Predictors of respiratory depression at birth in the term infant
Dr TF Baskett, Department of Obstetrics and Gynaecology, Dalhousie University, 5980 University Avenue, Halifax, Nova Scotia, Canada B3K 6R8. Email firstname.lastname@example.org
Objective To evaluate predictive factors for respiratory depression at birth in infants ≥37 weeks.
Design A population-based cohort study of respiratory depression at birth at term and post-term.
Setting Nova Scotia, Canada.
Population All 126 604 nonanomalous, singleton deliveries ≥37 weeks in cephalic presentation from 1988–2002.
Methods An analysis of maternal, antenatal, intrapartum, and neonatal factors associated with respiratory depression at birth ≥37 weeks.
Main outcome measures A composite outcome of delay in initiating and maintaining respiration after birth, 5-minute Apgar score ≤ 3, or neonatal seizures due to hypoxic–ischaemic encephalopathy.
Results The rate of respiratory depression at birth with delay in respiration was 5.2/1000, with Apgar ≤ 3 1.0/1000 live births, and with neonatal seizures 0.7/1000. A composite of any of the three respiratory depressions at birth criteria showed comparable low rates with spontaneous delivery (4.4/1000) and elective caesarean (4.8/1000). Compared with elective caesarean delivery, vacuum (13.2/1000, relative risk [RR] 3.97, P < 0.001), forceps (8.8/1000, RR 1.84, P= 0.003), failed vacuum (13.3/1000, RR 2.76, P= 0.005), failed forceps (33.3/1000, RR 6.93, P < 0.001), and caesarean in labour (17.0/1000, RR 3.54, P < 0.001) had significantly higher rates of the composite outcome.
Conclusion Overall, the rate of respiratory depression at birth in the term infant was low and the serious manifestation of seizures was less than 1 in 1000. There was a significant relationship between operative delivery in labour and respiratory depression at birth.
Neonatal respiratory depression at birth associated with events during pregnancy, labour and delivery, or the neonatal period may contribute to neonatal brain injury and affect the long-term outcome of the child. Respiratory depression at birth may be mild, with no permanent injury to the brain and no long-term developmental problems, or severe, associated with infant mortality or long-term neurological disabilities, such as cerebral palsy. While studies have considered clinical risk factors for respiratory depression at birth, neonatal encephalopathy and cerebral palsy,1–4 and clinical, laboratory, and radiological predictors of neonatal and long-term consequences following respiratory depression at birth,5–19 there is minimal population-based information with adequate number of cases and appropriate comparison groups in term deliveries, and the majority of risk factors have been associated with respiratory depression in preterm delivery.
Women and their families may reasonably expect that the majority of infants born at term with no congenital abnormalities in cephalic presentation should be at low risk for respiratory depression at birth. In addition, early identification of pregnancies at risk for respiratory depression at birth may allow for increased surveillance, obstetric intervention, or delivery at a hospital with appropriate resources.20 In this study, we assessed maternal factors, method of delivery, and fetal characteristics using data from a large provincial database in an effort to evaluate the predictive ability of these factors for respiratory depression at birth in an infant born ≥37 weeks of gestational age.
The Nova Scotia Atlee Perinatal Database is a provincial, population-based, clinically oriented, computerised database that encodes information on pregnancy outcomes and was employed to evaluate risk factors associated with respiratory depression at birth ≥37 weeks. Maternal and newborn data (such as demographic variables, procedures, maternal and newborn diagnoses, and morbidity and mortality information) are available for every pregnancy and birth (≥500 g) occurring in Nova Scotia hospitals and to Nova Scotia residents since 1988. Nova Scotia has a homogeneous, predominantly white population of approximately one million,21 with approximately 10 000 live births in Nova Scotia each year.22
Maternal data included in this study consist of information from pregnancies in Nova Scotia residents between 1 January 1988 and 31 December 2002. The obstetric population was defined by inclusion and exclusion criteria. Pregnancies were included if there was a liveborn singleton ≥37 weeks. Pregnancies were excluded if there was a major fetal anomaly (an anomaly described as any of lethal, life threatening, life shortening, requiring major surgery, or affecting in a significant way the quality of life, and includes chromosomal syndromes as well as inborn errors of metabolism), or if there was nonvertex presentation. Risk factors included maternal characteristics, pre-existing medical conditions, pregnancy complications, method of delivery, and fetal complications. Respiratory depression at birth was defined as delay in initiating and maintaining respiration after birth (requiring resuscitation by mask and/or endotracheal tube for ≥3 minutes), 5-minute Apgar score ≤ 3, or neonatal seizures due to hypoxic–ischaemic encephalopathy (Sarnat score > stage 1).23 A composite outcome of respiratory depression at birth was assigned to infants with one or more of these three clinical markers. Since 1996, neonatal cord arterial pH results have been coded in the Atlee database; therefore, from 1996 to 2002, the clinical markers of respiratory depression at birth were correlated with a cord arterial pH ≤ 7.0. Operative delivery, including caesarean with no labour, caesarean in labour, forceps-assisted and vacuum-assisted vaginal delivery, and delivery after failed forceps and failed vacuum, was compared with spontaneous vaginal delivery.
