies and review articles and obtained additional relevant articles. Two researchers (GLM and RKM or ZL) used a data collection sheet to extract information in duplicate from the selected articles. Data were extracted on study characteristics, quality, and results, and entered onto an Excel spreadsheet. Data were used to construct 2×2 tables of the association between the cord blood variable at the threshold reported in the paper and the postnatal outcome for each infant. When data were thought to be relevant but 2×2 tables could not be constructed, we contacted the relevant authors. Difficulties in data extraction were resolved by discussion with a third reviewer (KSK).

Study quality assessment

We assessed those articles meeting the selection criteria for methodological quality, defined as the confidence that the study design, conduct, and analysis minimised bias in estimation of the association. The articles were assessed using the complete STARD and QUADAS checklists.29 30 These are guidelines for reporting, and methodological quality of, studies on diagnostic accuracy. As the focus of this review was to determine association, the checklist items thought to be most relevant were selected for the purpose of defining the overall quality of included studies and to divide the studies according to quality for meta-analysis and metaregression, in accordance with published guidance.23 We did not assign a quality score as this has been shown to give flawed results.31 We considered the cohort study design to be superior to the case-control design, and we considered the cohort design as a covariate in metaregression. Because of the small number of studies included in each meta-analysis we did not think it appropriate to consider each remaining quality item as an individual covariate for metaregression,32 and we therefore divided the studies into two categories on the basis of several criteria. We rated a study as being of high quality if it had at least four of the following items: adequate description of population, adequate description of the test and outcome measure, consecutive recruitment, prospective recruitment, more than 90% completion of follow-up, appropriate outcome measurement, blinding of the investigators carrying out the outcome measure, and a statement on the use of intervention between the index test and outcome. When a study adhered to three or fewer of these criteria we considered it to be of medium or low quality.

Data synthesis

We used 2×2 tables to compute odds ratios and 95% confidence intervals for each pair of index test and outcome. The odds ratio was selected as the summary statistic as it is relatively constant regardless of the test threshold33 and is often used to show an epidemiological association.34 It represents the effect of the exposure on the odds in an unbiased fashion and enables linkage between the results of case-control and cohort studies.34 As the focus of this review was to establish the association between cord pH and adverse outcome rather than the value of cord pH as a prognostic test, we did not calculate other summary statistics (including sensitivity, specificity, and likelihood ratios). We calculated the estimated predictive interval for each meta-analysis, which relates to the effect of a new study that would be eligible for inclusion in meta-analysis and therefore allows the full uncertainty around inferences to be calculated, including both magnitude and consistency.35

When tables contained cells with a value of 0, we added 0.5 to these cells to allow the calculation of variances.36 Analyses were done for groups defined a priori according to index test (arterial cord pH, venous cord pH, and base excess). The main outcome measures considered were neonatal mortality, a composite measure of neonatal morbidity, and cerebral palsy. To maximise the number of events that could be included in the analysis and to avoid the need to select a single morbidity as a primary outcome measure, we used a composite outcome measure for neonatal morbidity. However, a hazard of composite outcome measures is the assumption that the significance of the result applies to all components.37 To deal with this, we analysed the component outcomes of hypoxic ischaemic encephalopathy, seizures, intraventricular haemorrhage, or periventricular leucomalacia. When the composite outcome measure was used, we took care to ensure that each individual was counted only once in each analysis, particularly when studies reported multiple outcomes for a single population. When multiple outcomes and test thresholds were reported, we attempted to select the most consistent threshold and outcome across the composite analysis—for example, where studies reported on hypoxic ischaemic encephalopathy, seizures, and intraventricular haemorrhage, we included hypoxic ischaemic encephalopathy and seizures in the meta-analysis as we believed this to be more clinically consistent and overall the more common outcome across the included studies.

We plotted odds ratios data in forest plots, assessing heterogeneity visually and statistically using the I2 statistic, a scale that measures the degree of heterogeneity across studies in a meta-analysis.38 Within the largest groups (arterial cord pH paired with neonatal mortality and neonatal morbidity) we explored the reasons for heterogeneity using metaregression, planned a priori in keeping with published recommendations.39 40 We considered study design (cohort v case-control), study quality (high v medium or low), and population risk (high v low/unselected or unreported) as potential sources of heterogeneity. We defined a population at high risk for complications on the basis of reported characteristics, including abnormalities on cardiotocograms, meconium liquor, a low Apgar score at birth, gestation less than 37 weeks, and birth weight less than 2500 g. It was not possible to use a low risk population as comparator because only one included study met the criteria for this definition.41 Given the reporting quality of the primary studies it was also not possible to explore other potential sources of heterogeneity. Metaregression analysis was univariate throughout, in accordance with published guidance that recommends allowing at least 10 studies per covariate explored.42 When a reason for heterogeneity was identified, we carried out subgroup analyses. As complications such as cerebral palsy and intraventricular haemorrhage have been shown to be increased in preterm and low birthweight infants we analysed studies with these populations separately and compared the results with that of a term population.

