Maternal Fever During Labor and the Risk of Neonatal Encephalopathy: Duration and magnitude of hyperthermia

Abstract

BACKGROUND:

Maternal fever occurs in up to 10% of laboring individuals. It is associated with adverse maternal and neonatal outcomes such as low Apgar scores, respiratory distress, sepsis, meconium aspiration syndrome, and death. Few studies have investigated the dose-response relationship between the duration and magnitude of maternal hyperthermia and hypoxic-ischemic encephalopathy (HIE).

OBJECTIVE:

To examine if the height of maximal maternal temperature and the duration from fever onset to delivery modify the risk of HIE.

DESIGN:

Population-based cohort study of non-anomalous singleton neonates born ≥ 35 weeks at 15 Kaiser Permanente Northern California hospitals (2012 - 2019). Births by elective cesarean section were excluded. Maternal fever was defined as at least one temperature ≥38°C before delivery. Maximal maternal temperature and timing of the first maternal fever were extracted from electronic medical records. Maximal maternal temperature was further classified as a five-level ordinal exposure: <37.5°C, 37.5-37.9°C, 38-38.4°C, 38.5-38.9°C, and ≥39°C. Duration of fever was defined as the duration from fever onset to delivery. HIE was defined as the presence of neonatal encephalopathy and perinatal acidosis (cord pH<7 or base deficit ≥10 within 2 hours after birth). Secondary outcomes included therapeutic hypothermia, neonatal seizures, acidosis, 5-min Apgar score<7, early onset sepsis, and neonatal intensive care unit admission. We used regression modeling, clustered by hospital sites, to evaluate the associations between maximal maternal temperature and duration of fever and neonatal outcomes, adjusting for duration between hospital admission and delivery, and duration of membrane rupture as proxies for labor duration.

RESULTS:

Among 248,594 laboring mothers, 25,760 (10.4%) had a fever during labor, and 487 (0.2%) delivered an infant with HIE. The presence of maternal fever was associated with a nearly fourfold increased risk of HIE compared to no fever (RR 3.92 [95% CI 3.24-4.75]). Even mild temperature elevations were associated with an increased risk of HIE; compared to mothers with a maximal temperature <37.5°C, the risk of HIE was higher among mothers with a temperature of 37.5°C to <38°C (RR 1.70 [95% CI 1.31-2.19]), 38°C to <38.5°C (RR 3.43 [95% CI 2.66-4.43]), 38.5°C to <39°C (RR 4.71 [95% CI 3.47-4.67] and ≥39°C (RR 8.47 [95% CI 5.92-12.1]). After adjusting for the duration of labor, the association between increasing maternal temperature and the risk of HIE remained significant. Similarly, the incidence of HIE increased with increasing duration from fever onset to delivery, even after adjusting for duration of labor.

CONCLUSIONS:

The higher the maternal temperature and the longer the duration from fever onset to delivery, the greater the risk of developing HIE, even when adjusting for the duration of labor. Novel strategies to predict and prevent HIE during labor and delivery should incorporate information regarding the height and duration of maternal fever during labor.

Tweet statement

In this cohort study, we show that the higher the maternal temperature in labor and the longer the duration from fever onset to delivery, the higher the risk of hypoxic-ischemic encephalopathy and other adverse neonatal outcomes.

Introduction

Maternal fever complicates up to 10% of term and late preterm deliveries.¹ The most common causes of fever in labor are maternal infection and epidural use.² Fever is more common in nulliparous mothers and those who have prolonged labor.^1,3

In animal studies, hyperthermia is associated with decreased tolerance of labor, fetal hypoxia, and metabolic acidosis.^{4 5} Even minor brain temperature elevation increases the risk of brain injury.⁶ In humans, maternal fever in labor is associated with increased risks of neonatal morbidities such as low Apgar scores, acidosis, respiratory distress, neonatal sepsis, meconium aspiration syndrome, hypoxic-ischemic encephalopathy (HIE), and seizures.^7–11 Fever in labor was also associated with long-term adverse neurodevelopmental outcomes and cerebral palsy.^10,12 However, whether the height and duration of fever in labor are associated with increased risk of HIE remains unclear. A recent study failed to show a difference in the risks of neurologic morbidity between neonates exposed to mild versus severe fever.⁸ However, this study was limited by a small sample size. Similarly, two previous studies failed to show a significant association between the duration of fever and the risk of HIE.^13,14

In this population-based cohort study, we determined the association between maximal maternal temperature in labor and HIE. We further assessed the association between the duration from fever onset to delivery time and neonatal outcomes, adjusting our analysis for the duration of labor.

Materials and Methods

Study population.

