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The Journal of Maternal-Fetal and Neonatal Medicine, 2013; 26(2): 207–210© 2013 Informa UK, Ltd.ISSN 1476-7058 print/ISSN 1476-4954 onlineDOI: 10.3109/14767058.2012.722727

Objective: To evaluate the diagnostic and therapeutic approach to full term neonates born to mothers with intrapartum fever. Methods: In a retrospective study, neonates born to mothers with intrapartum fever, (≥37.8°C), were compared to control group matched by gestational age and birthweight. Results: Overall, 159 singleton full term neonates born to women with intrapartum fever (study group) were compared to 159 control infants. No differences in neonatal outcomes were found between the two groups except for a higher rate of meconium-stained amniotic fluid in the maternal-fever group. There were no cases of neonatal infection, severe neonatal morbidity, or neonatal mortality in either of the groups. Full sepsis workup and intravenous antibiotic treatment were provided to 17.6% of the neonates in the study group. Logistic regression analysis revealed that delivery by Cesarean section was the only factor independently associated with the decision to perform a full sepsis work up and antibiotic treatment in cases of maternal intrapartum fever (OR 32.0, 95% CI 9.4–112.1). Conclusions: In low-risk women with asymptomatic intrapartum fever, neonatal infection is uncommon, so that aggressive evaluation and management of these infants may not be necessary and should be balanced against the low risk of neonatal sepsis.

Keywords: Intrapartum fever, cesarean section, sepsis

IntroductionEarly onset neonatal sepsis (EONS) is a life-threatening condi-tion mandating early detection and rapid treatment. Maternal intrapartum fever complicates up to 7% of term births [1] and is associated with a 4.6- to 10-fold increased risk of group B Streptococcus (GBS) EONS. [2]. Maternal intrapartum fever is also a strong predictor of neonatal death from EONS [3].

Considering the fact that intrapartum fever is an independent risk factor for neonatal GBS infection [4] and that it is difficult to clearly differentiate infectious from non-infectious fever during labor, intrapartum fever is often considered an indication for neonatal sepsis work-up and empirical antibiotic therapy. Indeed, 15–25% of neonates greater than 2000 g undergo a full sepsis evaluation [5] and 4.4–10.5% of all infants born in the US are treated with systemic antibiotics for a minimum of 48–72 h [6]. There are no clear guidelines for the evaluation and treatment of term neonates born to mothers with intrapartum fever, and there is a considerable diversity in the recommendations for neonatal management in these cases including observation, various

levels of sepsis workup and empirical antibiotic treatment until obtaining culture results [7].

Moreover, it has been shown that for women with term preg-nancies, a considerable proportion of cases of intrapartum fever are actually the consequence of benign non-infectious conditions such as regional analgesia [8]. As more than 99% of asymptom-atic term neonates born to mothers with intrapartum fever have a benign clinical course, aggressive evaluation and management of these infants may not be needed [9].

Our department policy until January 2007 was to perform a full sepsis workup and give antibiotic treatment to all infants born to mothers with intrapartum fever ≥37.8ºC. Since we had not identified over a 5-year period (2001–2006) any case of early neonatal sepsis in a full term asymptomatic singleton neonate, our protocol was changed in January 2007 so that a full sepsis work up and antibiotic treatment were provided only if intra-partum maternal fever co-existed with at least two additional risk factors. Cases not meeting these high risk criteria are managed conservatively by partial sepsis workup and close clinical obser-vation pending culture results.

The aim of this study was to evaluate the utility of our protocol and to identify factors associated with the need for full-sepsis work up and antibiotic treatment.

MethodsStudy population

A retrospective study performed in a tertiary university-affiliated hospital. The study was performed between January 2007 and July 2009 and included all full term infants born to women who had intrapartum fever (≥37.8°C) during the active phase of labor. For each newborn in the study group, a control newborn was selected consisting of the immediately preceding full term infant in the delivery-ward logbook matched for birth weight (±100 g) and gestational age at delivery, whose mother did not have intrapartum fever (maximal body temperature during delivery <37.3°C). Excluded were all neonates with major congenital malformations and/or chromosomal aberrations, and infants of multiple gestations. The study was approved by the Institutional Research Review Board.

