Depression at Birth in Term Infants Exposed to Maternal Chorioamnionitis: Does Neonatal Fever Play a Role?

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Original Article Depression at Birth in Term Infants Exposed to Maternal Chorioamnionitis: Does Neonatal Fever Play a Role?

Lina F. Shalak, MD have birth depression, than infants with lesser degree of temperature Jeffrey M. Perlman, MB elevation after birth. Within the NICU group, the extent of temperature Gregory L. Jackson, MD elevation was not associated with worse neurological outcomes. Abbot R. Laptook, MD Journal of Perinatology (2005) 25, 447–452. doi:10.1038/sj.jp.7211326 Published online 28 April 2005

OBJECTIVES: (1) To determine the incidence and the time course of elevated temperature following delivery in term infants with clinical chorioamnionitis (CHORIO) and (2) to determine if the extent of INTRODUCTION temperature elevation at birth is associated with increased likelihood of The presence of maternal fever has been associated with an NICU Admissions, birth depression, or with short-term neurological increased need of resuscitation at birth, lower Apgar scores, a abnormalities. higher incidence of seizures in the newborn and increased 1–3 DESIGN/METHODS: mortality. Moreover an association between clinical chorioamnionitis (CHORIO) and cerebral palsy has been described The infants were divided into two groups based on the median admission both in term and preterm infants.4–6 However, the mechanisms rectal temperature of 37.81C for the cohort. Depression at birth was that link these two conditions remain ill defined, especially for defined as either the need of positive pressure ventilation for >2 minutes, infants born at term. Since hyperthermia during and following intubation, or Apgar score <6 at 5 minutes. Neurological examination hypoxic insults in experimental animals enhances neuronal death, and assessment of encephalopathy (Sarnat staging) was performed at maternal fever associated with clinical CHORIO has been proposed birth and daily thereafter, by one investigator blinded to temperature as a potential mechanism of injury.7 However, the role of an findings. elevated temperature in the newborn, following delivery to a RESULTS: mother with CHORIO has not been systematically studied in relation to neonatal neurological outcomes. This prospective cohort Infants with higher rectal temperature at 30 minutes of life were more study of term infants delivered to mothers with CHORIO was likely to be admitted to NICU: OR (2.8, 95% confidence interval (CI) [1.8 undertaken with three objectives. First, to determine the incidence to 4.3]), and were more likely to have birth depression OR (3, 95%CI [1.4 of elevated temperatures following delivery in infants born to to 6.5]). For infants in NICU, a rectal temperature above 37.81C was mothers with clinical CHORIO admitted to the intensive care unit present in 87% in the delivery room, persisted in 47% at 30 minutes, and as compared to infants admitted to the newborn nursery, and declined to a normal temperature at 60 minutes of life in the absence of whether it is associated with depression at birth. Second, to medical interventions. There was no relationship between neurological determine the temperature decay following admission. Third, to scores and neonatal temperature. determine whether the extent of temperature elevation in infants CONCLUSIONS: born with maternal CHORIO and admitted to the intensive care Term infants exposed to CHORIO who had a higher neonatal temperature unit is associated with a greater incidence of abnormal at 30 minutes of life, were more likely to be admitted to the NICU and to neurological examination or encephalopathy.

MATERIALS AND METHODS Study Population Department of Pediatrics (L.F.S., G.L.J.), University of Texas, Southwestern Medical Center, Dallas, This prospective cohort was derived from all term infants with an TX, USA; Weill Medical College of Cornell University (J.M.P.), Providence, RI, USA; and Brown Medical School (A.R.L.), Providence, RI, USA. estimated gestational age >36 weeks, born to mothers with a

Address correspondence and reprint requests to Lina F. Shalak, MD, Department of Pediatrics, diagnosis of clinical CHORIO at Parkland Memorial Hospital in University of Arkansas Medical Center, 800 Marshall Street, Slot 512-5, Little Rock, USA. Dallas, Texas between July 1999 and January 2001. There were