As clinical heterogeneity was present between studies, we used a random effects model throughout. The presence of publication bias was determined using the Harbord test.42 43 To assess the effect of the use of different thresholds to define low pH, we repeated the meta-analyses using the bivariate method, which takes into account any threshold effect.44 We additionally analysed subgroups within the outcome measures of neonatal mortality and neonatal morbidity according to the arterial pH threshold reported (<7.00, <7.10, and <7.20). We statistically analysed data using Meta-Disc 1.3 software,45 and Stata version 10.0 using the metan, metandi, and meta-bias commands.46 47 48

To assess a causal association for each outcome we considered Hill’s criteria.21 25 We examined strength of association using point estimates of odds ratios and consistency using the direction of association in the forest plots and heterogeneity statistics.

Results

An initial search of 5690 citations identified 51 primary articles1 4 5 10 11 41 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91, two after obtaining information from the authors (fig 1).92 93 The included studies totalled 481 753 infants. Overall, 190 2×2 tables were produced; 43 of the studies providing these data were eligible for inclusion in meta-analyses according to predefined outcome measures, totalling 479 383 infants and 70 2×2 tables. One included study was thought to contain duplication60; however, the outcomes reported were different and therefore both papers60 61 were included in the review in separate meta-analyses. When more than one 2×2 table was produced per study, double counting of infants in any one analysis was avoided.

Fig 1 Study selection process

The included studies used various index tests (table 1): most papers (n=46) reported arterial cord pH, with thresholds ranging from 7.00 to 7.24. Arterial base excess was reported in four studies, with thresholds of 12-16 mmol/l.61 73 81 91 Five studies reported venous cord pH; three using a threshold of 7.20 and one a threshold of 7.10.55 69 78 85 93 Only one study utilised venous base excess.93 The cord pH level was obtained before the occurrence of the adverse outcome. A wide variety of outcome measures were reported, ranging from neonatal mortality and morbidity to long term outcomes, including cerebral palsy, unspecified neurological abnormality, IQs, and developmental assessments (for example, Bayley and Griffiths scores). When the same outcome was reported, the thresholds and ages at assessment varied between studies, therefore meta-analysis was not possible for long term outcomes other than cerebral palsy. The odds ratio point estimate varied widely. Thirty six studies reported on outcomes within the neonatal period only. Fifteen studies had long term follow-up; one did not report the age of ascertainment of the outcome. The age range reported in other studies was 1 to 8 years; the median across studies was 5 years.

Table 1

 Studies included in systematic review of association between cord pH at birth and neonatal and long term outcomes