Definitions and protocols

The department’s “maternal fever protocol” refers to all women with intrapartum fever ≥37.8°C (100.4°F). Partial sepsis workup (consisting of blood culture, complete blood count and C-reactive

Management of term newborns following maternal intrapartum fever

Nehama Linder1,2, Elena Fridman1, Ayman Makhoul1, Daniel Lubin1, Gil Klinger2,3, Tami Laron-Kenet3, Yariv Yogev2,4 & Nir Melamed2,4

1Department of Neonatology, Helen Schneider’s Hospital for Women Rabin Medical Center, PetachTikva, Israel, 2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, 3The Neonatal Intensive Care Unit, Schneider Children’s Medical Center, PetachTikva, Israel, and 4Department of Obstetrics and Gynecology, Helen Schneider’s Hospital for Women Rabin Medical Center, PetachTikva, Israel

Correspondence: Yariv Yogev, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tiqwa 49100, Israel. Tel: +972-3-9377400. Fax: +972-3-9377409. E-mail: yarivyogev@hotmail.com

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protein) accompanied with close clinical observation for 48 h is applied to all infants, while full sepsis work up (which includes also cerebrospinal fluid (CSF) culture) combined with empiric antibiotic treatment (Ampicilin and Gentamycin) is provided only in cases when maternal intrapartum fever is accompanied by at least two of the following additional risk factors: maternal tachycardia (>120 beats/min), fetal tachycardia (>160 beats/min for >than 60 min), uterine tenderness, foul odor of the amniotic fluid, maternal leukocytosis (>15,000 cells/mm3) or instrumental delivery.

Data collection

Detailed information was collected on each of the infants from the records of the hospital’s High-Risk Pregnancy Unit, Delivery Room, and the Neonatal Department as follows: maternal demo-graphic and obstetrical characteristics, GBS status (when avail-able), duration of labor, interval between membranes rupture and delivery, epidural anesthesia, maximal maternal temperature during labor, maternal tachycardia, fetal tachycardia, uterine tenderness, foul odor of the amniotic fluid, maternal leukocy-tosis, mode of delivery, presence of meconium in amniotic fluid, intrapartum antibiotic administration and results of maternal blood, urine and placental cultures. Neonatal data included gesta-tional age at delivery, birth weight, gender, 5-min Apgar score, cord pH (when available), the presence of respiratory morbidity (including respiratory distress and the need for oxygen admin-istration or mechanical ventilation), cultures results, neonatal leukocytosis (white blood cells count ≥30,000/mm3), leukopenia (white blood cells count ≤5000/mm3) and thrombocytopenia (platelets count ≤150,000/mm3), plasma C reactive protein (CRP) levels (CRP was considered to be elevated above cutoff point of 1 mg/dL),abnormalities on physical and neurological examina-tion, results of most recent brain ultrasound, length of hospital stay, number of days in the Neonatal Intensive Care Unit (NICU), type and duration of the antibiotic therapy, re-hospitalization during first month of life, and other types of neonatal morbidity or mortality reported during the neonatal period. Findings were compared between the study and the control groups.

Statistical analysis

Statistical analysis was performed using the BMDP Statistical Software (1993). Univariate analysis was performed to identify differences between neonates in the two groups. Comparisons of the study groups were performed using the Student’s t-test, Pearson’s chi-square test and Mann–Whitney non parametric test as appropriate. Statistical significance was defined as p value <0.05. Variables found to have a p value ≤0.1 in the univariate analysis were entered into a stepwise logistic regression model to identify factors independently associated with the need for a full sepsis work up and antibiotic treatment.

ResultsFrom January 2007 and July 2009, 22,628 neonates were born in our hospital. Excluded were 2081 preterm infants, 56 infants with major congenital malformations and/or chromosomal aberra-tions and 1289 infants of multiple gestations. Out of 19,202 full term singleton neonates born during the study period, 159 infants (0.8%) were born to women with intrapartum fever. The mean temperature in this group was 38.3 ± 0.4°C. For the 159 neonates in the control group, the mean temperature was 37 ± 0.1°C. The characteristics of the study and control groups are presented in Table I. Women in the study group were significantly younger,

more likely to be nulliparous, had a longer duration of labor and a higher rate of prolonged PROM, and were more likely to use epidural analgesia. The rate of instrumental delivery, Cesarean section and meconium stained amniotic fluid was significantly higher in the study group. The GBS colonization rate was similar for the two groups (Table I).

Risk factors for chorioamnionitis and neonatal infection were significantly more common in the maternal fever group (Table II). Twenty nine (18.2%) women in the intrapartum fever group were not given antibiotics during delivery due to imminent birth.