This retrospective population-based birth cohort study included all singleton live births ≥ 35 weeks gestational age, born between January 1, 2012, and July 31, 2019, in 15 Kaiser Permanente Northern California (KPNC) hospitals. Neonates born by elective cesarean section without labor, those with genetic or congenital anomalies, and those with missing temperature data were excluded. KPNC is an integrated healthcare system serving over 4.3 million members, representing approximately 40% of the region’s insured population. The sociodemographic distribution of the KPNC membership is broadly similar to that of the local and statewide California population, although the extremes of the income distribution are underrepresented.¹⁵ This study was approved by the institutional review boards of the University of California, San Francisco, and the Kaiser Foundation Research Institute and was exempt from obtaining individual patient consent.

For the remainder of this manuscript, we use the terms mothers and maternal to refer to all birthing parents, irrespective of gender identity. Maternal fever during labor was defined as any maternal temperature ≥38°C recorded in the electronic medical records during the birth admission between 72 hours before and 30 minutes after delivery.¹⁶ Temperatures up to 30 minutes after delivery were included to avoid missing fevers in the last hour before delivery, when documentation of maternal temperature can be delayed. We used a 72-hour window before delivery to avoid capturing fever distant from delivery in mothers with prolonged antepartum admission. Of note, delivery occurred within 72 hours of admission in 99.6% of mothers. The height of fever, defined as the highest recorded maternal temperature between 72 hours before and 30 minutes after delivery, was abstracted from the electronic medical record, and recorded as both a continuous and a five-level ordinal variable: <37.5°C, 37.5-37.9°C, 38-38.4°C, 38.5-38.9°C, and ≥39°C. Duration from fever onset to delivery was defined as the number of hours elapsed between the first maternal temperature of ≥38°C and the time of delivery.

The primary outcome, hypoxic-ischemic encephalopathy (HIE), was defined as the presence of both neonatal acidosis and neonatal encephalopathy (NE), as previously described.¹⁷ Briefly, neonatal acidosis was defined as at least one pH <7 or base deficit ≥10 from any cord blood, or a base deficit ≥10 on the first infant blood gas before 2 hours of age.¹⁷ Cord and infant blood gases were obtained at the clinician’s discretion. Maternal fever was not an indication for routine blood gas obtention. Neonatal encephalopathy was confirmed by medical record review and defined as an abnormal standardized neurologic exam¹⁸ between 1 and 6 hours of age that either 1) persisted beyond 6 hours of age, 2) was accompanied by seizures, or 3) was treated with active therapeutic hypothermia. Secondary outcomes included 5-minute Apgar <7, neonatal acidosis, neonatal encephalopathy, treatment with therapeutic hypothermia, neonatal seizures, and neonatal culture-positive sepsis.

Covariates:

Maternal, pregnancy, and delivery characteristics were collected from the KPNC data warehouse as previously described.¹⁹ The duration between hospital admission and time of delivery and between membrane rupture and time of delivery were collected as markers of labor progression. The time of epidural placement was collected, and fever was categorized as occurring with or without an epidural in place.

Statistical analyses

Descriptive statistics were used to assess the association between maternal, labor, and delivery characteristics and maternal fever. To visualize the association between the height of maximal maternal temperature and the duration from fever onset to delivery and HIE risks, we used unadjusted logistic regression modeling, with the continuous exposure (height or duration) transformed as a spline. We used modified Poisson regression models to estimate the relative risk and 95% confidence interval for HIE and other secondary outcomes between baseline and each category of maximal maternal temperature and duration from fever onset to delivery.²⁰ We evaluated unadjusted relative risks and relative risks adjusted for the duration between admission and time of delivery and between membrane rupture and time of delivery as splines. We clustered all analyses by hospital site. We used the Cochran-Armitage test of trend to assess the ordinal nature of increased risk between strata. In a sensitivity analysis, restricting our cohort to epidural-exposed mothers, we further adjusted our analysis for the duration of epidural analgesia as a spline. In an exploratory analysis, we assessed whether fever onset in the absence of an epidural was associated with higher rates of HIE compared to when the fever started in the setting of having an epidural. Finally, we assessed the association between mode of delivery and neonatal outcomes among febrile mothers using Poisson regression, adjusting for two variables: 1) the duration from fever onset to delivery, and 2) the height of maximal maternal temperature, as categorical variables. Guidelines from the STROBE Statements were followed. Stata version 17 (Stata Corp) was used for all analyses.