Studies	Risk factors	Index tests	Outcome measures
High risk population:
Baenziger et al 199950	All ventilated neonates; risk factors for HIE, including meconium liquor, abnormalities on cardiotocogram, low Apgar score or pH, gestation >34 weeks	Arterial cord pH <7.00	Death*; hypoxic ischaemic encephalopathy (Sarnat grade >1)*; neurological optimality score (age 1 year); Griffiths developmental scale (age 1 year)
Beeby et al 19944	Gestation <32 weeks; excluded congenital anomalies	Arterial cord pH <7.1	Death*; cerebral palsy (age 1 year); intraventricular haemorrhage grade 3 or 4 on cranial ultrasound scan or at autopsy*
Blackwell et al 200152	All neonates requiring ventilation >48 hours for meconium aspiration syndrome; gestation >37 weeks	Arterial cord pH <7.2	Seizures*
Bresadola et al 199551	Gestation >24 weeks, <37 weeks; birth weight >700 g; excluded congenital anomalies	Arterial cord pH <7.2	Death*
Casey et al 200153	Neonates who developed respiratory symptoms postnatally; gestation >37 weeks	Arterial cord pH <7.2	Death*; seizures*; respiratory distress requiring ventilation*; meconium aspiration syndrome*
Engle 199956	Neonates admitted to neonatal unit directly from delivery suite; gestation >37 weeks	Arterial cord pH <7.00	Hypoxic ischaemic encephalopathy including seizures*
Ertan 200191	Gestation 24-34 weeks	Arterial cord pH <7.10; arterial base excess >16 mmol/l	Intracranial haemorrhage (Papile, all grades) on cranial ultrasound scan*
Gaudier et al 199449	Birth weight 500-1000 g; gestation 23-34 weeks; excluded congenital anomalies	Arterial cord pH <7.05	Wechsler intelligence scale for children (IQ <70); cerebral palsy (chronic non-progressive motor disability characterised by abnormal posture and movements), follow-up to age 7 years; motor or mental deficit severe enough to interfere with normal function, including one or more of mental retardation, cerebral palsy, deafness, blindness, or hydrocephaly
Gea 200793	Birth weight <2000 g; gestation <37 weeks; excluded congenital anomalies, maternal diabetes, and rhesus incompatibility	Venous cord pH <7.20; venous base excess >10 mmol/l	Periventricular or intraventricular haemorrhage on cranial ultrasound scan*; ventilation >24 hours*; necrotising enterocolitis (Bell grade 2)*
Gonzalez de Dios et al 200059	At least one risk factor for asphyxia (for example, Apgar score <6, cord pH <7.00, antenatal risk factors); excluded if congenital anomaly, sepsis, metabolic disorder, postnatal depression; gestation >37 weeks	Arterial cord pH ≤7.00	Serum creatinine level >1.2 mg/dl*; hypoxic ischaemic encephalopathy (Levine’s criteria, all grades)*; abnormal neurological status (Amiel-Tison criteria), age 2 years
Graham et al 200461	Gestation 23-34 weeks	Arterial cord pH <7.00	Periventricular leucomalacia or ventricular dilatation on cranial ultrasound scan*
Haddad et al 200062	Neonates with Apgar score 0 at 1 and 5 minutes, resuscitated and transferred to neonatal unit; excluded congenital malformations, chromosome abnormalities, birth before arrival; gestation 25.5-42.1 weeks	Arterial cord pH <7.00	Death*; hypoxic ischaemic encephalopathy*
Hernandez et al 199363	Clinical and radiological evidence of meconium aspiration syndrome; excluded if congenital anomalies, cytomegalic inclusion disease, delivery outside hospital	Arterial cord pH <7.00, <7.10, and <7.20	Ventilation required*; ventilation ≥3 days*
Hibbard et al 199164	Birth weight 500-1500 g	Arterial cord pH ≤7.05 and ≤7.15	Death*; intraventricular haemorrhage (Papile grade 1-4) on cranial ultrasound scan*; abnormal neurological status defined as seizures, cortical atrophy, need for shunt placement*; hyaline membrane disease (chest radiography)*; bronchopulmonary dysplasia (chest radiography)*; necrotising enterocolitis*
Holmes et al 200166	Birth weight 750-2500 g; gestation 25-35 weeks; excluded if caesarean section before labour, congenital anomalies, uninterpretable fetal heart rate trace	Arterial cord pH <7.10	Death*; intraventricular haemorrhage (Papile grade 3 or 4)*; periventricular leucomalacia*
Kato 19975	Birth weight <1500 g. Congenital anomalies excluded	Arterial cord pH <7.20	Death*; cerebral palsy or mental retardation (at least 12 months old)
Loh et al 199872	Included if one or more of following risk factors: abnormality on cardiotocogram, scalp pH<7.25, thick meconium or no liquor, cord prolapse or bradycardia, antepartum haemorrhage, estimated fetal weight <1500 g, gestation <34 weeks, breech, poorly controlled type 1 diabetes, pre-eclampsia, suspected fetal anomalies, transverse or oblique lie at caesarean section, multiple pregnancies	Arterial cord pH <7.00	Hypoxic ischaemic encephalopathy
Luthy et al 198774	Gestation 26-32 weeks; excluded multiple pregnancy, non-cephalic presentation, malformations, delivery before labour, antenatal haemorrhage	Arterial cord pH ≤7.20	Death; cerebral palsy (age 18 months); intraventricular haemorrhage on cranial ultrasound scan (Papile grade 3 or 4)*
Murphy et al 199575	Gestation 23-32 weeks; excluded multiple pregnancy	Arterial cord pH ≤7.10	Cerebral palsy (permanent impairment of voluntary movement or posture), age unreported
Salafia et al 199578	Gestation <32 weeks; excluded if congenital anomalies, multiple pregnancy, maternal diabetes mellitus or chronic hypertension, fetal hydrops, placenta praevia, intrauterine growth restriction	Arterial cord pH <7.10; venous cord pH <7.10	Germinal matrix or intraventricular haemorrhage diagnosed on cranial ultrasound scan (grade 1-4)*
Socol 199481	Apgar score ≤3 at 5 minutes; excluded birth weight <2000 g and gestation <34 weeks	Arterial cord pH <7.00; arterial base excess >12 mmol/l	Cerebral palsy or motor deficit (age 1-7 years); seizures*; renal impairment (serum creatinine level >1.5 mg/dl, or oliguria)*; cognitive impairment on Wechsler scale (cut off <70), age 1-7 years
Spinillo et al 199582	Birth weight <2500 g	Arterial cord pH <7.20	Bayley index abnormal (71-84), age 2 years
Tejani and Verma 198983	Birth weight ≤2000 g; excluded major congenital anomalies	Arterial cord pH ≤7.10	Death*; intraventricular haemorrhage on cranial ultrasound scan (Papile grade 1-4)*; respiratory distress syndrome (radiological evidence of reticulogranular pattern and air bronchograms)*
