do very sick neonates born at term have antenatal risks? : 2. infants ventilated primarily for lung...

Acta Obstet Gynecol Scand 2001; 80: 917–925 Copyright C Acta Obstet Gynecol Scand 2001

Printed in Denmark ¡ All rights reservedActa Obstetricia et

Gynecologica ScandinavicaISSN 0001-6349

ORIGINAL ARTICLE

Do very sick neonates born at term haveantenatal risks?2. Infants ventilated primarily for lung disease

LEE SUTTON1,2,5, GEOFFREY P. SAYER3, BARBARA BAJUK1,2, VALERIE RICHARDSON1,2, GEOFFREY BERRY4 AND

DAVID J. HENDERSON-SMART2

From the 1New South Wales Neonatal Intensive Care Units’ Data Collection (NICUS), the 2Centre for Perinatal HealthServices Research, the 3Family Medicine Research Unit, Department of General Practice, University of Sydney, the4Department of Public Health and Community Medicine, University of Sydney and the 5School of Women’s and Children’sHealth, University of New South Wales, Australia

Acta Obstet Gynecol Scand 2001; 80: 917–925. C Acta Obstet Gynecol Scand 2001

Aims. 1. Ascertain antenatal and intrapartum risk factors for term neonates ventilated pri-marily for respiratory problems. 2. Describe the neonatal morbidity and mortality.Methods. Population-based case control cohort study.Setting. Sydney and four large rural/urban Health Areas in New South Wales, 1996.Subjects. Singleton term infants, no major congenital anomaly: subset of 99 infants ventilatedprimarily for respiratory problems from 182 cases admitted to a tertiary neonatal intensivecare unit (NICU) for mechanical ventilation, and 550 randomly selected controls.Outcome. Risk factors for case status by maternal, antenatal, labor, delivery, and combinedepochs, adjusted Odds Ratios (OR), 95 per cent Confidence Intervals (CI), p,0.05.Results. Predictors of case status by multivariate epochs: mother’s age Ø35 years (1.9 (1.1,3.2) pΩ0.03), primigravida (1.8 (1.1, 2.8) pΩ0.01), any antenatal complication (3.8 (2.4, 5.9)pΩ0.0001), birth weight ,3rd percentile (3.7 (1.5, 9.1) pΩ0.006), gestational diabetes (2.9(1.3, 6.9) pΩ0.01), maternal pyrexia (6.5 (1.6, 27.2) pΩ0.01), birth weight .90th percentile(1.8 (1.01, 3.2) pΩ0.047), gestation 37–38 weeks (2.3 (1.5, 3.6) pΩ0.0004), forceps (4.4 (2.1,9.1) pΩ0.0001), elective cesarean section (3.7 (2.0, 6.5) pΩ0.0001), emergency cesarean section(4.5 (2.4, 8.4) pΩ0.0001). Case mortality rate was 5 per cent.Conclusion. The pathways to neonatal respiratory morbidity in term infants are multifacto-rial. Several areas which warrant more in-depth study are: elective cesarean section at 37–38weeks gestation, fetal growth restriction, macrosomia and the pattern of in-utero growth,maternal weight gain during pregnancy, gestational diabetes, pyrexia in labor and the role ofchorioamnionitis.

Key words: neonatal intensive care; risk factors for mechanical ventilation; term neonate

Submitted 16 August, 2000Accepted 2 May, 2001

Many studies have followed up the preterm new-born. However, the very sick term neonate, whomake up 20% of the NICU population (1), have

Abbreviations:NSW: New South Wales; NICU: Neonatal Intensive Care Unit;MDC: Midwives Data Collection; NICUS: New South WalesNeonatal Intensive Care Units’ Data Collection; El C/S: elec-tive cesarean section; Em C/S: emergency cesarean section;

C Acta Obstet Gynecol Scand 80 (2001)

been relatively neglected (2–4). This is the secondof two papers (5) which examine mechanically ven-tilated term infants without major congenital

HR: heart rate; SNAP: Score of Acute Neonatal Physiology;CRS: Clinical Reporting Systems; SAS: Statistical AnalysisSoftware; c2: Chi square; OR: odds ratio; CI: confidence inter-vals; SGA: small for gestational age.

918 L. Sutton et al.

anomalies enrolled in the New South Wales Neo-natal Intensive Care Units’ Data Collection(NICUS).