Neonatal outcome is presented in Table III. There were no cases of culture-proven neonatal sepsis. The mean time elapsed between delivery and infant evaluation was 5.0 ± 4.5 h. The rate of full-sepsis work-up in the study group was 17.6% compared to 100% in the previous protocol. There were no differences in neonatal outcome except for longer in-hospital stay for neonates in the maternal-fever group. There were no differences in re-hospi-talization during the first month of life. None of the patients that were re-hospitalized had bacterial infection (Table III).

To determine whether the neonatal effect of intrapartum fever is related to the severity of maternal fever, three subgroups were selected for comparison: women with intrapartum temperature ≥38.5°C (high fever group, n = 44) women with intrapartum temperature >38.0°C (overt-fever group, n = 66) and women with maximal intrapartum temperature of 37.8–38°C (borderline-fever group, n = 49). The overt group and the high fever group were

Table I. Characteristics of the study and control groups.Control group Study group

p Value(n = 159) (n = 159)Mean maternal age (years) 30.5 ± 5.1 28.9 ± 4.8 0.004Mean parity 2.3 ± 1.2 1.4 ± 0.8 <0.001Nulliparous 89 (55.9%) 125 (78.6%) <0.001GBS carrier 6 (3.8%) 8 (5%) NSMean duration of PROM (h) 30 ± 16 33 ± 20 NSPROM >18 h 11 (6.9%) 29 (18.2%) 0.001Mean labor duration (h) 7.3 ± 5.2 14.1 ± 5.7 <0.001Epidural anesthesia 98 (62%) 151 (95%) <0.001Instrumental delivery 8 (6.4%) 36 (22.6%) <0.001Cesarean section 24 (15.2%) 34 (21.4%) <0.001MSAF 12 (7.6%) 51 (32.3%) <0.001GBS, group B streptococcus; PROM, premature rupture of membranes; MSAF,

meconium stained amniotic fluid.Data are presented as mean ± SD or N (%).

Table II. Risk factors for chorioamnionitis and neonatal infection in the study and control groups.

Control group (n = 159)

Study group (n = 159) p Value

Maternal maximal temperature (°C)

37 ± 0.6 38.2 ± 0.4 <0.001

Maternal leukocytosis* 29 (18.5%) 115 (72.8) <0.001Maternal tachycardia† 1 (0.8%) 12 (7.6%) 0.004Fetal tachycardia‡ 2 (1.5%) 31 (19.7%) <0.001Maternal antibiotics 20 (12.7%) 130 (81.8%) <0.001Maternal antipyretics 0.0% 88 (55%) <0.001Maternal bacteremia 0.0% 9 (5.7%) <0.001Maternal urinary tract infection

4 (2.5%) 2 (1.3%) <0.001

Positive placental culture 0 (0%) 22 (13.8%) <0.001*Leukocyte count >15,000 cells/mm3; †Heart rate >120 beats/min; ‡Heart rate >160

beats/min for > 60 min.Data are presented as mean ± SD or N (%).

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separately compared to the borderline fever group. There were no differences in characteristics as to maternal age, parity, duration of labor, rate of epidural anesthesia, mode of delivery, gestational age and birth weight, and neonatal outcome. The rate of intrapartum antibiotics prophylaxis was much higher in the high and overt fever groups. There were no differences in the rate of maternal leuko-cytosis, tachycardia, bacteremia, urinary tract infection, placental positive culture growth, nor of neonatal leukocytosis and throm-bocytopenia. The rate of fetal tachycardia was higher in the overt fever group vs. borderline-fever group (27% vs. 12.7%, p = 0.03). Hospital length of stay was prolonged in the high fever group vs. borderline-fever group (4.6 ± 1.7 days vs. 4.2 ± 1.2 days, p = 0.03).

To identify factors associated with the decision to perform a full sepsis work up in neonates born to mothers with intrapartum fever, we compared the characteristics of the cases in which a full sepsis work up was conducted (n = 34) to those in which a partial sepsis work up was performed (n = 145) and to those without sepsis work up (n = 139) (Table IV). Women who underwent sepsis workup (full or partial) were characterized by a longer duration of membranes rupture, a higher rate of epidural anes-thesia, meconium, and maternal antibiotic treatment (Table IV). The CS rate was significantly higher in the subgroup of neonates who underwent full-sepsis workup (Table IV). On multivariate logistic regression analysis the only factor that was independently associated with the decision for performing a full sepsis work up was delivery by CS (OR 32.0, 95% CI 9.4–112.1).