Results

Among 282,710 mother-infant dyads, we excluded 31,760 infants (11%) born by elective cesarean section, 574 (0.2%) infants with congenital or genetic abnormalities, and 1,782 (0.6%) mothers with missing maternal temperature. Among the 248,594 mothers in the final study cohort, 25,760 (10.4%) had a fever during labor. Fever was more frequent among Asian mothers, mothers living in the least deprived neighborhoods, and nulliparous mothers (Table 1). GBS-negative mothers were more likely to develop a fever during labor. Mothers who delivered ≥ 41 weeks of gestation, a male infant, or an infant weighing more than 4,000g were also more likely to develop a fever (Table 1). Among mothers who had a fever, most received epidural analgesia. While 12.2% of mothers who received epidural analgesia later developed a fever, only 1.8% of mothers developed a fever without an epidural in place.

Table 1: Maternal and infant characteristics among mothers with and without fever.

Data are presented as n(%) for categorical variable and median (IQR) for continuous variables.

	Total N=248,594	Fever N=25,760	No Fever N=222,834	P-value
Demographic characteristics
Maternal race				<0.001
Asian/PI	61,465 (24.7%)	8,689 (33.7%)	52,776 (23.7%)
Black	15,963 ( 6.4%)	1,270 ( 4.9%)	14,693 ( 6.6%)
Hispanic	64,341 (25.9%)	6,424 (24.9%)	57,917 (26.0%)
White	92,706 (37.3%)	7,910 (30.7%)	84,796 (38.1%)
Multiracial, other, missing	14,119 ( 5.7%)	1,467 ( 5.7%)	12,652 ( 5.7%)
Maternal age (Years)	30.5 (26.7-34.0)	29.7(26.0-33.2)	30.6 (26.8-34.1)	<0.001
Nulliparous	112,313 (45.2%)	19,995 (77.6%)	92,318 (41.4%)	<0.001
Neighborhood deprivation index1				<0.001
Least deprived	82,242 (33.1%)	9,452 (36.7%)	72,790 (32.7%)
Middle	82,514 (33.2%)	8,359 (32.5%)	74,155 (33.3%)
Most deprived	83,650 (33.7%)	7,938 (30.8%)	75,712 (34.0%)
Pregnancy and labor characteristics
Obesity2	49,885 (20.1%)	4,573 (17.8%)	45,312 (20.3%)	<0.001
Group B streptococcus	65,805 (26.5%)	5,465 (21.2%)	60,340 (27.1%)	<0.001
Preeclampsia	13,927 ( 5.6%)	1,631 ( 6.3%)	12,296 ( 5.5%)	0.72
Gestational diabetes	27,792 (11.2%)	2,863 (11.1%)	24,929 (11.2%)	<0.001
Epidural analgesia	173,824 (69.9%)	24,824 (96.4%)	149,000 (66.9%)	<0.001
Birth time				<0.001
<18h	174,567 (70.2%)	9,580 (37.2%)	164,987 (74.0%)
18-36h	56,174 (22.6%)	11,563 (44.9%)	44,611 (20.0%)
≥36h	17,853 ( 7.2%)	4,617 (17.9%)	13,236 ( 5.9%)
Rupture of membrane				<0.001
Before admission	68,788 (27.7%)	7,819 (30.4%)	60,969 (27.4%)
Within 2 hours of admission	22,689 ( 9.1%)	968 ( 3.8%)	21,721 ( 9.7%)
≥2 hours after admission	157,117 (63.2%)	16,973 (65.9%)	140,144 (62.9%)
Cesarean section delivery	38,329 (15.4%)	7,064 (27.4%)	31,265 (14.0%)	<0.001
Infant characteristics
Gestational age group				<0.001
Late preterm (35-36wk)	10,324 ( 4.2%)	431 ( 1.7%)	9,893 ( 4.4%)
Term (37-40wk)	205,363 (82.6%)	20,070 (77.9%)	185,293 (83.2%)
Post term (41-44wk)	32,907 (13.2%)	5,259 (20.4%)	27,648 (12.4%)
Male sex	127,244 (51.2%)	13,538 (52.6%)	113,706 (51.0%)	<0.001
Birth weight				<0.001
<3,000	48,731 (19.6%)	3,693 (14.3%)	45,038 (20.2%)
3,000-4,000	175,009 (70.4%)	18,914 (73.4%)	156,095 (70.1%)
≥4,000	24,853 (10.0%)	3,153 (12.2%)	21,700 ( 9.7%)

^1.The neighborhood deprivation index (NDI) is a composite score of socioeconomic status computed for each U.S. Census tract based on key socioeconomic factors, including the median aggregated wealth and income, education, occupation, and housing conditions of residents within the tract.⁴⁷ The NDI was categorized as tertiles, with the highest tertile indicating the most socioeconomically deprived neighborhoods.

^2.Obesity was defined as a BMI ≥30 at the last pre-pregnancy visit.

