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Original Article

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itiporn Sirivunnabood, M.D., Prapat Wanitpongpan, M.D., Piengbulan Yapan, M.D.

Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

Incidence and Risk Factors of Neonatal Sepsis in

Preterm Premature Rupture of Membranes before

34 Weeks of Gestation

ABSTRACT

Objective: Early-onset neonatal sepsis (EONS) is a leading cause of newborn morbidity and mortality, particularly in

preterm premature rupture of membranes (PPROM) before 34 weeks of gestation, in which expectant management

was performed until reaching 34 weeks of gestation, evidence of maternal chorioamnionitis, or unfavorable fetal

conditions. e interval between membrane rupture and delivery has a positive correlation with neonatal sepsis.

e purpose of this study was to investigate the incidence and risk factors of EONS in PPROM.

Materials and Methods: is was a retrospective cross-sectional study. e medical records of pregnant women

who gave birth between 2005 and 2018 and their newborns were reviewed. e inclusion criterion was singleton

pregnancies complicated by PPROM between 24 and 33

weeks of gestation. Multifetal pregnancies, fetal malformation,

stillbirths, and records with incomplete data were excluded. PPROM was diagnosed by obstetricians while EONS

was diagnosed by neonatologist.

Results: e incidence of EONS in with PPROM was 24%. Risk factors included excessive maternal weight gain

based on IOM (OR = 2.40, 95% CI = 1.16-4.94), extremely preterm at admission (before 28 weeks of gestation)

(OR = 3.38, 95% CI 1.12-10.21) and very low birth weight (≤ 1,500 g) (OR 3.68, 95% CI = 1.86-7.30). Maternal

hematologic laboratory results were not associated with neonatal sepsis.

Conclusion: e incidence of EONS in PPROM was similar to data provided by other studies. Obstetricians and

pediatricians should be cautious about neonatal sepsis, especially in cases of excessive maternal weight gain, extremely

preterm admissions, and very low birth weight.

Keywords: Early-onset neonatal sepsis; incidence; PPROM; risk factors (Siriraj Med J 2022; 74: 169-177)

Corresponding author: Piengbulan Yapan

E-mail: piengbulan.yap@gmail.com

Received 25 October 2021 Revised 15 January 2022 Accepted 21 January 2022

ORCID ID: https://orcid.org/ 0000-0001-7194-4365

http://dx.doi.org/10.33192/Smj.2022.21

All material is licensed under terms of

the Creative Commons Attribution 4.0

International (CC-BY-NC-ND 4.0)

license unless otherwise stated.

INTRODUCTION

Preterm birth is dened as babies born prior to

completion of 37 weeks of gestation. At Siriraj Hospital,

the incidence of preterm birth between 28 and 37 weeks

of gestation is 9-13%.

1,2

Due to the immature development

of several organs, these babies tend to have short-term

or long-term morbidities in the respiratory system

(respiratory distress syndrome, bronchopulmonary

dysplasia, apnea of prematurity), gastrointestinal system

(feeding intolerance, necrotizing enterocolitis, growth

failure), immunological system (infection) and central

nervous system (intraventricular hemorrhage, cerebral

palsy, neurodevelopmental delay, hearing loss, retinopathy

of prematurity).

One of the causes of preterm birth is preterm premature

rupture of membranes (PPROM) in which the fetal

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membranes spontaneously rupture before completion

of 37 weeks of gestation and onset of labor. At Siriraj

Hospital, the incidence of PPROM between 24 and

37 weeks of gestation is 2.93%.

Aer the rupture of

fetal membranes, microorganisms from the maternal

lower genital tract ascend the uterine cavity, resulting

in infectious morbidities such as chorioamnionitis, fetal

inammation and neonatal sepsis. Besides PPROM,

risk factors of neonatal sepsis include preterm labor,

low birth weight, maternal colonization of group B

streptococcus, chorioamnionitis and intrapartum infection.

5,6

e interval between the rupture of membranes and

delivery has a positive correlation with neonatal sepsis.

Early-onset neonatal sepsis (EONS) is an important

cause of morbidity and mortality of newborns. Short-

term outcomes are hypotension requiring vasopressor

support; respiratory distress or suppression requiring

intubation or noninvasive ventilation; and hyper- and

hypoglycemia, thrombocytopenia, and disseminated

intravascular coagulation (DIC). Long-term outcomes are

bronchopulmonary dysplasia (BPD), brain injury, including

periventricular leukomalacia (PVL), neurodevelopmental

delays, and cerebral palsy.