The aims of our case-control study of term neo-nates who require mechanical ventilation are to:

1. describe their morbidity and mortality2. seek antenatal and intrapartum risk factors

for this morbidity3. elucidate causal pathways which may open

up new preventative strategies4. follow the cases and controls to at least 3

years of age5. document those pathways which result in

poor outcome at age 3 years.The paper accompanying this one (5) describes

the study methods in detail and reports the majormorbidity categories and their case fatality ratesfor term mechanically ventilated neonates in a geo-graphically defined Australian population. It com-pares the occurrence of antenatal and intrapartumrisk factors between the case infants ventilated pri-marily for asphyxia-related causes, and the controlinfants.

This paper compares the occurrence of antenataland intrapartum risk factors between the case in-fants ventilated primarily for lung problems (eitherparenchymal or vascular), as well as the infantsventilated for non-neurological sepsis, and thecontrol infants.

Methods

This is a case-control study selected from the 1996birth cohort, with retrospective and prospectiveascertainment respectively of antenatal and peri-natal risk factors, and detailed prospective follow-up data collection to ascertain outcome.

The study area includes the Health Areas whichin 1992–93 represented 80 per cent of NSW birthsand 90 per cent of the NICU term mechanicallyventilated infants (1). Permission to conduct thestudy was granted from the 35 Hospital and AreaEthics Committees in the study area.

Cases were singleton infants of gestational agegreater than or equal to 37 weeks born between 1/1/96–31/12/96 to mothers resident in the studyarea, with no major congenital anomaly, who re-quired mechanical ventilation for at least 4 hoursand were admitted to a tertiary NICU in NSWwithin the first 96 hours of life.

Control infants were not mechanically ventilatedand were not admitted to a tertiary NICU cot.Controls were collected independently of cases. Arandom sample of births was generated from the1994 NSW Midwives Data Collection (MDC) formothers resident in the study area at the time ofthe infant’s birth. These 1994 births were then ap-


plied prospectively to the 1996 birth cohort, sothat a control baby was one born in the same hos-pital and closest in date and time to the randomlyselected 1994 baby. Birth times were generated forthe study by the TVW Telethon Institute for ChildHealth Research in Western Australia. If themother of a control baby declined to participate inthe study then the mother of the next baby bornclosest in date and time in that hospital was ap-proached. It was planned to collect two controlsfor each case. The study commenced on 1/1/96. In-formed, written consent was obtained from allmothers, either by the liaison /audit officer or theneonatologist/pediatrician managing the infant’scare.

Infants ventilated for mainly lung problems weredefined as those not having fits, nor having an ab-normal neurological examination at 3 or 7 days,and diagnosed with any of the following:

Respiratory distress syndromeTransient tachypneaMeconium aspiration syndromePulmonary hypertensionOther respiratory problems e.g. pneumothorax,pneumomediastinum, amniotic fluid aspiration.Infants ventilated for non-neurological sepsis:Mechanical ventilation with major problemproven infectionΩpositive blood culture or urineculture and treated with a course of antibiotics,no treated fits.Definitions: see appendixCollection of antenatal, perinatal and neonatal

data, validation of the data collection, and samplesize calculations are described in the methods sectionof the accompanying paper (5).

Statistical analysis

Data were analyzed using the same methods as inthe accompanying paper (5). Univariate associ-ation (chi square and odds ratios) between case/control status and risk factors was performed toidentify possible significant predictors for being acase (p,0.05), within the frame of maternal, ante-natal, labor and delivery epochs. For each epoch,all predictors identified from the univariate analy-ses at a significance level of 0.20 were entered intoa logistic regression model. To determine a parsi-monious model predicting case/control status, theleast significant predictors were eliminated fromthe model through a stepwise elimination methoduntil all remaining predictors were significant at0.05. Additional models were built incorporatingsignificant factors from the parsimonious model ofthe epoch and all the previous epochs. As the out-come (being a case baby) is rare, the odds ratios(OR) are interpreted as approximate relative risks.

Term neonates with lung disease 919

The strength of fit, or the extent to which the fittedlogistic regression discriminates between observedand predicted, is provided by the percentage ofconcordant responses, c. A value of c of 0.5 indi-cates no discrimination, and 1.0 perfect discrimi-nation; c is also the area under the Receiver Oper-ating Characteristic (ROC) Curve. The univariateand logistic regression analyses were performed onthe respiratory group as a whole, and also on theinfants ventilated for respiratory distress syn-drome, and those ventilated for meconium aspir-ation, as two separate groups.