In this cohort, 487 mothers delivered an infant with HIE (population incidence of 2.0 per 1,000 infants). The risk of HIE was higher among infants whose mothers had a fever than those of mothers without fever (5.9 vs 1.5/1,000 - RR 3.92 [95%CI 3.24-4.75]). Above 37.5°C, there was an increase in the risk of HIE with increasing maximal temperature during labor (Figure 1). The risk of HIE was lowest (1.4/1,000) among infants of mothers with a maximal temperature < 37.5°C, and highest (11.5/1,000) among infants born to mothers with a maximal temperature ≥39°C (Table 2). Adjusting for the duration between hospital admission and delivery, as well as the duration between rupture of membranes and delivery, the maximal maternal temperature in labor remained associated with an increased risk of HIE (Table 2). The risk of delivering an infant with HIE was higher if the fever started when no epidural was in place than if the fever only started after epidural placement (9.6 vs 5.1/1,000 - RR 1.89 [95% CI 1.34-2.68]). This association persisted even after adjusting for the duration between hospital admission and time of delivery and the duration of rupture of membranes (RR 1.51 [95% CI 1.11-2.05]). Among the subgroup of mothers exposed to epidural analgesia, the risk of delivering an infant with HIE still increased with increasing maximal temperature during labor, even after adjusting for the duration of epidural exposure (Supplement 1).

Figure 1: Incidence of HIE and 95% CI based on maximal maternal temperature in labor (A) and duration from fever onset to delivery (B).

Estimations obtained by logistic regression modeling transforming predictor variables (maximal maternal temperature and duration from fever onset to delivery) as restricted cubic splines.

Table 2:

Incidence and relative risk of HIE and other adverse neonatal outcomes stratified by maximal maternal temperature in labor

Outcomes	Maximal maternal temperature in labor	N with outcome	%	RR	95% CI	Adjusted RR1	95% CI	P-value2
HIE	<37.5°C	258	0.14	1	Ref	1	Ref	<0.001
	37.5 – 37.9°C	77	0.23	1.70	1.31-2.19	1.51	1.09-2.08
	38 - 38.4°C	76	0.47	3.43	2.66-4.43	2.71	1.93-3.82
	38.5 – 38.9°C	42	0.64	4.71	3.40-6.52	3.62	2.24-5.86
	≥ 39°C	34	1.15	8.47	5.92-12.1	6.64	4.23-10.42
5-minute Apgar score <7	<37.5°C	1429	0.75	1	Ref	1	Ref	<0.001
	37.5 – 37.9°C	579	1.74	2.31	2.09-2.54	1.54	1.37-1.74
	38 - 38.4°C	413	2.54	3.37	3.02-3.76	2.03	1.82-2.27
	38.5 – 38.9°C	199	3.04	4.03	3.47-4.67	2.36	2.00-2.79
	≥ 39°C	144	4.88	6.48	5.46-7.69	3.91	3.33-4.58
Acidosis 3	<37.5°C	2383	1.26	1.00	Ref	1	Ref	<0.001
	37.5 – 37.9°C	712	2.14	1.70	1.56-1.85	1.48	1.31-1.68
	38 - 38.4°C	529	3.25	2.59	2.35-2.84	2.12	1.82-2.47
	38.5 – 38.9°C	310	4.73	3.76	3.34-4.24	3.04	2.58-3.56
	≥ 39°C	227	7.70	6.12	5.34-7.02	4.95	4.19-5.87
Therapeutic hypothermia	<37.5°C	327	0.17	1.00	Ref	1	Ref	<0.001
	37.5 – 37.9°C	59	0.18	1.61	1.21-2.16	1.34	0.99-1.80
	38 - 38.4°C	60	0.37	3.36	2.52-4.48	2.53	1.73-3.68
	38.5 – 38.9°C	30	0.46	4.17	2.85-6.12	3.04	1.97-4.69
	≥ 39°C	26	0.88	8.03	5.34-12.1	5.97	3.95-9.03
Neonatal seizures	<37.5°C	208	0.11	1.00	Ref	1	Ref	<0.001
	37.5 – 37.9°C	41	0.12	1.74	1.23-2.47	1.49	0.96-2.29
	38 - 38.4°C	35	0.22	3.04	2.10-4.42	2.51	1.59-3.96
	38.5 – 38.9°C	22	0.34	4.75	3.03-7.46	3.83	1.81-8.13
	≥ 39°C	12	0.41	5.76	3.19-10.4	4.73	2.59-8.65
Early onset sepsis	<37.5°C	30	0.02	1.00	Ref	1	Ref	<0.001
	37.5 – 37.9°C	18	0.05	3.42	1.90-6.13	3.12	1.82-5.34
	38 - 38.4°C	9	0.06	3.56	1.66-7.36	2.94	1.40-6.15
	38.5 – 38.9°C	7	0.11	6.75	2.97-15.37	4.77	1.72-13.24
	≥ 39°C	10	0.34	21.42	10.47-43.8	18.0	9.97-32.3
NICU Admission	<37.5°C	10327	5.45	1.00	Ref	1	Ref	<0.001
	37.5 – 37.9°C	2429	7.30	1.34	1.28-1.40	1.11	0.99-1.24
	38 - 38.4°C	1672	10.2	1.89	1.79-1.99	1.47	1.25-1.73
	38.5 – 38.9°C	1427	21.7	4.00	3.78-4.23	3.07	2.42-3.89
	≥ 39°C	1135	38.5	7.06	6.64-7.51	5.51	4.59-6.63