Yudkin et al 199489	Apgar score ≤3 at 1 minute; gestation >37 weeks; excluded multiple pregnancies and death related to congenital anomaly or rhesus disease	Arterial cord pH <7.15	Death*; any impairment (age 5 years); serious impairment (global delay, lateralising signs and severe deficit in a specific area), age 5 years
Yoon et al 199688	Gestation 25-36 weeks; excluded major congenital malformations or death before examination	Arterial cord pH <7.15	Periventricular leucomalacia on cranial ultrasound scan or at autopsy*
Unselected or low risk population:
Dennis et al 198954	Gestation >37 weeks; singletons surviving to age 4.5 years	Arterial cord pH ≤7.10; arterial base excess >12 mmol/l	Griffiths developmental scales age 4.5 years: locomotor, personal or social, hearing and speech, performance, and overall impairment
Dijxhoorn et al 198641	Gestation >37 weeks; excluded caesarean delivery or breech presentation	Arterial cord pH ≤7.10 and ≤7.20	Neurological status (abnormal if one of hyperkinesias or hypokinesia, hypertonia or hypotonia, hemisyndrome, apathy syndrome, or hyperexcitability syndrome)*
D’Souza et al 198355	Normal pregnancy, vaginal delivery 39-42 weeks	Venous cord pH <7.27	Neurological status (abnormal if one of hypotonia, lethargy, feeding difficulties, jittery)*
Ghosh et al 200357	Gestation >37 weeks; singletons excluded if rhesus isoimmunisation, maternal anaemia, or diabetes mellitus	Arterial cord pH ≤7.15	Hypoxic ischaemic encephalopathy*; death*
Gilstrap et al 198958	Gestation >37 weeks, cephalic presentation, birth weight >2500 g; excluded congenital anomalies	Arterial cord pH <7.00	Hypotonia >24-48 hours*; respiratory distress requiring oxygen*; seizures*
Graham 200260	Excluded congenital anomalies	Arterial cord pH <7.00	Seizures*
Heller et al 20031	Excluded congenital anomalies	Arterial cord pH ≤7.00, ≤7.10, and ≤7.20	Death*
Hogan 200765	Gestation >37 weeks	Arterial cord pH ≤7.15	Composite reference standard hypoxic ischaemic encephalopathy (Sarnat, all grades) or hypoxic death*
Huisjes and Aarnoudse 197967	Population characteristics unreported	Arterial cord pH ≤7.09	Abnormal neonatal neurological status (Prechtl method)*
Ingemarrson et al 199768	Population characteristics unreported	Arterial cord pH <7.05 and <7.00	Death*; cerebral palsy (age 4 years); impact of events scale (Sarnat grade 1-3)*; attention deficit (age 4 years); speech difficulty (age 4 years); motor delay (age 4 years)
Jurgens- van der Zee et al 197969	Neonates; excluded if neonatal death or parents refused examination	Venous cord pH <7.20	Abnormal neurological examination result (Prechtl method): 1 or more of increased or decreased excitability including seizures, apathy or coma; abnormal motility or tone; peripheral or central nervous system lesions*
Larma et al 200770	Gestation ≥24 weeks	Arterial cord pH <7.00	Seizures*; periventricular leucomalacia*; intraventricular haemorrhage*; respiratory dysfunction*; renal dysfunction* (thresholds unreported)
Litschgi et al 197471	Population characteristics unreported	Arterial cord pH <7.09	Abnormal neurological examination result (24 hours after birth)*
Low 199773	Gestation ≥37 weeks	Arterial base excess >12 mmol/l	Composite outcome score*; neurological abnormality (lethargy, abnormal tone, coma, or seizures)*; respiratory dysfunction (continuous positive airway pressure or ventilation required)*; cardiovascular dysfunction (hypotension, hypertension, abnormal electrocardiogram or echocardiogram)*; renal dysfunction (serum creatinine level >100 umol/l, anuria, or oliguria <1 ml/kg/h)*
Perlman and Risser 199676	Gestation ≥37 weeks	Arterial cord pH ≤7.00	Seizures*
Sakuraba and Saling 198977	Population characteristics unreported	Arterial cord pH ≤7.19 and ≤7.24	Intracranial haemorrhage diagnosed on cranial ultrasound scan*
Schneider and Tanner 198579	Twins only included	Arterial cord pH <7.20	Binet Simon Kramer (intelligence); language test; emotional intelligence test; Raven intelligence test (non-spoken); neurological status (all tests carried out at age 5-7 years)
Silva et al 200880	Gestation ≥34 weeks; excluded congenital malformations and chromosome anomalies	Arterial cord pH <7.00 and <7.10	Hypotonia at birth necessitating admission to neonatal unit*; hypoxic ischaemic encephalopathy*; seizures*
Svirko et al 200892	Gestation ≥36 weeks; one of reference tests done and cord pH available; excluded if delivered by prelabour elective caesarean section	Arterial cord pH <7.10	Wechsler objective reading dimensions (age 6-8 years); test for comprehension of grammar (age 5-7 years); Naglieri non-verbal ability (age 6-8 years); cut off <100 age standardised score used for all tests
Thoulon et al 197284	Population characteristics unreported	Venous cord pH <7.20	Death*; abnormal neurological examination (age 18 months)
Valentin et al 199385	Anomalies not excluded	Arterial cord pH ≤7.00 and ≤7.10; venous cord pH ≤7.10 and ≤7.20	Composite measure of neonatal sequelae, including severe symptoms requiring treatment (for example, ventilation, intravenous fluids), death, or survival with sequelae*
Van den Berg 199610	Excluded chromosomal or major congenital anomalies or intrauterine infection	Arterial cord pH <7.00 (compared with group of neonates with cord pH >7.24)	Seizures*; intracranial haemorrhage on cranial ultrasound scan*; periventricular leucomalacia on cranial ultrasound scan*; renal impairment (serum creatinine level >90µmol/l*); abnormal liver function (aspartate transaminase level >33 U/l, alanine aminotransferase level >25 U/l)*; necrotising enterocolitis (criteria unreported)*
Vintzileos et al 199390	Gestation ≥26 weeks; excluded known congenital or chromosomal anomalies	Arterial cord pH <7.10	Death*
Wildshut et al 200511	Gestation 37-42 weeks; neonates included if growth between 2.3 and 97.7th centiles, vertex position, stay in hospital at least 3 days after birth; excluded if hypoxia ischaemia other than caused by perinatal adverse conditions. Exclusions included meconium aspiration, respiratory distress syndrome, infection, birth after complicated pregnancy, congenital malformations, maternal medication, alcohol or drug misuse, metabolic disorders	Arterial cord pH <7.10	Movement ABC test (score <16 or unable to perform due to movement disorder), age 4 years
Winkler 199186	Gestation ≥37 weeks	Arterial cord pH <7.20	Composite reference standard: seizures or neonatal death*
Wu et al 199887	Gestation ≥37 weeks; singletons only	Arterial cord pH <7.19	Motor delay; speech delay; difficulty concentrating (all assessed age 4 years)