Results

There were 99 infants ventilated for primarily lungproblems. Table I shows the main indication formechanical ventilation in these infants with thecase fatality rate and cause of death. The majorrespiratory problems diagnosed in the 31 infantsventilated for respiratory distress syndrome werehyaline membrane disease (nΩ26), transient ta-chypnea (nΩ1), ‘poor respiratory effort’ (nΩ1),and pulmonary hypertension (nΩ3). For the 41 in-fants ventilated for meconium aspiration, themajor respiratory problems diagnosed were mec-onium aspiration (nΩ33), and pulmonary hyper-tension (nΩ8). The major respiratory problems di-agnosed in the 12 infants ventilated for pulmonaryhypertension, were pulmonary hypertension (nΩ8), hyaline membrane disease (nΩ2), and pneu-monia (nΩ2). Of the four infants ventilated forsepsis, two were diagnosed with pneumonia, andthe others with septicemia, one of whom also hadpulmonary hypertension.

Risk factors for mechanical ventilation forrespiratory problems – univariate analysis

In Tables II–IV, case infants ventilated for mainlyrespiratory problems are compared with the con-trols, with respect to potential risk factors ateach stage in the pregnancy and delivery: mat-

Table I. Main indication for mechanical ventilation and case fatality rate amongst cases ventilated primarily for lung problems or sepsis

Indication n (%) of cases Case fatality rate Cause of death

Meconium aspiration* 41 (41.4) 2 (4.9) 1 MAS, 1 PHTRespiratory distress syndrome 31 (31.3) 3 (9.7) 1 renal vein thrombosis, 2 SIDSPulmonary hypertension* 12 (12.1) 0Transient tachypnea* 5 (5.1) 0Infection no neuro symptoms 4 (4.0) 0Other (mainly respiratory)** 6 (6.1) 0Total 99 (100.0) 5 (5.1)

MASΩmeconium aspiration syndrome, PHTΩpulmonary hypertension, SIDSΩsudden infant death.*neurologically normal.

**pneumothorax, amniotic fluid aspiration, pneumomediastinum.


ernal, antenatal (Table II), labor, delivery (TableIII), infant factors (Table IV). For the rest of thispaper, the term ‘case infants’ will refer to thoseventilated for primarily respiratory problems, ex-cept when describing the risk factors for the in-fants ventilated for respiratory distress syndromeor meconium aspiration. Mothers of case infantswere more likely (p,0.05) than control infants’mothers to be 35 years or older, to be a primi-gravida, or to have insulin dependent diabetesmellitus (Table II). Thirteen per cent (13/99) ofcase mothers were primigravidae aged 35 yearsor older compared with 3 per cent (15/550) ofcontrol mothers (OR 5.4 (2.5, 11.8), pΩ0.001).There was no difference in maternal educationlevel between primigravida and multigravida caseand control mothers. During the pregnancy, casemothers were more likely than control mothersto have had any antenatal complication, and inparticular, gestational diabetes (Table II). Al-though they did not reach significance at a uni-variate level (p,0.05), maternal education level,essential hypertension, the combined maternaldisease variable, and antepartum hemorrhagewere retained for inclusion in logistic regressionmodelling as they had a p-value of ,0.2.

There was no difference in rates of induction oflabor or use of prostaglandins between case andcontrol mothers. Mothers of case infants weremore likely than control infant mothers to havepyrexia in the 48 hours before vaginal delivery orcesarean section. Although it did not reach sig-nificance at a univariate level (p,0.05), prolongedrupture of membranes was retained for inclusionin logistic regression modelling as it had a p-valueof ,0.2. Case infants were more likely to have beenborn by an operative delivery, either forceps, cesar-ean section before labor, or cesarean during labor(Table III). Fifty per cent (3/6) of teenage casemothers had a cesarean section in labor, comparedwith none of the 31 control teenage mothers (pΩ0.003). There was no statistical difference in theproportion of case (1/6) and control (3/31) teenage


Table II. Distribution of maternal and antenatal risk factors amongst cases ventilated for mainly respiratory related causes, and controls

Cases (nΩ99) Controls (nΩ550) Odds RatioRisk factor n (%) n (%) (95% CI) p-value

Maternal epoch:Maternal age Ø35 24 (24.2) 84 (15.3) 1.78 (1.06, 3.0) 0.027Insulin dependent diabetes 2 (2.0) 0 0.023Primigravida 54 (54.6) 230 (41.8) 1.67 (1.09, 2.6) 0.019