^1.Adjusted relative risks were estimated using Poisson regression with robust standard errors, clustered by hospital sites and adjusting for the duration between hospital admission and delivery and between rupture of membrane and delivery as splines.

^2.P-value for the test of trend obtained by Cochran- Armitage test for trend

^3.Acidosis is defined as at least one pH <7 or base deficit ≥10 from any cord blood, or a base deficit ≥10 on the first infant blood gas before 2 hours of age.

Among the 25,760 mothers exposed to fever, 6,858 (26.6%) had fever onset less than 1 hour before delivery, 8,062 (31.3%) 1- 3 hours before delivery, 5,719 (22.2%) 3- 6 hours before delivery, and 5,121 (19.9%) ≥6 hours before delivery. The incidence of HIE increased with the duration from fever onset to delivery, ranging from 2.3/1,000 when the duration was less than 1 hour to 10.5/1,000 when the duration was ≥6 hours (Table 3). Among neonates exposed to fever, compared to those exposed to a duration from fever onset to delivery of 1 to <3 hours, those exposed to fever <1 hour before delivery had half the risk of HIE (RR 0.52 [95% CI 0.29-0.94]), while those whose fever onset was ≥ 6 hours before delivery had 2.4 times the risk of HIE (RR 2.4 [95%CI 1.6-3.6]) – Table 3. After adjusting for the duration between hospital admission and time of delivery and the duration of rupture of membranes, the association between duration of fever and HIE persisted (Table 3).

Table 3:

Among 25,760 infants exposed to maternal fever in labor, incidence and relative risk of HIE and other adverse neonatal outcomes stratified by the duration of fever

Outcomes	Duration between first fever and delivery	N with outcome	%	RR	95% CI	Adjusted RR1	95% CI	P-value2
HIE	< 1 hour	16	0.23	0.53	0.29-0.94	0.56	0.34-0.91	<0.001
	1- < 3 hours	36	0.45	1	Ref	1	Ref
	3- < 6 hours	46	0.80	1.80	1.16-2.79	1.67	1.10-2.52
	≥ 6 hours	54	1.05	2.36	1.55-3.60	1.80	1.26-2.58
5-minute Apgar score <7	< 1 hour	124	1.81	0.66	0.53-0.82	0.71	0.58-0.85	<0.001
	1- < 3 hours	221	2.74	1	Ref	1	Ref
	3- < 6 hours	194	3.39	1.24	1.02-1.50	1.17	0.98-1.39
	≥ 6 hours	217	4.24	1.55	1.28-1.86	1.28	1.06-1.55
Acidosis 3	< 1 hour	191	2.79	0.69	0.58-0.83	0.71	0.52-0.95	<0.001
	1- < 3 hours	324	4.02	1	Ref	1	Ref
	3- < 6 hours	266	4.65	1.16	0.98-1.36	1.14	0.97-1.32
	≥ 6 hours	285	5.57	1.38	1.18-1.62	1.28	1.11-1.47
Therapeutic hypothermia	< 1 hour	13	0.19	0.59	0.30-1.14	0.67	0.44-1.03	<0.001
	1- < 3 hours	26	0.32	1	Ref	1	Ref
	3- < 6 hours	33	0.58	1.79	1.07-2.99	1.61	1.04-2.48
	≥ 6 hours	44	0.86	2.66	1.64-4.33	1.81	1.16-2.79
Seizures	< 1 hour	10	0.15	0.62	0.29-1.33	0.69	0.32-1.48	0.025
	1- < 3 hours	19	0.24	1	Ref	1	Ref
	3- < 6 hours	24	0.42	1.78	0.98-3.25	1.65	0.88-3.06
	≥ 6 hours	16	0.31	1.33	0.68-2.58	0.98	0.47-2.06
Early onset sepsis	< 1 hour	12	0.17	1.57	0.66-3.72	1.51	0.62-3.68	0.003
	1- < 3 hours	9	0.11	1	Ref	1	Ref
	3- < 6 hours	5	0.09	0.78	0.26-2.33	0.74	0.20-2.77
	≥ 6 hours	0	0.00	NA	NA	NA	NA
NICU Admission	< 1 hour	861	12.6	0.74	0.68-0.81	0.74	0.69-0.80	<0.001
	1- < 3 hours	1,368	17.0	1	NA	1	NA
	3- < 6 hours	1,022	17.9	1.05	0.97-1.14	1.04	0.98-1.09
	≥ 6 hours	983	19.2	1.13	1.04-1.23	1.08	1.00-1.16