In order to evaluate the unique relationship of each predictor to the outcome of respiratory depression at birth, binary logistic regression was run. This procedure was run separately for each of the variables that were used to define respiratory depression at birth (i.e. low Apgar, neonatal seizures, and resuscitation of 3 minutes or more) and for the composite variable (i.e. any one of the defining variables). The variables entered in the multivariate model came from data gathered on both the mothers and on the infants. Maternal variables included age at delivery (i.e. 35 years of age or older, yes/no), parity (i.e. nulliparous, yes/no), smoking status at admission (i.e. smoker, yes/no), socio-economic status (i.e. lowest two quintiles of income approximated by postal code, yes/no), diagnosis of pre-existing diabetes, pre-existing hypertension, or pre-existing heart disease, pregnancy complications such as gestational diabetes, gestational hypertension, placental abruption, placenta praevia, other antepartum bleeding after 20 weeks, prelabour rupture of membranes (spontaneous rupture of membranes before onset of contractions, regardless of gestation), intrapartum infection (at least one of chorioamnionitis, marked or severe, or funisitis, as stated on the pathology report), and method of delivery. Neonatal predictors were related to weight and were expressed as two variables: weight for age at or below the 3rd percentile (yes/no) and birthweight in categories of weight less than 4000 g, weight between 4000 and 4499 g, and weight of 4500 g or more. For the dichotomous (yes/no) variables, the reference groups were the subjects in the ‘no’ categories. For the birthweight categories, the babies in the 4000- to 4499-g category were the reference group. For type of delivery, spontaneous, unassisted delivery was the reference group.
Categorical variables were compared using chi-square analysis. Predictive factors were evaluated using logistic regression. Statistical analyses were performed using the SAS programming package for Windows (Version 8.0; SAS Institute Inc., Cary, NC, USA) and EpiInfo (CDC, Atlanta, GA, USA). Ethical approval was obtained from the Reproductive Care Program of Nova Scotia and the Research Ethics Board at the IWK Health Centre in Halifax, Nova Scotia.
A population of 126 604 deliveries satisfied inclusion and exclusion criteria in Nova Scotia over a 15-year period (1988–2002). The rates of delay in initiating and maintaining respiration after birth, 5-minute Apgar score ≤ 3, and neonatal seizures, and the composite morbidity are summarised in Table 1, as is the relationship between the clinical markers for respiratory depression at birth and cord arterial pH ≤ 7.0. The rate of respiratory depression at birth with delay in respiration was 5.2/1000, with 5-minute Apgar ≤ 3 1.0/1000, and with neonatal seizures 0.7/1000. The rate of respiratory depression at birth with the composite outcome of at least one of the defining variables was 6.2/1000.
Table 1. Relationship between composite morbidity outcome, the composite morbidity outcome components, and cord arterial pH ≤ 7.0
|Delay in respiration after birth||698||5.5||206||24 (11.7)|
|5-minute Apgar ≤ 3||133||1.1||33||6 (18.2)|
|Neonatal seizures||93||0.7||34||13 (38.2)|
|Composite morbidity*||815||6.4||244||31 (12.7)|
In the study population, 20 765 pregnancies (16.4%) had cord pH recorded and of those, 152 (0.7%) had a cord arterial pH ≤ 7.0. Among newborn infants born since 1996 with neonatal seizures, 13/34 (38.2%) had a cord arterial pH ≤ 7.0, while among infants with delay in respiration, 5-minute Apgar ≤ 3, and composite morbidity, 24/206 (11.7%), 6/33 (18.2%) and 31/244 (12.7%) had a cord arterial pH ≤ 7.0, respectively.