Antenatal epoch:Any antenatal complication 64 (64.7) 181 (32.9) 3.73 (2.4, 5.8) 0.001Gestational diabetes 9 (9.1) 18 (3.3) 2.96 (1.3, 6.8) 0.008

Table III. Distribution of labor and delivery risk factors amongst cases ventilated for mainly respiratory related causes, and controls


Labor epoch:Maternal pyrexia* 4 (4.0) 4 (0.73) 5.74 (1.41, 23.33) 0.022

Delivery epoch:Cesarean: elective 22 (22.2) 57 (10.4) 2.47 (1.43, 4.27) 0.001

emergency 19 (19.2) 40 (7.3) 3.03 (1.67, 5.49) 0.001Forceps delivery 13 (13.1) 28 (5.1) 2.82 (1.41, 5.65) 0.002

*Temperature.37.5æ within 48 hours before onset of labor or cesarean section.

Table IV. Distribution of infant risk factors amongst cases ventilated for mainly respiratory related causes, and controls


Gestational age 37–38 weeks 38 (38.4) 123 (22.4) 2.16 (1.38, 3.40) 0.002Birth weight ,3rd percentile 8 (8.1) 13 (2.4) 3.63 (1.46, 9.01) 0.003Birth weight .90th percentile 20 (20.2) 64 (11.6) 1.92 (1.10, 3.35) 0.019

mothers having a cesarean section before laborcommenced. The older control mothers (Ø35years) were more likely (19 per cent) than those,35 years (9 per cent) to have an elective cesareansection (pΩ0.005), whereas elective cesarean sec-tion was not related to older maternal age in thecase mothers.

Significantly more cases than controls weregrowth restricted (birth weight less than the 3rdpercentile) (Table IV). Seven of the eight growthrestricted cases were ventilated for meconium as-piration (compared with 37 per cent of case infantswho were not growth restricted, pΩ0.049).

There was also a significantly higher pro-portion of cases who were large for gestationalage (birth weight greater than the 90th percen-tile) (Table IV). Case mothers with gestationaldiabetes (nΩ9) had five times more risk of havinga baby who was large for dates than those with-out gestational diabetes (OR 4.9 (1.5, 16.7), pΩ0.015). Control infants who were large for dates


were more likely (OR 2.4 (1.1, 5.3), pΩ0.038) tobe born by emergency cesarean section thanthose less than the 90th percentile, with no dif-ference in the elective cesarean section rates. Asignificantly higher proportion of case (38 percent) than control infants (22 per cent) wereborn at the lower end (37–38 weeks gestation) ofthe ‘term’ gestational age range (37–41 weeks)(Table IV). Thirty-seven per cent (nΩ14) of the37–38 week case infants were born by cesareansection not in labor, compared with 23 per centof the control infants of the same gestationalage. Infants born at 37–38 weeks gestation inboth the case and control groups were four timesmore likely to have been delivered by cesareansection before labor commenced, than infantsborn at 39 weeks or more. Ten of the 14 case in-fants born at 37–38 weeks gestation by electivecesarean section were ventilated for hyaline mem-brane disease (nΩ9) or transient tachypnea (nΩ1).


Risk factors for mechanical ventilation forrespiratory problems–multivariate analysis

The significant predictor variables of case status inlogistic regression are shown in Table V, for theindividual and combined epochs. Maternal andantenatal factors associated with being a case inthe individual epochs were primigravida, maternalage 35 years or more, any antenatal complication,gestational diabetes and growth restriction. Casemothers were six times more likely than controlmothers to have pyrexia in the 48 hours before lab-or or cesarean section, and three to four timesmore likely to have an operative delivery (Table V).Case infants were more likely than control infantsto be of gestational age 37–38 weeks, to be growthrestricted or to be large for gestational age (birthweight .90th percentile).