To further investigate the reason for this association, we analyzed the frequency of the various criteria for full sepsis work up among women who underwent cesarean delivery (n = 58) and those to delivered vaginally (n = 213). Fetal tachycardia and maternal leukocytosis were more common among woman who delivered by CS than those who delivered vaginally (28.6% vs. 7.2%, p < 0.001 and 84.4% vs. 35.4%, p < 0.001, respectively). Other signs of infection such as maternal tachycardia, uterine tenderness or foul odor of amniotic fluids did not differ between the groups.

DiscussionThe aim of this study was to evaluate our local protocol for assess-ment and treatment of apparently healthy, full term newborns

born to mothers with intrapartum fever. We demonstrated that use of our protocol enabled 82% of our study group to be spared from undergoing a full sepsis evaluation and receiving intrave-nous antibiotics. The study group infants had a shorter duration of hospital stay and did not have a higher incidence of complica-tions or re-hospitalization during the first month of life. Since the rate of the adverse outcomes was not different between the groups in our study, we assume that the longer hospitalization was due to the pending blood and CSF culture results and in addition higher rate of CS. No culture proven neonatal sepsis was found. Aggressive evaluation and management of these infants may not be necessary [9]. Logistic regression analysis revealed that CS was the only independent factor associated with full sepsis work up and antibiotic treatment. Instrumental delivery, fetal tachycardia and maternal antibiotic treatment were part of our protocol. In our opinion, the CS was probably implemented due to multiple risk factors suggesting fetal infection.

Previous investigations have suggested that women with intra-partum fever are more likely to undergo operative abdominal or instrumental assisted vaginal delivery, mostly due to lack of labor progression [8,10]. Clinical chorioamnionitis increases the risk for CS even further [3,11]. Preceding works showed that persis-tent fetal tachycardia during the second stage of labor defines a population at increased risk for subsequent neonatal sepsis/pneumonia. Fetal tachycardia, and not maternal tachycardia or leukocytosis, were highly associated with the decision to perform full sepsis workup and treat with IV antibiotics empirically, prob-ably suspecting fetal infection [12,13]. Severity of maternal fever was not associated with infection or adverse neonatal outcome.

Accurate and timely diagnosis of EONS remains challenging and observation of clinical signs is considered to be the best diagnostic method. The number of tests that the clinician can rely on for the diagnosis of infection is relatively limited [14,15]. Early reports described a high prevalence of elevated CRP levels in infected infants, but levels are elevated only in 35–65% of neonates with bacterial infection at the onset of illness. Recognition that a delay of at least several hours is intrinsic to the cascade of events leading to elevation of serum CRP levels led to appropriate criticism of this test as having insufficient sensitivity to guide therapy. New and more

Table III. Neonatal outcome in the study and control groups.Control group

(n = 159)Study group

(n = 159) P valueMean gestational age (weeks) 39.3 ± 1.2 39.5 ± 1.2 NSMean birth weight (g) 3321 ± 390 3313 ± 400 NSMean 5-min Apgar score 9.9 ± 0.5 9.9 ± 0.4 NSMale gender 85 (53.5%) 84 (52.8%) NSNeonatal sepsis 0 (0%) 0 (0%) NSResuscitation 3 (1.9%) 2 (1.3%) NSFull sepsis work up 6 (3.8%) 28 (17.6%) <0.001Partial sepsis workup 14 (8.9%) 131 (82.3%) <0.001Neonatal leukocytosis 0 (0%) 8 (5.1%) <0.001Neonatal thrombocytopenia 0 (0%) 6 (3.8%) <0.001C reactive protein>1.0 1 (0.6%) 6 (3.8%) NSNeurological insult* 1 (0.6%) 3 (1.9%) NSAbnormal hearing test 1 (0.6%) 5 (3.2%) NSLength of hospital stay (days) 3.7 ± 1.1 4.2 ± 1.3 0.001Early re-hospitalization† 5 (3.2%) 8 (1.5%) NS*Hypoxic ischemic encephalopathy, convulsions or hypotonia; †Defined as re-hospital-

ization during the first month of life.Data are presented as mean ± SD or N (%).

Table IV. Factors associated with the need to perform a full sepsis work up in cases of maternal intrapartum fever – univariate analysis.