Of the 227 cases with the composite outcome delivered by caesarean, 108 (47.6%) had nonreassuring fetal status as primary indication. Dystocia was present in 77 (33.9%) and placental abruption was the indication in 10 (4.4%). Of the 2468 pregnancies delivered by caesarean in labour because of nonreassuring fetal status, 96 (3.9%) had the composite outcome, and of the 182 delivered by caesarean without labour because of nonreassuring fetal status, 12 (6.6%) had the composite outcome. Placental pathology (one of chorioamnionitis, placental infarction, true knot, single umbilical artery, abnormalities in cord insertion site or placental development) was seen with only 3.7% of those infants with the composite outcome.
The rates of potential risk factors for respiratory depression at birth ≥37 weeks, and the rates of the composite outcomes associated with each risk factor are summarised in Table 2. Respiratory depression at birth was most commonly associated with placental abruption, intrapartum infection, operative delivery in labour, small for gestational age <3rd percentile, and birthweight > 4500 g. A composite of any of the three criteria showed comparable low rates with spontaneous delivery (4.4/1000) and elective caesarean (4.8/1000). Compared with elective caesarean delivery, vacuum (13.2/1000, RR 3.97, P < 0.001), forceps (8.8/1000, RR 1.84, P= 0.003), failed vacuum (13.3/1000, RR 2.76, P= 0.005), failed forceps (33.3/1000, RR 6.93, P < 0.001), and caesarean in labour (17.0/1000, RR 3.54, P < 0.001) had significantly higher rates of the composite outcome.
Table 2. Pregnancy factors and composite outcome, Nova Scotia, 1988–2002
|Maternal age ≥ 35 years|
|Low socio-economic status|
|Other antepartum haemorrhage|
|Prelabour rupture of membranes|
|Method of delivery|
|Spontaneous vaginal delivery||73.6||4.4|
|Caesarean (no labour)||4.8||4.8|
|≥4000 and <4500 g|
The significant associations between risk factors and the composite outcome following logistic regression are summarised in Table 3. Maternal age, pre-existing diabetes, pre-existing hypertension, pre-existing heart disease, gestational hypertension, placenta praevia, other antepartum haemorrhage, and prelabour rupture of membranes had no association with the clinical markers of respiratory depression at birth. Being nulliparous had an increased risk of the composite variable compared with being multiparous (RR 1.90, 95% CI 1.61–2.25, P < 0.001); being a smoker carried an increased risk over being a nonsmoker (RR 1.21, 95% CI 1.04–1.42, P= 0.02); having low neighbourhood socio-economic status had an increased risk over moderate or high neighbourhood socio-economic status (RR 1.18, 95% CI 1.02–1.36, P= 0.03); and having gestational diabetes had an increased risk over not having it (RR 1.60, 95% CI 1.12–2.29, P= 0.01). When looking at the factors that influenced the likelihood of being assigned any one of the markers of respiratory depression at birth (i.e. the composite variable), the stronger relationships appeared to be with intrapartum infection (RR 4.08, 95% CI 3.0–5.46, P < 0.001), placental abruption (RR 4.91, 95% CI 3.23–7.42, P < 0.001), and delivery involving failed forceps (RR = 4.84, 95% CI 3.09–7.58, P < 0.001). While the overall frequency of intrapartum infection (1.2%) was double that of placental abruption (0.5%), the frequency associated with the composite outcome was comparable between the two risk factors (41.3 and 40.8%, respectively). Every type of delivery, with the exception of caesarean delivery without labour, had a statistically significant unique relationship to the probability of having at least one marker of respiratory depression at birth, as compared with spontaneous vaginal delivery. Also, newborns who had birthweight below the 3rd percentile for gestational age and newborns who were ≥4500 g at birth had an increased risk of having at least one of the markers of respiratory depression at birth (RR 2.02, 95% CI 1.51–2.71, P < 0.001 and RR 1.63, 95% CI 1.13–2.38, P= 0.02, respectively). When the associations between each of the defining variables and the outcomes were considered separately, delay in respiration after birth showed the most consistent agreement with the composite outcome (Table 4).