*Outcomes within neonatal period.

Quality assessment

Overall, study quality was variable (table 2). Most studies were retrospective but with a cohort design, allowing inferences on temporality of association. Over 80% of studies met the following quality items: appropriate outcome measure, more than 90% verification with outcome measure, and cohort design. Studies scored poorly for adequate description of index test and outcome measure, and consecutive recruitment. All included studies were unclear about the use of medical intervention between the index test and outcome measure. Overall, 45% (n=23) of studies were of high quality, 39% (n=20) of medium quality, and 16% (n=8) of low quality. Study design and quality did not seem to influence results on metaregression (table 3).

Table 2

 Methodological quality of studies in systematic review of association between low cord pH at birth and neonatal and long term morbidity

Quality item	No (%) of studies (n=51)
	Yes	No	Unclear
Cohort study design	42 (82)	9 (18)	0
Population adequately described	40 (78)	2 (4)	9 (18)
Consecutive recruitment	2 (4)	1 (2)	48 (94)
Prospective recruitment	15 (29)	29 (57)	7 (14)
Appropriate outcome measure	51 (100)	0	0
Outcome measure blinded	7 (14)	0	44 (86)
>90% of infants had outcome measure	41 (80)	10 (20)	0
Index test and outcome measure described	8 (16)	12 (24)	31 (61)
Intervention between index test and outcome	0	0	51 (100)
Quality classification:
High	23 (45)	0	0
Medium	0	20 (39)	0
Low	0	0	8 (16)

Table 3

 Exploration of heterogeneity in estimation of association between low arterial cord pH at birth and neonatal mortality and morbidity

Factor	Univariable analysis
	Odds ratio (95% CI)	P value
Neonatal mortality:
Cohort v case-control design	0.4 (0.03 to 6.5)	0.52
High quality v medium or low quality study	0.8 (0.3 to 2.4)	0.63
High risk v unselected population	0.3 (0.1 to 1.0)	0.048*
Composite neonatal morbidity:
Cohort v case-control design	1.1 (0.2 to 5.3)	0.90
High quality v medium or low quality study	1.4 (0.5 to 3.7)	0.51
High risk v unselected or low risk population	0.4 (0.2 to 0.9)	0.03*

Dummy variables were used to set the reference category as medium or low quality, case-control design, and unselected or low risk population.

*P<0.05.

Association between cord pH and neonatal mortality

Fifteen studies (13 cohort, two case-control) totalling 469 395 infants reported on the association between arterial cord pH and mortality. The Harbord test was not significant, suggesting no influence of small study effect (see web extra on bmj.com). All studies had an odds ratio point estimate greater than 1.0. Heterogeneity was significant (I2=61.0%) overall. Metaregression (table 3) identified population risk as a significant explanatory factor. Within subgroups (fig 2) the association was consistent across studies. The association of low arterial cord pH with neonatal mortality was stronger in the unselected population (odds ratio 16.9, 95% confidence interval 9.7 to 29.5, estimated predictive interval 5.0-57.3, I2=0.0%) than in the high risk population (4.2, 2.6 to 6.9, 1.3-13.7, I2=35.1%). The analysis for the unselected population was dominated by one large study,1 which was based on data from a regional perinatal register where cord pH was determined at most of the births. A sensitivity analysis excluding this study this did not significantly alter the point estimate (17.0, 4.4 to 65.5); however, the estimated predictive interval became wide (0.0-106 299.0)

Fig 2 Association of low arterial cord pH with neonatal mortality. EPI=estimated predictive interval

Examination of the high risk population further showed that when studies reporting on a population of infants born at less than 32 weeks’ gestation, or with a birth weight of less than 2000 g, were analysed separately (seven studies), a significant association was found between cord pH and mortality (3.5, 2.3 to 5.4, I2=0.0%). When limited to a term (>37 weeks’ gestation) population (four studies), the association was also strong (9.3, 1.4 to 63.2, I2=84.0%); however, heterogeneity was significant and the predictive interval broad (0.0-38 169.8). Grouping the studies according to quality did not affect the significance or direction of association of the pooled result (fig 2). Exploration for a threshold effect (table 4) showed that for a cut-off pH threshold of 7.00 the association did not reach significance overall (6.1, 0.9 to 41.6) and the predictive interval was broad (0.0-20 406.6). The results for a threshold of 7.10 gave a similar point estimate but achieved significance (7.1, 3.3 to 15.3); however, the predictive interval remained broad (0.8-64.3) and crossed the line of no effect. For a threshold of 7.20, the odds ratio was lower (4.3, 2.2 to 8.7), with a broad predictive interval (0.5-40.6). Only one study examined all three thresholds,1 with the strongest association at threshold 7.00 (16.9, 9.2 to 31.1) and the weakest at 7.20 (3.1, 2.3 to 4.1).