All the epochs were combined first in one modelwith primigravida, maternal age .35 years, ges-tational diabetes, maternal pyrexia, growth restric-tion (birth weight ,3rd percentile), gestational age37–38 weeks, forceps delivery, cesarean section be-

Table V. Logistic regression: Significant risk factors for individual and com-bined epochs

c value MultivariateRisk factors for model OR (95% CI) p-value

Maternal epoch: 0.57Primigravida 1.78 (1.13, 2.80) 0.013Maternal age .35 years 1.86 (1.07, 3.22) 0.03

Antenatal epoch model 1*: 0.678Any antenatal complication 3.75 (2.39, 5.887) 0.0001Birth weight ,3rd percentile 1.92 (1.08, 3.41) 0.027

Antenatal epoch model 2.: 0.553Gestational diabetes 2.98 (1.29, 6.88) 0.011Birth weight ,3rd percentile 3.66 (1.47, 9.13) 0.006

Labor epoch: 0.619Maternal pyrexia 6.50 (1.56, 27.21) 0.010Birth weight .90th percentile 1.79 (1.01, 3.16) 0.047Gestational age 37–38 weeks 2.29 (1.45, 3.62) 0.0004

Delivery epoch: 0.662Cesarean: elective 3.65 (2.04, 6.51) 0.0001

emergency 4.49 (2.40, 8.40) 0.0001Forceps delivery 4.39 (2.12, 9.06) 0.0001

Combined epochs 0.725Maternal age .35 years 1.74 (1.01, 3.02) 0.048Maternal pyrexia 4.65 (1.05, 20.65) 0.043Gestational age 37–38 weeks 2.14 (1.30, 3.52) 0.003Birth weight ,3rd percentile 3.29 (1.24, 8.75) 0.017Cesarean: elective 2.64 (1.42, 4.90) 0.002

emergency 4.07 (2.13, 7.78) 0.0001Forceps delivery 4.47 (2.11, 9.44) 0.0001

*variables entered into model: any antenatal complication, gender, birthweight ,3rd percentile,birth weight.90th percentile.. variables entered into model: gestational diabetes, antepartum hemorrhage,gender, birth weight ,3rd percentile.


fore labor or in labor. The factors which remainedas significant predictors of case status in this modelwere maternal age .35 years, maternal pyrexia,gestational age 37–38 weeks, growth restriction,cesarean section before labor or in labor, and for-ceps delivery (Table V). In the second model, anyantenatal complication and birth weight .90thpercentile replaced gestational diabetes in themodel. Factors which remained significant in thismodel were any antenatal complication (OR 2.78(1.72, 4.49) pΩ0.0001), gestational age 37–38weeks, forceps delivery, and cesarean section be-fore labor or in labor (c value for this modelΩ0.741).

Intrapartum and neonatal morbidity, and mortalityof case infants

Mothers of case infants had significantly higherrates of fetal distress before and during labor andthick meconium liquor in labor (Table VI); andcase infants were more likely to have one and fiveminute Apgar scores less than 4, and need majorresuscitation at birth (Table VI). The median (25per cent, 75 per cent) 1 minute Apgar was 6 (4, 8),and 5 minute Apgar was 8 (7, 9). Just under aquarter of the infants required intubation at birth.The median (25 per cent, 75 per cent) birth weightof case infants was 3340 (3040, 3750) grams. Fortyper cent (40/99) of the infants were diagnosed withpulmonary hypertension (including the 12 venti-lated for this), and 31 per cent (31/99) needed in-otropes in the NICU. Only seven infants had renaldysfunction defined as a serum creatinine measure-ment greater than 1.5 mmol/litre (or 150 mmol/litre) on at least one occasion.

Five (5 per cent) infants died due to the follow-ing causes (Table I): one meconium aspiration (day2), one pulmonary hypertension (day 3) – this babywas ventilated for meconium aspiration, one renalvein thrombosis (day 17), two sudden infant deathsyndrome (SIDS) [days 38 and 204]. The infantsdying from renal vein thrombosis and SIDS wereall originally ventilated for respiratory distresssyndrome. Four of the infants who died were se-dated or paralyzed on day 3. All infants exceptthe one dying of renal vein thrombosis had a postmortem examination. The median (25 per cent, 75per cent) duration of mechanical ventilation for allsurvivors (including the two infants who died afterday 28) was 3 (2, 6) days, compared with 9.5 (8,14) days for those infants still sedated or paralyzedon day 7. The median (25 per cent, 75 per cent)duration of tube feeds for survivors was 3 (2, 8)days. The median (25 per cent, 75 per cent) age atdischarge home for survivors varied from 8 (6, 12)days for infants not sedated on day 3 (nΩ41), to


Table VI. Comparison of intrapartum and neonatal morbidity between cases ventilated for mainly respiratory related causes, and controls