^1.Adjusted relative risks were estimated using Poisson regression with robust standard errors, clustered by hospital sites and adjusting for the duration between hospital admission and delivery and between rupture of membrane and delivery as splines.

^2.P-value for the test of trend obtained by Cochran- Armitage test for trend

^3.Acidosis is defined as at least one pH <7 or base deficit ≥10 from any cord blood, or a base deficit ≥10 on the first infant blood gas before 2 hours of age.

Increasing maternal temperature height was associated with an increased risk of all studied adverse neonatal outcomes (low 5-minute Apgar score, acidosis, receiving therapeutic hypothermia, neonatal seizures, early-onset sepsis, and NICU admission). This association persisted even after adjusting for labor duration (Table 2). Similarly, all adverse neonatal outcomes studied increased with increasing duration from fever onset to delivery, except for early-onset sepsis, where duration from fever onset to delivery was associated with a significant risk decrease (Table 3).

Of note, in mothers with fever, delivery by cesarean section was associated with worse neonatal outcomes (Supplement 2), even after adjusting for the height of maximal maternal temperature or the duration from fever onset to delivery.

Comment

Principal Findings

In this large population-based cohort, fever occurred in 1 in 10 laboring mothers. Both increasing height of maximal maternal temperature and increasing duration from fever onset to delivery were associated, in the offspring, with an increased risk of HIE, as shown in Figures 1A and 1B, and adverse neonatal outcomes. Even mild elevations in temperatures, which would not result in a fever diagnosis, were associated with an increased risk of HIE and adverse neonatal outcomes compared to lower maternal temperatures. This association persisted after adjusting for the duration of labor.

Results in the context of what is known

Fever occurs when the hypothalamic thermoregulatory center resets to a higher-than-normal temperature or when there is insufficient heat elimination.¹ Intrapartum fever can result from both infectious and non-infectious etiologies. In the absence of a preexisting febrile disorder, most pregnant persons who develop a fever during labor are presumed to have clinical chorioamnionitis and are treated with broad-spectrum antibiotics. However, the most common cause of fever in labor is epidural analgesia.^3,21

While the CDC reported rates of maternal fever in labor around 3.3% in 2010,²² more recent multicentric US studies have reported rates between 2.4% and 9%.^23,24 The rate of intrapartum fever in our study (10%) is somewhat higher than previously described. This may be explained by our population comprising laboring mothers and excluding mothers who delivered by elective cesarean section. It may also be explained by our definition of fever, which includes maternal temperature measurements up to 30 minutes after delivery. Furthermore, our study population may have higher rates of labor induction and epidural use due to universal health care insurance coverage.¹

Previous studies have yielded contradictory results regarding the relationship between maternal fever height, duration, and the risk of HIE. Although maternal fever during labor is known to increase the risk of neonatal complications such as low Apgar scores, neonatal unit admission, and sepsis,^7,8,14 previous studies lacked adequate sample size to assess the risk of more severe outcomes such as HIE. ^1,8,12,25 For example, a recent smaller study, including 352 patients with fever, found no significant difference in the risk of neurologic morbidity between neonates exposed to mild versus severe fever during labor.⁸ Similarly, two previous studies found no significant association between the duration of fever and the risk of HIE.^13,14 However, both studies showed a non-significant trend toward an association between fever duration and HIE risk. With our study’s large sample size, we demonstrated that both height and duration of fever are associated with an increased risk of HIE and adverse outcomes in neonates.

In this cohort, even mild maternal temperature elevation (i.e., maximal temperature 37.5-37.9°C) was associated with an increased risk of HIE and other adverse neonatal outcomes. This is not surprising since maternal temperature is 0.6-0.8°C below the fetal skin temperature and 1-1.5°C below the fetal core temperature.^1,26,27 Hence, when the maternal temperature is 37.5°C, the fetus’s core temperature is likely >38°C. Animal studies have shown that even a small increase in brain temperature can potentiate brain injury.⁶ In neonates with HIE, therapeutic hypothermia, decreasing the body temperature of the neonates to 33.5°C for 72 hours, is associated with a decreased risk of adverse neurodevelopmental outcomes.²⁸

While a 2015 NICHD workshop recommended diagnosing maternal fever only if the mother had two consecutive temperatures ≥38°C or one temperature above ≥39°C²⁹, more recent guidelines have supported treating a single maternal temperature ≥ 38°C.¹⁶ The July 2024, ACOG statement also recognized that suspected intraamniotic infection may be diagnosed in the absence of maternal fever when other associated clinical signs and symptoms are present.³⁰ Our work supports the recognition that adverse neonatal outcomes may occur even with mild temperature elevations that do not meet criteria for fever.