Table 4

 Effect of using varying thresholds of arterial cord pH at birth on accuracy to predict neonatal morbidity and mortality

Variables	Odds ratio (95% CI)	Overall odds ratio (95% CI); estimated predictive interval
Neonatal mortality
pH threshold 7.00:
Baenziger et al 199950	3.00 (0.1 to 73.6)	6.1 (0.90 to 41.6); 0.0-20 406.6
Haddad et al 200062	1.07 (0.2 to 7.3)
Heller et al 20031	16.9 (9.2 to 31.1)
Ingemarrson et al 199768	20.8 (1.0 to 439.0)
pH threshold 7.10:
Beeby et al 19944	2.9 (1.6 to 5.4)	7.1 (3.3 to 15.3); 0.8-64.3
Heller et al 20031	10.6 (7.4 to 15.1)
Holmes et al 200166	5.8 (0.2 to 155.3)
Vintzileos et al 199390	18.8 (3.4 to 105.2)
Yudkin et al 199489	25.9 (1.3 to 518.6)
pH threshold 7.20:
Bresadola et al 199551	11.8 (5.2 to 26.8)	4.3 (2.2 to 8.7); 0.5-40.7
Casey et al 200153	1.9 (0.7 to 4.9)
Heller et al 20031	3.1 (2.3 to 4.1)
Kato et al 19965	29.0 (1.4 to 10.5)
Luthy et al 198774	3.6 (1.2 to 10.5)
Neonatal morbidity
pH threshold 7.00:
Baenziger et al 199950	2.7 (0.2 to 45.1)	12.5 (6.1 to 25.6); 1.7-89.9
Engle et al 199956	42.4 (2.3 to 782.1)
Graham et al 200260	22.9 (1.1 to 494.6)
Gonzalez de Dios 200059	9.2 (3.2 to 26.5)
Haddad et al 200062	8.0 (0.3 to 255.8)
Hernandez et al 199363	2.4 (0.8 to 7.4)
Ingemarrson et al 199768	18.5 (3.8 to 89.6)
Larma et al 200770	8.6 (1.1 to 69.7)
Loh et al 199872	92.1 (3.7 to 2309.1)
Perlman 199676	50.3 (2.7 to 955.6)
Silva et al 200880	47.4 (2.2 to 1030.3)
Socol 199481	14.4 (0.7 to 311.8)
Valentin et al 199385	1.8 (0.2 to 15.8)
Van den Berg 199610	10.0 (1.2 to 80.5)
Gilstrap et al 198958	169.9 (22.5 to 1281.4)
pH threshold 7.10:
Beeby et al 19944	3.9 (1.9 to 7.9)	2.4 (1.3 to 4.2); 0.4-12.7
Dijxhoorn et al 198641	0.3 (0.04 to 13.4)
Ertan et al 200691	2.0 (0.9 to 4.5)
Hernandez et al 199363	1.6 (0.6 to 4.1)
Holmes et al 200166	3.1 (0.1 to 75.5)
Huisjes 197967	4.8 (2.6 to 8.7)
Silva et al 200880	14.7 (4.3 to 50.6)
Tejani 198983	1.2 (0.3 to 4.3)
Valentin et al 199385	0.8 (0.2 to 3.9)
Salafia et al 199578	0.7 (0.04 to 13.4)
pH threshold 7.20:
Blackwell et al 200152	1.0 (0.3 to 4.2)	2.2 (1.3 to 3.7); 0.5-9.9
Casey et al 200153	3.1 (1.8 to 5.3)
Dijxhoorn et al 198641	1.4 (0.6 to 3.0)
Hernandez et al 199363	1.6 (0.7 to 3.9)
Luthy et al 198774	5.5 (1.9 to 15.7)

Association between cord pH and neonatal morbidity

Thirty one studies compared arterial cord pH with a variety of neonatal outcomes (fig 3). One of these61 was excluded from meta-analysis of composite neonatal morbidity because it contained a duplicate population to another included study,60 therefore the dataset to assess the association of arterial pH with a composite measure of morbidity included 30 studies with 10 904 infants. The Harbord test was significant, suggesting the presence of a small study effect (see web extra on bmj.com). Only two studies had an odds ratio point estimate of less than 1.0, the rest showing an association. Significant heterogeneity was, however, present (I2=58.2%). Metaregression showed population to be an explanatory variable (table 3). Subgroup meta-analysis for a high risk population (fig 3) showed a weaker association (3.4, 2.3 to 4.9, 1.4-8.4, I2=26.4%) than in an unselected or undefined population (10.6, 4.7 to 24.1, 0.8-135.8, I2=66.4%). When analysed in subgroups according to quality, the direction of effect remained consistent and significant between the group of 12 high quality studies (6.6, 3.7 to 11.8, 1.3-32.6, I2=51.2%) and 18 low or medium quality studies (4.6, 2.6 to 8.0, 0.7-29.2, I2=61.5%). Exploration by subgroup analysis for a threshold effect (table 4) showed the most substantial association at a pH threshold of 7.00 (12.5, 6.1 to 25.6). The predictive interval was broad but did not cross the line of no effect (1.7-89.9). The results were similar for a threshold of 7.10 (2.4, 1.3 to 4.3) and 7.20 (2.2, 1.3 to 3.7).