Full sepsis work up (n = 34)

Partial sepsis work up (n = 145)

No sepsis workup

(n = 139) p Value*Mean maternal parity 3.18 ± 0.94 1.5 ± 0.94 2.3 ± 1.2 0.03Duration of PROM (h) 9 (26.4%) 30 (20.7%) 1 (0.7%) <0.001Mean labor duration (h) 13.1 ± 5.4 13.2 ± 5.4 7.1 ± 5 0.09Epidural anesthesia 26 (76.4%) 136 (93.7%) 85 (61.2%) <0.001Mean maximal maternal temperature (oC)

34.5 ± 0.3 38 ± 0.54 36.6 ± 0.2 0.1

Cesarean delivery 22 (64.7%) 15 (10.3%) 21 (15.1%) <0.001Instrumental delivery 8 (23.5%) 31 (21.4%) 7 (5.0%) NSMSAF 9 (26.4%) 43 (29.6%) 10 (7.2%) <0.001Maternal antibiotic treatment

28 (82.3%) 112 (77.2%) 8 (5.7%) <0.001

Maternal leukocytosis 26 (76.4%) 91 (62.7%) 25 (18.0%) <0.001Maternal tachycardia 3 (8.8%) 8 (5.5%) 1 (0.7%) 0.03Fetal tachycardia 13 (38.2%) 18 (12.4%) 1 (0.7%) <0.001* Refers to comparison of 3 infant groups: infants that underwent a full sepsis work up, infants that underwent a partial sepsis work up and infants that had no sepsis work up.

PROM, premature rupture of membranes; MSAF, meconium stained amniotic fluid.Data are presented as mean ± SD or N (%).

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sophisticated laboratory tests, with high sensitivity such as molec-ular techniques -16S rRNA PCR [16], serum ferritin concentration [17], nucleated red blood cells count [18], procalcitonin level [19], and interleukins IL-6 and IL-8 [20] in association with CRP level [21] may enable early diagnosis. To achieve sensitive and specific indicator of infection in standard clinical practice, further studies are needed and assay techniques need to be standardized.

Fear of infection in NICU’s often leads to early use of empiric broad-spectrum antibiotics. As this strategy selects for resistant bacteria, a renewed concern regarding perinatal infections caused by antimicrobial resistant organisms is arising [22,23]. Emergence of multi drug resistant organisms is a worrying perspective [24]. Furthermore, since the exposure to antibiotics in early life influ-ences the pattern of gut colonization, use of early IV antibiotic treatment may interfere with the process of developing toler-ance to gut flora, thus contributing to development of inflam-matory bowel diseases, neoplasms, etc. [25]. Keeping in mind that antibiotics can disturb the micro flora of the intestines and enhance gastrointestinal absorption problems, reducing avoid-able antibiotics administration will help enhance the health of future neonatal populations [26]. It is important to remember that a large retrospective study found Apgar scores lower than 7 at 1 min and perinatal mortality to be significantly associated with maternal fever during delivery, thus fever by itself may be associ-ated with poor short-term neonatal outcome [27].

The main limitation of this study is the number of mothers with peripartum fever studied. A statistical power analysis shows that for term infants born following maternal fever, an expected inci-dence of 0.8–2.5% [5] of EONS would require a study cohort of 160 neonates to find at least 1 case of EONS. In our population out of 2002 term neonates born following maternal peripartum fever, the rate of EONS was lower than that reported in the literature (<0.6%). Another limitation is having only one measurement of CRP level, and in most cases taken earlier than recommended in the literature.

In conclusion, since most asymptomatic term neonates born following maternal intrapartum fever have a benign clinical course, aggressive evaluation and management of these infants may not be necessary. The excess in performing sepsis work-ups and giving antibiotic treatment should be balanced against the possible risk of not detecting neonatal sepsis. This is especially true considering that neonatal sepsis work-up and administration of IV antibiotics are associated with the risk of antibiotic-related side effects, long-term antimicrobial resistance, and possible influence on maternal bonding, which may further enhance maternal post partum depression. Evaluation and treatment of these infants requires substantial additional health care resources. Further prospective well controlled multicenter studies are needed to design an optimal standardized protocol for the management of full term neonates born to mothers with peripartum fever, with the aim of prevention excessive diagnostic procedures and unnec-essary antibiotic treatments and treatment complications.

Declaration of Interest: The authors report no conflict of interest.

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