Cases (nΩ99) Controls (nΩ550)Risk factor n (%) n (%) Odds ratio (95% CI) p-value

Thick meconium liquor 39 (42.5) 29 (5.3) 11.68 (6.74, 20.24) 0.001Antenatal fetal distress 41 (41.4) 55 (10.0) 6.36 (3.90, 10.36) 0.001Fetal distress in labor 37 (37.4) 54 (9.8) 5.48 (3.34, 8.99) 0.0011 minute Apgar score ,4 21 (21.2) 14 (2.6) 10.31 (5.03, 21.11) 0.0015 minute Apgar score ,4 3 (3.0) 0 0.049

Resuscitation:none 24 (24.2) 447 (81.3) 0.074 (0.044, 0.122) 0.001oxygen 27 (27.3) 72 (13.1) 2.49 (1.50, 4.13) 0.001Mask IPPR* 25 (25.3) 30 (5.5) 5.86 (3.27, 10.50) 0.001ETT IPPR* 23 (23.2) 1 (0.2) 166.15 (22.12, 1248.0) ,0.0001Cardiac massage 4 (4.0) 0 0.018

Drugs/fluids used in resuscitation 22 (22.2) 7 (1.3) 22.2 (9.16, 53.61) 0.001

*IPPR – Intermittent positive pressure ventilation.

28 (24.5, 30.5) days for infants who were sedatedon both days 3 and 7 (nΩ12).

Subsets of infants ventilated for respiratory distresssyndrome and meconium aspiration

The subsets, infants ventilated primarily for RDS(nΩ31), and infants ventilated primarily for mec-onium aspiration (nΩ41) were analyzed separately.In logistic regression analysis, factors associatedwith being ventilated primarily for RDS were hy-pertensive disease of pregnancy (OR 3.05(1.18,7.88), pΩ0.02), any antenatal complication(OR 2.19 (1.06, 4.52), pΩ0.03), gestational age 37–38 weeks (OR 6.31 (2.94, 13.53), pΩ0.0001), andcesarean section before labor commenced (OR6.25 (2.90, 13.41), pΩ0.0001). The c value (areaunder the ROC) was greatest for gestational age37–38 weeks (cΩ0.711), and cesarean section be-fore labor commenced (cΩ0.658). Factors associ-ated with ventilation for meconium aspirationwere (maternal age .35 years OR 3.70 (1.70, 8.10),pΩ0.001), primigravida (OR 5.26 (2.42, 11.49), pΩ0.0001), any antenatal complication (OR 5.50(2.58, 11.74), pΩ0.0001), birth weight ,3rd per-centile (OR 5.67 (1.99, 16.11), pΩ0.001), birthweight .90th percentile (OR 3.22 (1.43, 7.26), pΩ0.005), gestational age .40 weeks (OR 2.75 (1.39,5.46), pΩ0.004), cesarean after labor commenced(OR 6.57 (3.03, 14.25), pΩ0.0001), forceps delivery(OR 5.48 (2.16, 13.90), pΩ0.0003. The c value(area under the ROC) was greatest for the modelscontaining maternal age . 35 years and primigra-vida (cΩ0.708), and any antenatal complication,birth weight ,3rd percentile, birth weight .90thpercentile (cΩ0.782).


Discussion

The pathways to severe respiratory disease in theterm neonate commence in the antenatal period.Although there are some factors in common be-tween the pathways to the various indications formechanical ventilation in the term neonate, thisstudy suggests a different cascade of risk factors toterm infants requiring mechanical ventilation forRDS, compared with those being ventilated formeconium aspiration, or with those who needventilation because of poor adaptation to the ex-tra-uterine environment/‘asphyxia’/encephalopathy(5). A primigravida mother was a risk factor forrespiratory case status (in particular meconium as-piration), and an association between nulliparityand meconium aspiration syndrome has beennoted before (6). We examined associations be-tween being a primigravida and possible risk fac-tors which might predispose to neonatal morbidity.There were no associations between specific mat-ernal medical problems (eg. diabetes, hyperten-sion,) or antenatal complications (gestational dia-betes, hypertensive disease of pregnancy, antepart-um hemorrhage) and being a primigravida, butboth case and control primigravida mothers weremore likely than multigravidas to have had someantenatal complication. A larger study with collec-tion of more detailed information in the antenatalperiod would be required to examine factors forwhich primigravida status may be a proxy.