Management of PPROM remains challenging as it

is dicult to balance the risk of terminating a pregnancy

as long as expectant management exists. While expectant

management poses a risk of maternal and fetal infection,

placental abruption, and umbilical cord accidents,

termination of pregnancy, especially at an early gestational

age, presents a danger of prematurity.

Over the last few

decades, the decision to terminate a pregnancy with

PPROM complications have been based on evidence of

maternal chorioamnionitis or unfavorable fetal conditions.

Chorioamnionitis is dened by maternal fever and uterine

tenderness, which results in severe infection in newborn

babies. Indications of early stage chorioamnionitis have

been proposed, however, they remain controversial and

unreliable. Our aim was to study the incidence of EONS

and parameters associated with this condition.

MATERIALS AND METHODS

Study design

is was a retrospective cross-sectional study approved

by the institutional ethical committee.

Participants

Based on previous report from Arora and colleagues

the sample size of 274 samples would yield a power

of 80% and type I error of 5%, 2-sided. e medical

records of pregnant women who gave birth between

2005 and 2018 were reviewed. e inclusion criterion

was singleton pregnancies aected by PPROM between

24 and 33

weeks of gestation. Multifetal pregnancies,

fetal malformation, stillbirths, indicated preterm birth

conditions such as maternal diseases, preeclampsia and

placenta previa, and records with incomplete data were

excluded. Gestational age was dened by menstrual

history or ultrasonography performed before 20 weeks

of gestation.

Outcomes

e clinical parameters included maternal demographic

data, parity, history of previous preterm birth, body mass

index (BMI), weight gain during pregnancy according

to the Institute of Medicine (IOM) pregnant women,

diabetes mellitus status, gestational age at PPROM and

at delivery, interval between rupture of membranes and

delivery, dexamethasone dosage, delivery mode, birth

weight of newborns, APGAR score, diagnosis of EONS,

length of neonatal hospital stay, and neonatal discharge

status. e maternal hematological parameters included

complete blood count (CBC), neutrophils to lymphocytes

(N/L) ratio, and erythrocyte sedimentation rate (ESR).

e IOM recommended that pregnant women should

have a total weight gain of 12.5 to 18 kg, 11.5 to 16 kg, 7

to 11.5 kg, and 5 to 9 kg for those whose pre-pregnancy

BMI were categorized as underweight (<18.5 kg/m

normal weight (18.5-24.9 kg/m

), overweight (25.0-29.9

kg/m

), and obesity (≥30 kg/m

), respectively.

11,12

All newborns were assessed by neonatologist at Siriraj

Hospital. e EONS was dened by a positive culture of

pathogenic bacteria in the blood or cerebrospinal uid

(CSF) within 72 hours aer birth. Blood culture remains

the diagnostic standard for EONS. CSF culture should

ideally be performed along with blood culture for newborns

who are at the highest risk for EOS. However, lumbar

puncture should not be performed if the newborn’s clinical

condition was compromised, or antibiotic initiation

would be delayed by the procedure.

In our institute, all PPROM cases of less than

34 weeks of gestation were managed by a combined

administration of antibiotics (ampicillin/amoxicillin

plus erythromycin)

, corticosteroids, and short-term

tocolytics to complete course of corticosteroids. Aer

completing the course of antibiotics and corticosteroids,

expectant management was performed until 34 weeks

of gestation when delivery was induced. Termination

of each pregnancy was individually encouraged before

34 weeks using evidence of maternal chorioamnionitis

or unfavorable fetal conditions. Complete blood count

and ESR were checked every other day from admission

until delivery.

Sirivunnabood et al.

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Statistical analysis

e continuous variables are presented as mean

± SD, median, and range. e categorical variables are

presented as frequencies and percentage. A T-test was

used to compare two groups ofcontinuous datawhich

were normally distributed while the Mann-Whitney

U test was used to compare dierences between two

independent groups when the dependentvariableswere

either ordinal orcontinuous, but not normally distributed.

e Chi-square test was used to compare a group with a

value or to compare two or more groups, always using

categorical data. Risk factors of EONS were shown as an

odds ratio by binary logistic regression analysis. IBM SPSS

Statistics version 21 (Copyright International Business

Machines Corporation and other(s) 1989, 2012) was

used for statistical analysis. A P-value of less than 0.05

was considered statistically signicant.