23,231 total deliveries during the study interval, of whom 1660 Short-Term Neonatal Outcomes (7%) were born to mothers with a diagnosis of clinical CHORIO Depression at birth. Defined prior to the start of the study as: and were eligible for enrollment into this study. Clinical CHORIO An Apgar score <6 at 5 minutes, the need for bag and mask was defined according to obstetrical criteria of maternal fever ventilation >2 minutes, or requiring intubation in the delivery (axillary temperature Z381C) in the presence of fetal or maternal room for respiratory support. tachycardia, uterine tenderness or foul smelling amniotic fluid.8 The Institutional Review Board of the University of Texas Assessment of neurological abnormalities. Each infant Southwestern Medical Center approved the study. Informed consent admitted to the intensive care unit underwent serial neurological was obtained from the parents of eligible infants in the NICU prior examinations performed by one examiner (L.S.) in the first to enrollment. 12 hours after birth (mean age 6±5 hours), and a second examination at 24 hours following the initial assessment. Infants NBN Cohort with abnormalities in their neurological examinations had daily The majority of infants, that is, 1571 of 1660 (95%) infants born at examinations performed until normalization or hospital discharge term to a mother with CHORIO were admitted to a regular as previously reported.9 A Modified Dubowitz Score (MDS) was used newborn nursery (NBN). Data were systematically collected for to objectively assess for abnormalities of tone as previously 667 of these infants based on alternate month schedule over a reported.9–10 Hypotonia was defined as two SDs above the normal 12 month period during the study interval. Upon arrival to the score of 15 (MDS>19), while a score two SDs below the mean nursery, all infants had a septic work up for chorioamionitis (MDS<11) was indicative of hypertonia. The Sarnat staging was exposure that included a blood culture and complete blood cell used to characterize the degree of the encephalopathy11 as mild, count with administration of ampicillin and gentamicin for 48 moderate and severe. Infants with persistent abnormalities in their hours until confirmation of negative blood cultures. As a criterion neurological examination were further evaluated by neuroimaging for a regular nursery admission, none of the infants had required studies, as part of clinical care. respiratory support in the delivery room (i.e. no bag mask ventilation, intubations or sustained oxygen requirement). Temperature Measurements and Thermal Regulation Admission temperature was measured within 30 minutes after Temperature measurements were obtained from the rectum using birth. The medical charts were reviewed for Apgar scores, cord a digital thermometer for all infants upon admission to the blood gases, abnormal WBC counts, culture results, length of intensive or NBN at 30 minutes after birth (T 30 minutes). hospital stay, duration of antibiotics, as well as documentation of 1 Thermometers were inserted no more than 12 in rectally. pneumonia or abnormal neurological examinations as determined Subsequent temperature measurements were obtained from the by the attending physician. axilla, at 60 minutes after birth and hourly until 4 hours of age. Infants in both cohorts (Intensive Care and Newborn Nursery) were NICU Cohort admitted and placed under radiant warmers following birth and A minority of infants born to mothers with CHORIO, that is, 89 of temperature control was via servo control of the abdominal skin 1660 (5%) were admitted to the Neonatal Intensive Care unit temperature to 36.51C. (NICU Group). Infants at term were admitted to the NICU by After study initiation, an additional rectal temperature protocol if they met any of the following criteria: need for bag measurement was obtained in the delivery room, after appropriate mask ventilation, use of continuous positive airway pressure resuscitation but prior to transport to the intensive care unit (CPAP) or intubation, sustained need of oxygen, use of volume (Temperature upon delivery). Since the latter measurement expansion or any medications in the delivery room, and an Apgar included implementing a change in our nursing protocols, data score <7 at 5 minutes. The medical charts of all infants were were available for approximately two-thirds of the infants admitted reviewed for the following: maternal temperature closest to the time to the NICU. of delivery, perinatal complications such as meconium, fetal heart rate abnormalities, rectal temperature of the newborn in the Evaluation for Neonatal Sepsis delivery room, 30 and 60 minutes after birth, mode of delivery, use All infants born to mothers with CHORIO and triaged to the NICU of epidural anesthesia, need for resuscitation, Apgar scores, had two sets of blood cultures obtained at birth, and complete medications to support blood pressure, postnatal illnesses and blood counts (CBC) at 0, 12 and 24 hours. The total white cell morbidities, for example, sepsis, pneumonia, air leaks, days in count was measured with a Coulter S Counter. An immature to hospital and discharge diagnosis. Part of this cohort has been used total neutrophil proportion was calculated (I/T ratio), with a ratio in a separate report9 to assess the inflammatory mediator response greater than 0.17 considered abnormal.12 Chest radiographs and and neonatal neurological outcomes in term infants with clinical lumbar punctures were obtained as clinically indicated. All infants CHORIO.9 were started on Ampicillin and Gentamicin following birth. Infants