Table 3. Significant associations between composite morbidity outcome and identified antenatal, pre-existing, labour and delivery, and fetal/neonatal factors, Nova Scotia, 1988–2002
|Low socio-economic status||1.18 (1.02–1.36)||0.03|
|Gestational diabetes||1.60 (1.12–2.29)||0.01|
|Placental abruption||4.91 (3.23–7.42)||<0.001|
|Intrapartum infection||4.08 (3.04–5.46)||<0.001|
|Caesarean (no labour)||1.29 (0.88–1.91)||0.19|
|Caesarean (labour)||2.55 (2.10–3.07)||<0.001|
|Failed forceps||4.84 (3.09–7.58)||<0.001|
|Failed vacuum||2.46 (1.26–4.82)||0.008|
|<3rd centile||2.02 (1.51–2.71)||<0.001|
|≥4500 g||1.63 (1.13–2.38)||0.02|
Table 4. Significant associations between composite morbidity outcome and identified antenatal, pre-existing, labour and delivery, and fetal/neonatal factors and the contribution of the composite outcome components, Nova Scotia, 1988–2002
|Low socio-economic status||0.03||0.02||0.84||0.29|
|Caesarean (no labour)||0.19||0.52||0.70||0.16|
Discussion and conclusion
This population-based study evaluated antepartum, intrapartum, and neonatal factors associated with clinical markers for respiratory depression at birth ≥37 weeks in singleton pregnancies in cephalic presentation. Overall, the rate of respiratory depression at birth was low (6.2/1000) and the rate of the serious manifestation of seizures was less than 1 in 1000. Of the three clinical markers of respiratory depression at birth used in this study, seizures had the strongest relationship with fetal acidosis (cord arterial pH ≤ 7.0). The main antenatal and intrapartum risk factors for respiratory depression at birth were nulliparity, intrapartum infection, placental abruption, caesarean in labour, failed forceps-assisted vaginal delivery, and small for gestational age.
The findings in our study are consistent with studies evaluating risk factors in related adverse outcomes, such as neonatal encephalopathy and cerebral palsy, and confirms both the role and the magnitude of the predictive effect of the factors considered in this study. Studies of antepartum and intrapartum risk factors for neonatal encephalopathy at term11,12 have also demonstrated significant contributions of maternal age, social factors such as employment and health insurance, maternal pyrexia, operative delivery in labour, and small for gestational age. While our study showed that caesarean delivery without labour was not protective for respiratory depression at birth (adjusted OR 1.29, 95% CI 0.88–1.91) compared with spontaneous vaginal delivery, Badawi et al.12 demonstrated that elective caesarean delivery was protective for neonatal encephalopathy (adjusted OR 0.17, 95% CI 0.05–0.56) compared with spontaneous vaginal delivery. Our study demonstrated that birthweight ≥ 4500 g was an additional predictor of respiratory depression at birth. Chorioamnionitis has been shown to be an independent risk factor for cerebral palsy (adjusted OR 3.8, 95% CI 1.5–10.0),1 similar to the effect of intrapartum infection in our study (adjusted OR 4.08, 95% CI 3.04–5.46).
This study considered delay in initiating and maintaining respiration after birth, Apgar score ≤ 3, and neonatal seizures due to hypoxic–ischaemic encephalopathy as clinical markers for respiratory depression at birth. Severe intraventricular haemorrhage (IVH) (grades 3 and 4) was initially considered as one of the clinical markers of respiratory depression at birth; however, the rate of severe IVH was low (0.07/1000) and the regression analysis was unstable due to small numbers.
This study was not able to address the impact of nonreassuring fetal heart rate tracings as a predictive tool although some studies have suggested that electronic fetal monitoring may affect the rate of respiratory depression at birth.24 This study was also not able to address the effect of respiratory depression at birth on later disability, or anomalies or other diseases diagnosed after the infant was discharged from the birth hospital. In addition, while retrospective studies in general are limited by the reliability of data, information in the Nova Scotia Atlee Perinatal Database is known to be of high quality. Data checks and edits are routinely made at the time of data collection by qualified health records personnel, and validation25,26 and abstraction studies confirm the quality of the data in the database.
This population-based cohort study, like few others, examined antepartum, intrapartum, and fetal predictive factors associated with respiratory depression at birth in the term infant. It shows a low rate of respiratory depression in the infant born at ≥37 weeks of gestational age, which may be reassuring to parents who increasingly expect a good outcome in a term pregnancy. Identification of the major risk factors found in this report may help guide clinical management, such as promoting increased antepartum and intrapartum surveillance and careful evaluation for operative delivery, to reduce further the incidence of respiratory depression at birth.
V.M.A. is supported by a Clinical Research Scholar Award from Dalhousie University. The authors are grateful to the Reproductive Care Program of Nova Scotia for data access.