Fig 3 Association of low arterial cord pH with neonatal morbidity. HIE=hypoxic ischaemic encephalopathy; IVH=intraventricular haemorrhage; PVL=periventricular leucomalacia; NS=not stated; WM=cerebral white matter; EPI=estimated predictive interval

When components of the composite outcome were analysed (fig 3), the odds ratio for an association between arterial cord pH and hypoxic ischaemic encephalopathy was 13.8 (6.6 to 28.9, 5.2-36.4, I2=0.0%), between arterial cord pH and seizures was 8.1 (3.0 to 21.9, 0.4-153.6, I2=66.3%), and between intraventricular haemorrhage or periventricular leucomalacia was 2.9 (2.1 to 4.1, 2.0-4.3, I2=0.0%). Only two of nine studies reporting this outcome were not limited to a preterm (<32 weeks) or low birthweight (<2000 g) population. Excluding these two studies did not affect the strength or significance of the association.

Five studies reported on the association between venous cord pH and neonatal morbidity.55 69 78 85 93 Meta-analysis showed a significant association (4.0, 1.2 to 13.3, I2=44.5%). However the predictive interval crossed the line of no effect (0.1-125.3). Four studies examined the association between arterial base excess and neonatal morbidity, which was similar to venous cord pH and also had an estimated predictive interval that crossed the line of no effect (2.5, 1.3 to 4.8, 0.6-10.4, I2=0.0%).61 73 81 91 Owing to the small number of studies reporting this variable, it was not possible to combine the cord pH and base excess to compare the difference between respiratory and metabolic acidosis.

Association between cord pH and cerebral palsy

Seven studies totalling 1117 infants examined the association between arterial cord pH and cerebral palsy.4 5 49 68 74 75 81 Of those, two had an odds ratio point estimate of less than 1.0, but the rest showed an association of low pH with cerebral palsy (table 4). Only two studies gave the criteria used to diagnose cerebral palsy.49 75 The overall association was odds ratio 2.3 (1.3 to 4.2, 1.1-5.0, I2=0.0%l fig 4). It was not possible to explore the threshold effect by subgroup analysis owing to the small number of studies reporting this outcome, therefore bivariate meta-analysis was carried out, which did not change the overall results (2.1, 1.2 to 4.1).

Fig 4 Association of low arterial cord pH with cerebral palsy. NS=not stated; EPI=estimated predictive interval

Discussion

Low arterial umbilical cord pH had a strong, consistent, and temporal association with neonatal mortality and morbidity (composite of hypoxic ischaemic encephalopathy, seizures, and intraventricular haemorrhage or periventricular leucomalacia) and long term outcome (cerebral palsy). In all of the associations between arterial cord pH and outcome explored, with the exception of composite morbidity in a low risk population and seizures, the estimated predictive interval suggested that a future study would have the same direction and significance of effect observed. The associations observed are biologically plausible.6 94 95 96

Strengths and limitations of the review

This review provides the best available evidence, at the time of publication, of the association between cord pH at birth and outcomes. The strength of our review and the validity of our inferences lie in the methods used. We complied with existing guidelines for the reporting of systematic reviews of diagnostic22 97 and observational studies evaluating causal association.15 25 We used the most up to date techniques for carrying out and interpreting meta-analysis.35 44 An extensive literature search was done in relevant databases with no language restrictions applied. The studies we pooled had heterogeneity in terms of quality, population risk, threshold of cord pH used, and ascertainment of neonatal outcome. We carried out recommended analyses to tackle this problem, including bivariate and subgroup meta-analysis to take into account the threshold effect,44 metaregression analysis to explore reasons for heterogeneity,39 and component outcome analysis to examine the suitability of the composite morbidity outcome. This did not significantly affect our results. Recent work suggesting the differences between standard and bivariate techniques may be small.98 The observed associations were qualitatively in the same direction, and statistical heterogeneity, when present, arose from variation in strength of associations from study to study rather than opposition in direction of association. We are therefore confident that our inference concerning a causal association between low arterial cord pH at birth and neonatal mortality and a variety of neonatal morbidities merits consideration.

This review has several limitations. Despite our efforts to search for published and unpublished literature, the Harbord test suggested that the meta-analysis of the relation of arterial cord pH and neonatal morbidity may be affected by small study bias. The quality of the primary studies varied. We used both metaregression and subgroup analysis to explore for the effect of this problem, which showed that study quality did not affect our inferences. The poor reporting of population characteristics limited the subgroup analysis according to risk factors: a large number of the papers with an “unselected” population did not fully report characteristics such as birth weight or gestational age, making it difficult to extrapolate our findings to the general obstetric population. Only one paper included in the meta-analysis specified that it was limited to a low risk term population. With regard to the index test examined, only a small number of papers reported base excess, which meant that it was not possible to compare metabolic acidosis with respiratory acidosis. We found that a high base excess was associated with neonatal morbidity, but in clinical practice the pH and base excess level would be considered together in any infant, and we are unable to comment on this. Additionally, we were only able to base our analysis on the thresholds reported in the primary studies, which limited our exploration of the effect of varying pH levels. Some of these issues may be dealt with using meta-analysis of individual patient data.99

Venous cord pH and arterial base excess showed weaker associations with neonatal morbidity than that of arterial cord pH, with estimated predictive intervals that crossed the line of no effect. This analysis was, however, based on a small number of studies, and as no other subgroup analysis could be done, a direct comparison with arterial cord pH was not possible. It seems likely from our results that arterial cord pH has a stronger association with outcome than venous cord pH.