448 Journal of Perinatology 2005; 25:447–452 Fever in the Newborn and Birth Depression Shalak et al.

without evidence of infection and an uncomplicated clinical course NBN Group had antibiotics discontinued at 48 hours, while infants with a The mean and SD for temperature at 30 minutes for infants triaged clinical diagnosis of sepsis, pneumonia (defined by the radiological to the NBN was 37.5±0.61C. The median temperature was 37.41C presence of focal or multifocal infiltrates), or persistently abnormal with 371C as the lowest quartile (25%), and 381C as the top WBC in the presence of clinical signs such as increased work of quartile (75%). The temperature distribution for all 667 infants breathing or oxygen requirement were treated for at least 7 days. born to mothers with CHORIO and triaged to the NBN was as Cytokines immunoassays: Plasma levels of interleukin (IL)-6 follows: 125 (18%) had a rectal temperature <371C at 30 minutes and IL-8 were measured in the first 12 hours after birth in all after birth, 379 infants (57%) had a temperature between 37 and enrolled infants in the NICU cohort, simultaneously with the 381C, and 164 infants (25%) had a temperature >381C. All infants neurological evaluation. ELISA double sandwich immunoassay had a drop in their temperature to below 371C at 60 minutes of life techniques were performed, using commercial kits (R& D Systems, without medical or pharmacological intervention. None of the Minneapolis, Minnesota for IL-8 measurements; Immunotech infants in the NBN had adverse outcomes requiring transfer to the Coulter Co, France for IL-6 measurements). Detection limits of the NICU. In 638 (96%) infants there was a negative septic work up assays as indicated by the manufacturer were 10 pg/ml for IL6, and and antibiotics were discontinued at 48 hours, and 29 infants (4%) 4.6 pg/ml for IL8. The coefficient of variation for both intra- and received 5 to 7 days of antibiotics secondary to radiographic interassay precision was less than 10% for each assay. evidence of pneumonia. Elevated neonatal temperature was not Placental pathology: Available placentas were evaluated for associated with the use of antibiotics beyond 48 hours. All blood inflammation using the histological grading system of Salafia cultures were negative for this cohort. et al.13 NICU Group Statistical Analysis The mean and SD for temperature at 30 minutes for infants triaged Statistical analysis was completed using SigmaStat 3.0. (SPPSS, to the NICU was 37.7±0.61C. The median temperature in the NICU Chicago, IL). Data are presented as mean and SD or as median was 37.8, with 37.21C as the lowest quartile (25%), and 381Cas and 25 to 75% quartiles depending on the data distribution. the top quartile (75%). Mann–Whitney Rank Sum test was used to compare two variables Temperature distribution at 30 minutes after birth in the 89 for data not normally distributed. ANOVA for ranks was used when infants admitted to the NICU with a diagnosis of maternal CHORIO more than two normally distributed variables were compared. To was the following: 15 (17%) had a rectal temperature <371C, avoid using an arbitrary definition for neonatal fever in studying 38 (43%) infants had a temperature between 37 and 381C, and the impact of temperature elevation on the incidence of birth 36 (40%) infants had a temperature >381C. depression, we used the median temperature value at 30 minutes of Temperatures for the NICU cohort (groups I and II combined) age to divide infants into groups with more (group I) and less are plotted in Figure 1a. Delivery room temperature measurements (group II) temperature elevations. Unadjusted odds ratios with 95% were available in 60 infants. Mean neonatal temperature in the confidence intervals (CI) were calculated for higher vs lower delivery room was 38.3±0.71C, declined upon admission to the neonatal temperatures and each of the outcome studied, that is, NICU to 37.7±0.71C, and declined still further at 60 minutes after NICU admission, birth depression and an abnormal neurological birth to 36.7±0.41C(p<0.01, ANOVA). No specific interventions outcome. Significance was denoted with p-value <0.05. were used to reduce the temperature other than servo control of the skin at 36.51C. The pattern of change in temperature was similar for groups I and II (Figure 1b). Both groups converged to a RESULTS temperature of 36.71C at 60 minutes of age. Entire Cohort The mean rectal temperature for all cohort of 750 infants exposed Maternal and Neonatal Characteristics at Birth to CHORIO was 37.51C. The median temperature was also 37.51C Maternal characteristics were similar in the two groups of with 371C as the lower quartile and 381C as the higher quartile infants with higher vs lower temperature at 30 minutes after (25 to 75%, respectively). birth (Table 1). There were no differences in the frequency of A neonatal temperature >37.81C by 30 minutes following epidural use. More than 75% of the mothers received one delivery occurred in 184 (27%) of the 667 infants triaged to the dose of ampicillin and gentamicin and one dose of oral Tylenol NBN and 42 (47%) of the 89 infants triaged to the NICU. This prior to delivery. Mean maternal temperature 1 hour prior to incidence of an elevated temperature at 30 minutes of >37.81C delivery was 38.21C, and was not significantly different between was significantly more common in those infants triaged to the the two groups of infants. The duration of labor was longer in NICU vs the NBN (p<0.01), with an odds ratio for a NICU group I (17±7 hours) compared to Group II (13±6 hours, admission of 2.8, 95% CI (1.8 to 4.3). p<0.005).