Fig 1. Flow of PPROM cases in

Siriraj Hospital from 2005 to

2018

Fig 2. Incidence of EONS in

PPROM pregnancies before 34

weeks of gestation at Siriraj

Hospital from 2005 to 2018.

RESULTS

A total number of 407 medical records were initially

included into this study. One hundred and thirty-three

records were excluded. Data from the remaining 274

records were used for further analysis (Fig 1).

e overall incidence of EONS in PPROM before 34

weeks of gestation was 24%. e trend of incidence has

decreased over the past 14 years (Fig 2). e maternal

characteristics and pregnancy outcomes were shown

in Table 1. Maternal age was not signicantly dierent

between those with and without EONS, which was similar

to parity and history of previous preterm birth. e PPROM

interval prior to delivery, clinical chorioamnionitis and

unfavorable fetal conditions did not relate to neonatal

sepsis. Most pregnant women received four doses of

dexamethasone before delivery. ere was only one case

of prolapsed cord among those without EONS. Placental

abruption was not found in both groups.

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TABLE 1. Maternal characteristics and pregnancy outcomes of 274 women enrolled in the study in the PPROM

without EONS or PPROM with EONS group.

Variables PPROM without EONS PPROM with EONS P

(n=221) (n=53)

Maternal age (years) 27.9 ± 7.2 28.8 ± 6.5 0.386*

<20 37 (16.7%) 5 (9.4%) 0.381

20-34 139 (62.9%) 38 (71.7%)

≥35 45 (20.4%) 10 (18.9%)

Parity

Nulliparous 125 (56.6%) 37 (69.8%) 0.088

Multiparous 96 (43.4%) 16 (30.2%)

Previous PTB history 23 (10.4%) 1 (1.9%) 0.056

Weight gain (kg) 9.8 ± 4.7 11.7 ± 5.0 0.021*

Non-excessive 161 (81.7%) 28 (65.1%) 0.016

Excessive 36 (18.3%) 15 (34.9%)

GA at admission (weeks) 32 (25 - 34) 31 (25 - 34) 0.007

†

24-27

8 (3.6%) 6 (11.3%) 0.027

28-31

60 (27.1%) 18 (34.0%)

32-33

153 (69.2%) 29 (54.7%)

GA at delivery (weeks) 33 (25 - 34) 32 (26 - 34) 0.003

†

24-27

8 (3.6%) 6 (11.3%) 0.150

28-31

50 (22.6%) 13 (24.5%)

32-33

163 (73.8%) 34 (64.2%)

PPROM interval prior to delivery (hr) 26 (0 - 523) 25 (0 - 241) 0.279

†

<18 99 (44.8%) 25 (47.2%) 0.353

18-48 35 (15.8%) 12 (22.6%)

>48 87 (39.4%) 16 (30.2%)

Dexamethasone (dose)

0 14 (6.3%) 6 (11.3%) 0.164

1 80 (36.2%) 15 (28.3%)

2 17 (7.7%) 9 (17.0%)

3 11 (5.0%) 2 (3.8%)

4 99 (44.8%) 21 (39.6%)

Delivery mode

Vaginal delivery 163 (73.8%) 40 (75.5%) 0.863

Cesarean section 58 (26.2%) 13 (24.5%)

Clinical chorioamnionitis 8 (3.6%) 2 (3.8%) 1.000

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TABLE 1. Maternal characteristics and pregnancy outcomes of 274 women enrolled in the study in the PPROM

without EONS or PPROM with EONS group. (Continue)

Variables PPROM without EONS PPROM with EONS P

(n=221) (n=53)

Unfavorable fetal conditions 16 (7.2%) 6 (11.3%) 0.396

Birth weight (g) 1891 ± 389 1626 ± 350 <0.001*

<1,500 29 (13.1%) 19 (35.8%) <0.001

1,500-2,499 179 (81.0%) 34 (64.2%)