Older mothers are known to be at increasingrisk of complications in the antenatal and intra-partum periods (7). As there were only 11 casemothers who were primigravida and older than 35years, the numbers were too small to look for as-


sociations with perinatal morbidity within thissubgroup. There were also too few teenage primi-gravida amongst the cases and controls to look atassociated antenatal and perinatal risk factors.Maternal education level and socioeconomic sta-tus are strong predictors of problems in the peri-natal period (7), but no association was found be-tween maternal education level or private hospitalinsurance and respiratory case status. This wasalso so in the current study. Older mothers andwomen of higher socioeconomic status are morelikely to have technological interventions in laborand cesarean section (7, 8). The teenage casemothers in the present study were more likely thanthe controls to have had an emergency cesareansection. Unfortunately, with such small numbers,no conclusions can be drawn about adequacy ofpreventative measures before and during labor inteenage mothers. We found an association betweenolder mothers and elective cesarean sectionamongst controls but not cases. More details areneeded of the reasons for these elective cesareansections, before assessing whether an elective cesar-ean section may have prevented some of the casesborn to older mothers.

It is not surprising that not one individual mat-ernal medical problem remained as a significantpredictor of case status in the logistic regressionanalysis, given their rarity in the general popula-tion of NSW mothers, and the small numbers inthis study. Insulin-dependent diabetes mellitus isfound in 0.4 per cent of NSW mothers (9), noneof the control mothers in the present study, and 2/99 (2%) of respiratory case mothers.

The association between gestational diabetesand case status in this study is in keeping with theinternational literature (10, 11). We did not collectdata on maternal glycemic control during preg-nancy. It has been shown that neonatal outcome isrelated to maternal glycemic control (10). Worsen-ing carbohydrate intolerance was related to longerneonatal nursery length of stay and phototherapy,but there was no relationship between carbo-hydrate control and Respiratory Distress Syn-drome in a North American study (11). This samestudy found that ‘gestational diabetes shifts obstet-ric practice towards cesarean section’ despite betterblood glucose control. In the present study, theproportion of infants born by cesarean section be-fore labor commenced was the same for motherswith and without gestational diabetes. In the pres-ent study, infants with birth weight greater thanthe 90th percentile, were associated with about halfof the nine case mothers, and an even smaller percent (4/18) of the control mothers with gestationaldiabetes (difference not significant). Data on gly-cemic control during pregnancy need to be col-


lected. The most common reason for mechanicalventilation amongst the large for gestational agecase infants was meconium aspiration (10/20).There is a documented association between macro-somia and neonatal morbidity (12). In a recentstudy from Scandinavia (13), women with greaterincrease in weight during pregnancy gave birth toinfants of higher birth weight. We did not collectdata on maternal weight gain during pregnancy,but this may be a worthwhile exercise in futurestudies of pathways to term neonatal morbidity.

Maternal pyrexia in labor was a significant pre-dictor of respiratory case status (Table V). Thereis currently a lot of interest in the association be-tween maternal infection and cerebral palsy interm infants (14, 15), but we could find no reportsin the literature on an association between pyrexiain labor and subsequent neonatal respiratory mor-bidity in term infants. Pyrexia was not associatedwith prolonged rupture of membranes.

Morrison et al. (16) found an increase in respir-atory morbidity amongst infants delivered bycesarean section before onset of labor (the equiva-lent of elective cesarean section in NSW) at 37–38 weeks gestation. In the present study, a higherproportion of cases (14/99Ω14 per cent) than con-trols (28/550Ω5 per cent) was born by electivecesarean section at 37–38 weeks gestation (OR 3.07(1.55, 6.06), pΩ0.001).

For those infants born at greater than 38 weeksgestation, operative delivery could be a symptomof already being a case or itself a risk factor forneonatal morbidity, and it is difficult to tease thesefactors out. The present study did not collect car-diotocogram data as quality control would nothave been feasible, and the predictive value of suchdata is questionable (17, 18).

No significant associations were found betweengrowth restriction in the respiratory cases and thecommon predisposing factors (maternal smoking,hypertension or education level). The limitationsof the maternal and placenta data collected in elu-cidating causal pathways to the growth restrictionand neonatal morbidity were explained in the ac-companying paper (5). Some researchers categor-ize growth restriction into ‘wasted’ and ‘stunted’groups (19), which was not done in the presentstudy because of the unreliability of collectingbirth length in over 50 hospitals. For infants whosebirth weight is in the normal range, it may be im-portant to look for ultrasound evidence of inad-equate growth as measured by fall in percentilesduring pregnancy (20).

This study has found several areas which war-rant a more detailed and larger study, there beingno one factor which, if prevented, would result ina significant decrease in term neonatal morbidity.