Maternal temperature increases gradually throughout the duration of labor, even when labor is physiologic and uncomplicated.^31,32 Between the onset of labor and the time of delivery, maternal temperatures increase by a median of 0.3°C in mothers without an epidural and by 0.7°C in mothers receiving an epidural.^32,33 The duration of labor is associated with adverse neonatal outcomes, at least in nulliparous mothers.³⁴ However, when adjusting for the duration of labor, both the highest maternal temperature and the duration from fever onset to delivery were significantly associated with HIE risk, suggesting that the height and duration of maternal temperature, independent of labor duration, are associated with HIE in the offspring. This was further demonstrated by our subgroup analysis in mothers with epidurals, where the height of fever remained associated with the risk of HIE even when adjusting for epidural duration.

In this study, we investigated the impact of fever during labor on neonatal outcomes. Hence, we excluded infants born by elective cesarean section. These infants born without labor would both be exposed to low maximal maternal temperature and have a low risk of HIE, which would increase our quantification of the overall effect of maximal maternal temperature. However, we did not adjust for delivery mode as the decision to perform a cesarean section in labor could occurs after fever onset and could therefore be influenced by the presence of fever and many other factors. Thus, adjusting for the mode of delivery would adjust for a potential mediator.

Clinical implications

A better understanding of the relationship between the height and duration of maternal fever and the risk of HIE may help to guide labor management decisions. Maternal fever has been associated with labor dystocia and decreased uterine contractility despite labor augmentation, which can lead to prolonged labor.³⁵ However, labor augmentation and increased contraction rates may not be as well tolerated by fetuses exposed to fever as by those who are not exposed to fever.^36–38

While this study shows an association between the magnitude and duration of hyperthermia during labor and adverse neonatal outcomes, it does not demonstrate or imply that a cesarean section at a lower temperature threshold or soon after fever onset would decrease the incidence of HIE. As expected, among mothers with fever, delivery by cesarean section is associated with worse neonatal outcomes. Clinicians decide to perform a cesarean in labor if they are concerned about neonatal or maternal outcomes. They may be concerned due to many factors, including abnormal fetal heart tracings, abnormal labor progression, or maternal fever. It is hence expected that a cesarean section in labor would be associated with higher rates of adverse outcomes, including HIE. The association is unlikely to be causal (i.e., it is unlikely that a cesarean “causes” adverse neonatal outcomes), but rather reflects that clinicians are performing cesareans for reasons that extend beyond maternal temperature alone.

Furthermore, the unadjusted risk difference for HIE between neonates exposed to fever for less than 1 hour before delivery (0.23%) and those exposed for more than 6 hours before delivery (1.05%) is 0.8%. Hence, assuming that the association between fever duration and HIE is causal and that we could predict whose mother will not deliver within the next 6 hours at fever onset, one would still need to perform 125 cesareans (1/0.008) in febrile mothers to prevent one case of HIE. Thus, performing a cesarean in mothers with or at risk of developing fever is unlikely to decrease the incidence of HIE, but would likely dramatically increase the number of unnecessary cesareans performed, hence increasing the associated morbidity and mortality for the neonate, mother, and future potential pregnancies.^39,40 The goal of our study is not to recommend performing a cesarean section for maternal fever, but rather to remind clinicians that these neonates are at higher risk than neonates unexposed to fever, regardless of mode of delivery. Future studies could assess how fever prevention and management in labor could impact HIE risks. For example, it is unknown whether reducing maternal temperature through mechanical or pharmacological means can reduce the risk of HIE and other adverse neonatal outcomes. The optimal temperature threshold for initiating antipyretic therapy also warrants further study. Notably, previous studies have shown that acetaminophen does not decrease maternal fever due to epidural analgesia.⁴¹ Other pharmacological and non-pharmacological means to decrease maternal temperature during labor could be tested to assess their potential for improving neonatal outcomes. On the other side, maternal and early neonatal hypothermia are also associated with adverse neonatal outcomes, suggesting that a fine balance is needed.⁴² Future studies could also assess if the duration of elevated maternal temperature, rather than the duration from fever onset to delivery, or the response to acetaminophen treatment, further enhances our ability to identify infants at high risk of adverse neonatal outcomes. Epidural analgesia is associated with an increase in maternal body temperature, which in turn is associated with an increased risk of HIE. However, epidural analgesia is not independently associated with an increased risk of HIE.³³ Among pregnant individuals with fever in our study, we found that those whose fever started when no epidural was in place had nearly double the risk of HIE compared to those with fever that began after epidural placement. This finding was attenuated but persisted when adjusting for labor duration. Infectious and non-infectious etiologies can cause maternal fever. It is possible that infection, rather than epidural-related hyperthermia, could be more deleterious to the fetus.