Journal of Perinatology 2005; 25:447–452 449 Shalak et al. Fever in the Newborn and Birth Depression

40 40

a 38.3±0.7 39 39 C ° C

° b * 37.7±0.7

38 * 38 c 36.7±0.4 37

Rectal Temperature 37 Rectal Temperature 36 Group II Group I

35 36 Delivery 30 Min 60 Min Delivery 30 Min 60 Min Figure 1. Rectal temperature after birth in: (a) All term infants with maternal CHORIO admitted to NICU. (a) Temperatures shown are mean±SD for groups I and II. Temperatures between the two groups were signiﬁcantly different in the delivery room, and at 30 minutes (*p<0.01). (b) Group I vs group II based on values above and below the median temperature (37.81C). (b) Temperatures are represented as a box and whisker presentation with median (solid line), mean (dashed line), 25 and 75% percentiles as bottom and top lines of the box, and 5 and 95% as the bottom and top of the error bar. Mean and SD are written on top of each box. Each temperature at times of the delivery room, 30 and 60 minutes are different from each other (a, b, c; p<0.05).

Table 1 Maternal Characteristics of Term Infants in NICU with Table 2 Neonatal Characteristics of Term Infants in NICU with CHORIO Exposure: group I (T>37.8 at 30 minutes) and group II CHORIO Exposure: group I (T>37.8 at 30 minutes) and group II (Tr37.8 at 30 minutes) (Tr37.8 at 30 minutes) Group I Group II Group I Group II (n ¼ 42) (n ¼ 47) (n ¼ 42) (n ¼ 47)

Race Birth weight (g) 3684±830 3331±772 Hispanic 71% 75% Gestational age (weeks) 40±2 40±2 Black 16% 19% Sex (% male/% female) (52/48) (52/48) White 4% 5% Cord pH 7.21±0.12 7.18±0.14 5 minutes Apgar <5 6 (14%) 8 (19%) Delivery type Temperature (1C) delivery roomw 38.7±0.5 38.0±0.6* Vaginal 64% 55% Temperature (1C) 30 minutes 38.2±0.4 37.2±0.4* C/section 36% 45% Temperature (1C) 60 minutes 36.7±0.4 36.7±0.3 Heart Rate (bpm) 30 minutes 180±13 171±16* Use of epidural 31 (74%) 30 (67%) Respiratory rate 30 minutes 60±16 53±17 ROM duration (hours) 10.8±5.3 12.8±8.2 Blood pressure (mmHG) 30 minutes 47±8 48±4 Labor duration (hours) 17±7 13±6* *p<0.05. Maternal antibiotics (# doses) 1 [1–1] 1 [1–1] wDelivery room temperature available for 51 infants. Maternal antipyretics (# doses) 1 [1–1] 1 [1–1] Maternal temperature (T closest to delivery, 1C) 38.2±0.3 38.1±0.5 two groups at 30 minutes. Mean blood pressure upon admission *p<0.05. Medication doses are shown as median (25–75%). was comparable in both groups.

Markers of Neonatal Infection Characteristics of infants admitted to the NICU are shown in Infants in both groups had similar percentages of abnormal WBC. Table 2. There were no differences in birth weight, gestational age, The I/T ratio at birth and at 12 hours, IL-6 and IL-8 concentrations gender, Apgar score, and cord arterial pH between groups. Infants at 6 hours after birth were elevated and similar in both groups in group I with a higher temperature had an elevated heart rate (Table 3). The incidence of pneumonia was similar in each group. (180±13 bpm) compared to group II (171±16 bpm, p<0.01) at Similar proportions of infants in both groups received antibiotics 30 minutes of age. Respiratory rate was not different between the for intervals greater than 48 hours, that is, 18 infants (45%) in