There are increasing numbers of primigravidamothers over the age of 35 years, and it is import-ant that they have regular antenatal checks. Thedevelopment of any antenatal complication, suchas hypertension or gestational diabetes, in an olderprimigravid mother, further increases the risk ofneonatal morbidity. A record of maternal weightgain during pregnancy, and more detailed infor-mation on glycemic control in women with ges-tational and insulin dependent diabetes may pro-vide important etiological data. Fetal growth re-striction and macrosomia, as well as the pattern ofin-utero growth, are important areas to consider.Gestational age at delivery seems to have a role inthe etiological pathway, either at the more imma-ture end of the term gestation range (37–38 weeks)associated with RDS, or the post–mature gestation(.40 weeks) associated with meconium aspiration.The current elective cesarean section rate needs tobe reviewed. Pyrexia in labor is involved in thepathways to both ‘respiratory’ and ‘asphyxiated’morbidity in term infants, and a closer look at theplacenta and the role of chorioamnionitis is there-fore warranted. More centers need to becomeinterested in the term baby, so that a larger multi-center study can be designed.

Appendix

Definitions:

Full term infant – Gestational age 37 or more com-pleted weeks. Gestational age was determined bythe duration of pregnancy in completed weeksfrom the first day of the last normal menstrualperiod. If accurate information on the date of thelast normal menstrual period was not available, aclinical estimate of gestational age was obtainedfrom ultrasound during the first half of pregnancyor by examination of the newborn infant (21). The‘best estimate’ was used.Any pre-existing medical problem – maternal dis-ease present before the onset of this pregnancy andaffecting this pregnancy, includes insulin depend-ent diabetes mellitus, chronic renal failure, essen-tial hypertension, thyroid disease, narcotic drugaddiction, systemic lupus erythematosis, or anyother maternal medical condition recorded.Essential hypertension – known essential hyperten-sion or an elevation of blood pressure over 140/90present on two or more occasions prior to the 20thweek of pregnancy, which is not due to any ap-parent pathological condition.Any antenatal complication – any antenatal compli-cation present at any time during the pregnancy,including pre-term pre-labor rupture of mem-branes, preterm labor, pregnancy induced hyper-tension, antepartum hemorrhage, intrauterine


growth restriction, rhesus isoimmunization, ante-natal fetal distress, or any other complication ofpregnancy recorded.Hypertensive disease of pregnancy – 1. Systolicblood pressure Ø140 mmHg and/or diastolic bloodpressure Ø90 mmHg or 2. Rise in systolic bloodpressure Ø25 mmHg and/or rise in diastolic bloodpressure Ø15 mm Hg from blood pressure readingbefore conception or in first trimester of this preg-nancy (must be confirmed by two readings sixhours apart).Antenatal fetal distress – sustained fetal brady-cardia (HR,100) or sustained tachycardia(HR.160) not during labor and leading to inter-vention by the obstetric team.Elective cesarean section (El C/S) was defined asin the MDC, as cesarean section before labor hascommenced (9).Emergency cesarean section (Em C/S) was definedas cesarean section after labor has commenced (9).Complication of labor – includes cord prolapse,hemorrhage due to placental problems, or anyother complication of labor.Pulmonary hypertension – clinical or echocardio-graphic evidence of pulmonary hypertension. In-cludes loud P2, O2 requirement unexplained bychest Xray and/or differential pre– and post–ductal TCPO2.Small for gestational age – birth weight less thanthe 3rd percentile, using the NSW population per-centile data (22).Multigravida – previous delivery greater than 20weeks gestation.

Acknowledgments

The first part of our study was made possible by financial sup-port from the NSW Pregnancy and Newborn Services Net-work. We would like to thank the audit officers in the ninetertiary neonatal intensive care units in NSW, as well as theliaison officers in the 57 obstetric hospitals, who collected datafor this study. We would also like to thank all the families whoagreed to take part in the study. Thank you to Professor FionaStanley for her very helpful advice regarding this manuscript.

References

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Address for correspondence:

Lee Sutton, Ph.D.New South Wales Neonatal Intensive Care

Units’ Data Collectionc/o NSW Centre for Perinatal Health Services ResearchQueen Elizabeth II Research InstituteBuilding DO2, University of SydneyNSW, 2006, Australiae-mail: lee.sutton/perinatal.usyd.edu.au

do very sick neonates born at term have antenatal risks? : 2. infants ventilated primarily for lung...

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