2,500-3,999 13 (5.9%) 0

APGAR score at 1 min 8 (0 - 10) 8 (1-10) 0.149

†

APGAR score at 5 mins 10 (0 - 10) 9 (5 - 10) 0.016

†

Length of neonatal hospital stay (days) 10 (0 - 158) 30 (2 - 218) <0.001

†

<7 61 (27.6%) 1 (1.9%) <0.001

7-30 111 (50.2%) 26 (49.1%)

>30 49 (22.2%) 26 (49.1%)

Neonatal discharge status

Alive 217 (98.2%) 52 (98.1%) 1.000

Deceased 4 (1.8%) 1 (1.9%)

Abbreviations: PPROM=preterm premature ruptured of membranes, EONS=Early-onset neonatal sepsis, PTB=preterm birth, GA=

gestational age

* Mean ±SD, p-value (T-test)

Count, p-value (Chi-square)

Count, p-value (Fisher’s exact test)

†

Median, p-value (Mann-Whitney U test)

e parameters signicantly associated with EONS

included excessive maternal weight gain, gestational

age at admission, gestational age at delivery and birth

weight. An earlier gestational age at admission meant

higher incidence of EONS as well as gestational age

at delivery. Again, a lower birth weight meant higher

chance for neonatal sepsis.

Newborns with EONS stayed in the hospital longer.

e overall mortality rate of newborns from PPROM

mothers is 2%. ere is no statistical dierence in mortality

rate between the two groups.

Laboratory results were obtained from 241 women

and data comparing cases with and without EONS at

admission, before delivery and dierence from admission

to delivery are shown in Table 2. All maternal laboratory

results were similar between the EONS and no EONS

group.

Pregnant women in the EONS group gained more

weight than the other group. According to IOM guidelines

for weight gain during pregnancy, the odds ratio (OR) of

EONS among pregnant women with excessive weight gain

was 2.40 (95% CI 1.16-4.94). Furthermore, risk factors

of EONS at admission before 28 weeks of gestation was

preterm (OR = 3.38, 95%CI 1.12-10.21) and low birth

weight ≤ 1,500g (OR 3.68, 95%CI = 1.86-7.30), as shown

in Table 3.

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TABLE 2. Maternal laboratory results in PPROM without EONS and PPROM with EONS groups

Variables At admission Before delivery Difference from admission

to delivery

No EONS EONS P No EONS EONS P No EONS EONS P

(n=193) (n=48) (n=193) (n=48) (n=92) (n=20)

Hb (g/dl) 11.5 ± 1.3 11.3 ± 1.2 0.21* 11.2 ± 1.5 11.2 ± 1.2 0.89* -0.6 ± 1.2 -0.1 ± 0.9 0.08*

Hct (%) 35.2 ± 3.8 34.2 ± 3.6 0.10* 34.3 ± 4.4 34.1 ± 3.6 0.73* -1.8 ± 3.3 -0.2 ± 2.8 0.06*

WBC 13.5 ± 7.3 13.3 ± 4.2 0.86* 14.5 ± 7.5 15.1 ± 4.6 0.60* 2.1 ± 5.0 4.3 ± 4.2 0.74*

(10

cells/ul)

N (%) 78.2 ± 7.3 76.9 ± 8.7 0.32* 80.0 ± 8.2 80.0 ± 8.7 0.99* 3.9 ± 9.8 7.4 ± 11.4 0.16*

L (%) 15.4 ± 6.0 16.3 ± 6.9 0.40* 14.1 ± 6.6 14.0 ± 6.9 0.93* -2.7 ± 7.0 -5.4 ± 8.2 0.14*

N/L ratio

5.2 (1.1

–

27.4) 4.3 (1.7

–

21.5) 0.32

†

5.6 (1.1

–

46.4) 6.4 (1.7

–

36.8) 0.99

†

1.6 (-2.3

–

40.1) 3.0 (-8.1

–

34.2) 0.74

†

Plt 271.4 ± 62.9 272.7 ± 78.7 0.90* 268.7 ± 61.6 269.6 ± 73.3 0.93* -5.6 ± 38.2 -7.4 ± 38.5 0.84*

(10

cells/ul)

ESR 64.2 ± 19.5 62.2 ± 18.0 0.56* 64.2 ± 21.2 62.7 ± 18.2 0.69* 0.1 ± 18.8 7.6 ± 14.4 0.15*

(mm/hr)