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Table 3 Markers of Infection in Term Infants Admitted to NICU with and adverse neonatal outcomes such as depression after birth, Maternal CHORIO: group I (T>37.8 at 30 minutes) and group II seizures and mortality.5,15 In spite of these experimental and (Tr37.8 at 30 minutes) clinical observations, there are no data examining temperature Group I (n ¼ 42) Group II (n ¼ 47) elevations after birth and short-term neurological outcomes. Results of this study delineate the changes in temperature following # Abnormal WBC at birth 23 (54%) 23 (50%) birth and the associated short-term outcomes in term infants born # Z2 Abnormal WBC 11 (26%) 14 (29%) to mothers with clinical CHORIO. Principal findings were: (1) I/T at birth 0.23±0.12 0.29±0.23 Infants born to mothers with CHORIO with higher neonatal I/T at 12 hours 0.21±0.20 0.25±0.21 temperatures were more likely to be admitted to NICU, (2) the odds IL-6 (pg/ml) 1546 [413–2370] 768 [174–2173] for birth depression is higher with temps after birth, (3) elevations IL-8 (pg/ml) 108 [58–240] 149 [83–480] in body temperature in the NICU cohort are self-limited and resolve Pneumonia 10 (24%) 6 (13%) by 60 minutes of age. WBC ¼ white blood count; I/T ¼ immature to total neutrophils proportion; The influence of temperature on the initiation of respiration at IL ¼ interleukins. birth has been studied in fetal lamb where initiation of continuous breathing occurred only with decreasing body temperature by group I and 21 infants (46%) in group II. None of the infants in 1.2oC, and was not modified by application of external heat.16,17 either group had a positive blood culture; however, all the mothers Our association of higher neonatal temperatures with a need for had received at least one dose of intravenous ampicillin before ventilation at birth and triage to the NICU agree with the published delivery. A concomitant diagnosis of histological CHORIO was effects of maternal temperature.2 In the latter report infants born to made in 19 (73%) of the 26 placentas available for pathology and mothers with a temperature above 381C were more likely to require there were no differences between groups. bag and mask resuscitation compared to infants not exposed to maternal fever.6 In a cohort of infants requiring resuscitation, the Summary of Short-Term Outcomes maternal condition most commonly associated with a 5 minute Entire cohort. In all, 17 infants (7.5%) of the 226 with the Apgar <5 was maternal fever with a concomitant diagnosis of higher temperature showed evidence of birth depression vs 12 clinical CHORIO.15 Our study differs from these prior reports, by infants (2.6%) of 460 without temperature elevation; p<0.005; examining neonatal temperature after birth in infants born to OR 3 [95% CI (1.4 to 6.5)]. mothers with CHORIO. A potential confounding factor to our findings is the high use of NICU group. Serial median MDS scores at 12 hours after birth epidural analgesia since it has been linked to a higher maternal were not significantly different between groups (group I: 14, 13 to temperature, even in the absence of proven maternal 15, and group II: 15, 13 to 18). The scores were also similar at 24 infection.6,19,20 Since epidural use is associated with higher hours following the first examination, that is, group I: 13 (13 to maternal temperatures, which itself is associated with birth 14) and group II: 13 (13 to 15). Two infants in group I and two depression; epidural use itself may be contributing to the birth infants in group II showed evidence of encephalopathy. One other depression and not temperature per se. However, in our study the infant in group II had isolated generalized tonic–clonic seizures at use of epidural was equally high in infants with higher vs lower 30 minutes after birth; his lumbar puncture and CT scan showed temperatures. Interestingly, a longer duration of labor was observed no abnormalities and the etiology of his seizures was unclear. in the group with high temperature after birth in this report, Length of hospital stay was similar in both groups (5±3 and supporting the experimental association of higher fetal temperature 6±4 days for groups I and II, respectively). with duration of labor following epidural administration.21 The present results provide important information about the temporal changes in body temperature over the first hour after DISCUSSION birth, under conditions of servo control of the abdominal skin Thermoregulation of the newborn has been focused primarily on temperature using a radiant warmer. No other specific avoidance of cold stress in the delivery room, and maintaining interventions were used to modulate the temperature. Results infants in a neutral thermal zone once in the nursery. Evidence in showed a progressive fall in body temperature from 87% with a newborn and adult animals indicates a powerful effect of temperature >37.81C immediately after birth, to 47% at 30 temperature on the brain during specific pathological conditions. minutes after birth, to none at 60 minutes after birth. The profile When the brain temperature is elevated by 2 to 41C during and of temperatures following birth from infants triaged to the NICU following ischemia, neurological outcome is worse compared to support the maternal origins of the elevated temperature at birth normal or 2 to 41C reductions in temperature.14 There are and the absence of an independent febrile response in the newborn. important clinical associations between intrapartum maternal fever Experimental studies indicating that thermoregulation of the fetus

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