Evidence supporting causality of association of low arterial cord pH with adverse outcomes

Hypoxic ischaemia initiates energy depletion, the accumulation of extracellular glutamate, and activation of receptors, leading to a deleterious cascade of events resulting in neuronal death.100 However, different areas of the brain are susceptible to injury at various stages in development, and the consequences of injury are unpredictable.101 This would support our findings of a strong association with hypoxic ischaemic encephalopathy but a weaker association with cerebral palsy. Only 10% of infants with evidence of hypoxic ischaemic encephalopathy develop cerebral palsy, but the reasons for this are not yet fully understood.102 This issue is further highlighted by the findings of the term breech trial, where long term follow-up did not show any difference in neurodevelopmental delay, despite an apparent increase in neonatal morbidity in the vaginal breech group.103

It is difficult to comment on the specificity with which cord pH is associated with the outcomes examined within our review. All of the outcomes may arise from a variety of causes—for example, in addition to hypoxia, neonatal seizures may be caused by congenital brain anomaly, infection, and metabolic disorders. Although some of the included studies excluded infants with congenital anomaly, others did not specify whether they had excluded from their analysis infants with an outcome related to another cause. This may explain why the strength of association of arterial cord pH with neonatal mortality and morbidity was stronger in the unselected group than in the high risk group. The infants in the high risk group had other factors (for example, prematurity, low birth weight) that may have contributed to the adverse outcome, thus diluting the strength of association. This is supported by the higher number of deaths in the high risk population, with a higher specificity for low arterial cord pH and death in the unselected population.

We explored for the presence of a dose-response relation by examining the strength of association between arterial cord pH and neonatal mortality and morbidity at different pH thresholds. Although the meta-analysis did not show a clear dose-response relation, and the estimated predictive intervals were broad, the association for both neonatal mortality and neonatal morbidity was weakest at the highest threshold. Only one study1 explored the association of arterial cord pH and neonatal mortality at all three thresholds examined. A clear dose-response relation was apparent within this study, with the strongest association at a threshold of 7.00 and the weakest at a threshold of 7.20. Comparison within a study may be more valid than comparisons between studies as it avoids confounding by other study level factors.

Conclusions and practice implications

Our review did not explore the use of cord pH as a prognostic test, and therefore the extent to which our results can be used to counsel parents and target interventions for infants with a low cord pH at birth is limited. To explore this matter, further research is required. A recent review highlighted the current deficits in prognosis research and suggested that when high quality primary studies exist, meta-analysis of individual patient data enables the prognostic value of a test to be assessed at an individual level.104 Our review, however, highlights the lack of high quality primary studies, and therefore a large prospective cohort study with long term follow-up and accounting for potential confounding factors is required. Such a study must include evaluation of outcomes relevant to the individual and society, such as impaired development and use of healthcare and educational resources, before the evaluation of use of cord pH as a prognostic test and its cost effectiveness. This will enable further exploration of the threshold effect and the use of combined cord pH and base excess to predict outcome.

Cord pH is currently assessed in infants believed to be at high risk for neonatal asphyxia. Our results suggest, however, that the strength of association with cord pH and outcome is not limited to this high risk population. Therefore future research should assess the use of cord pH across neonatal populations, particularly exploring the cost effectiveness of testing all neonates. Systematic reviews to establish the association of other neonatal wellbeing measures with long term outcomes are ongoing in our department.

Based on our review, increased initial surveillance of neonates born with a low arterial cord pH, regardless of their clinical condition, is warranted as the odds of complications have been shown to be higher in this group. The avoidance of a low cord pH at birth should continue to be a target for day to day obstetric practice. Our findings justify the use of arterial cord pH as an important outcome measure alongside neonatal morbidity and mortality in obstetric clinical trials. It is difficult to draw strong conclusions on the necessity of long term follow-up for babies with low arterial cord pH, as the observed association with cerebral palsy was in a limited number of primary studies and the association, although statistically significant, was only moderately strong and based on studies of varying quality. We therefore support the use of long term follow-up with childhood assessments in obstetric trials, as this may show developmental anomalies and allow evaluation of cord pH as a predictive test for these outcomes.

Umbilical cord pH at birth is frequently used to measure perinatal asphyxia

Neonatal and childhood mortality and morbidity, including cerebral palsy, are often attributed to fetal acidosis, as defined by a low cord pH at birth

Existing reports of the association between cord pH and adverse outcome are conflicting

Low cord pH is substantially associated with neonatal mortality and morbidity and cerebral palsy in childhood

These outcomes justify the increased surveillance of infants born with a low cord pH

Further research is, however, needed to explore the cost effectiveness of doing this test in all neonates