While increasing duration from fever onset to delivery was associated with an increased risk of HIE and some secondary outcomes, the duration from fever onset to delivery was not associated with the risk of early-onset sepsis in our cohort. The lack of association between the duration from fever onset to delivery and early-onset sepsis could be partially explained by a more prolonged exposure to maternal antibiotics in mothers with a longer duration of fever before delivery. To evaluate an infant’s risk of early-onset sepsis, the most commonly used risk calculator uses the height of maximal maternal temperature as a risk factor and the duration between antibiotic administration and delivery as a protective factor.⁴³

Research implications

Using modern machine learning methods, it may be possible to develop predictive models during labor that will decrease the risk of HIE while also aiming to reduce the rate of unnecessary cesarean sections.^44–46 It will be essential to incorporate detailed clinical information during labor to improve our ability to predict and prevent HIE. Our data suggest that incorporating information regarding the height of maternal temperature and timing of maternal fever, rather than the mere presence or absence of fever, could enhance our ability to discern the risk of HIE during the labor process. Similarly, studying whether certain FHR tracings are more suggestive of elevated adverse outcomes in the setting of fever could be informative in guiding clinicians’ decision-making.

Because the risk of acidosis increased with increasing maximal maternal temperature in labor and to a lesser extent with increasing duration from fever onset to delivery (Tables 2&3), the relationship between fever height and duration and HIE might be partially mediated by increased risk of acidosis. Evaluation of fetal heart tracing patterns associated with acidosis in febrile mothers also warrants further analysis.

Further studies are needed to determine whether interventions aimed at decreasing the height and duration of fever in laboring mothers can decrease the risk of HIE and other adverse neonatal outcomes.

Strengths and limitations

This study involves a well-characterized, population-based cohort with a primary outcome, i.e, HIE, that was ascertained by chart review. Given the large sample size, our study has adequate statistical power to determine the relationship between maternal fever and HIE, adjusting for important confounders. This study also has limitations. First, because this is an observational study, temperature was recorded only when deemed clinically indicated. Similarly, blood gases were not obtained on all infants, potentially biasing the results. However, in clinical practice, a blood gas should be obtained in all infants with clinical signs of encephalopathy at least within two hours after birth. Second, we did not assess the role of antipyretics or antibiotics and their efficacy. It is possible that some mothers received antipyretics before reaching 38°C and hence did not reach the fever threshold because of antipyretic administration. Third, due to the observational nature of our cohort, we are unable to determine whether reducing maternal temperature or shortening fever duration can lead to improved outcomes. Finally, we did not assess how chorioamnionitis impacts the relationship between fever and HIE, as the diagnosis of chorioamnionitis is subjective and varies among individual clinicians. Future studies should aim to assess the reliability of ICD diagnosis of chorioamnionitis and assess how a diagnosis of chorioamnionitis impacts the risk of HIE in neonates exposed to fever in labor.

Conclusions

About 1 in 10 laboring mothers experienced a fever during labor. In this study, we showed that both the height of maternal temperature and the duration from fever onset to delivery are associated with an increased risk of HIE and other adverse neonatal outcomes. However, our study does not suggest that cesarean section should be performed in febrile mothers, but rather that to improve the prediction and prevention of HIE and other adverse neonatal outcomes, it will be essential to incorporate detailed clinical information regarding fever height and duration during labor. Whether interventions aimed at decreasing fever height and duration in laboring mothers can reduce the risk of HIE remains unknown.

AJOG at Glance:

A). Why was this study conducted?

Maternal fever in labor is associated with adverse maternal and neonatal outcomes. However, how the height and duration of maternal fever affect the risk of hypoxic-ischemic encephalopathy (HIE) is unknown.

B). What are the key findings?

In a population-based cohort study, we found that higher maximal maternal temperature is associated with higher risk of HIE and other adverse neonatal outcomes. This association persisted after adjusting for the duration of labor. Similarly, increased duration from fever onset to delivery was associated with an increased risk of HIE.

C). What does this study add to what is already known?

Elevated maternal temperature and prolonged duration from fever onset to delivery are associated with increased risks of HIE and other adverse neonatal outcomes.