Abbreviations: Hb = Hemoglobin, Hct = Hematocrit, WBC = White Blood Cells Count, N = Neutrophils, L = Lymphocytes, Plt = Platelets,

ESR = Erythrocyte Sedimentation Rate

* Mean ±SD, p-value (T-test)

†

Median, p-value (Mann-Whitney U test)

TABLE 3. Maternal laboratory results in PPROM without EONS and PPROM with EONS groups

Risk factors OR 95% CI P

Excessive weight gain 2.40 1.16 – 4.94 0.016

BMI at admission 1.04 0.96 – 1.12 0.324

Gestational age at admission

24-27

weeks 3.38 1.12 – 10.21 0.023

28-31

weeks 1.57 0.81 – 3.04 0.177

32-33

weeks 1.00 - -

VLBW (≤ 1,500 g) 3.68 1.86 – 7.30 <0.001

Abbreviations: BMI = body mass index, VLBW = very low birth weight

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DISCUSSION

e overall incidence of EONS in pregnant women

with PPROM before 34 weeks of pregnancy was found to

be 24% in this study. We chose to study gestational age

less than 34 weeks because PPROM that arises beyond

34 weeks of gestation is not treated expectantly, newborn

sepsis is infrequent. Our incidence was in agreement with

certain research

but not with others.

15,16

We hypothesize

that the dierence in incidence between hospitals is due

to the varying diagnostic criteria used to identify EONS.

During the 14-year period, the incidence of EONS in

PPROM pregnancies before 34 weeks of gestation seems

to have decreased. is could either be the result of

better guideline management for premature rupture of

membranes

or more advanced neonatal management.

However, EONS incidence in preterm was higher than

term deliveries. In Siriraj Hospital, the perinatal mortality

rate has continuously declined and was less than 10%.

e survival rate of premature babies has been increased

due to the improvement of obstetric and newborn care.

e well-trained neonatologists and excellent equipment

result in the best care for newborns.

Our study found that a maternal risk factor for

EONS was excessive weight gain during pregnancy,

according to IOM recommendations (OR = 2.40, 95%CI

= 1.16-4.94; p=0.016). According to Stotland NE, et al.,

who conducted a retrospective cohort study in singleton

births, the rate of neonatal infection was higher when

maternal weight gain was above IOM guidelines, when

compared to the appropriate or low weight gain group

(5.86%, 4.44% and 3.38% respectively).

It was reported

earlier that the incidence of sepsis among newborns of

obese women was higher than those of normal-weight

women.

18,19

Maternal overweight and obesity increased

the risk of EOS by group B Streptococcus, Staphylococcus

aureus, and Escherichia coli. Half of the association was

mediated through preeclampsia, cesarean section, and

preterm delivery.

Furthermore, obesity is a low-grade

inammatory state mediated primarily by leptin

, which

is associated with an increase in circulating inammatory

markers that are well characterized in the context of

preeclampsia and maternal intrauterine infections. Since

incremental weight gain has been associated with higher

leptin levels

, systemic inammation may play a role in

the higher incidence and trends of neonatal morbidities.

Neonatal conditions at birth aect a baby’s life

in many aspects. According to previous studies

22-26

unanimous agreement states that gestational age, birth

weight and APGAR scores play a vital role in neonatal

well-being and complications. A study by Belachew A,

et al. found that prematurity increased the risk of neonatal

sepsis 3.36 times compared with term newborns (95%

CI 2.50-4.54), and low birth weight (birth weight <2,500

grams) increased the risk of neonatal sepsis 1.42 times

compared to the normal birth weight group (95% CI

1.07-1.88).

Meanwhile, avarajah H, et al. claimed

that there was a statistically signicant dierence in the

incidence of neonatal sepsis among dierent APGAR

groups (low = 0-3, intermediate 4-6, normal = 7 or more).

Prematurity impairs adequate tissue oxygenation due to

an immature respiratory function. An underdeveloped

immune system along with hypoxic conditions put these

babies at higher risk of infection. Our study found that

a very low birth weight ≤ 1,500 g was associated with

increased risk of EONS (OR 3.68, 95%CI 1.86-7.30).

Maternal hematological parameters such as white

blood cell count (WBC) and erythrocyte sedimentation rate

(ESR) have been proposed as predictors of chorioamnionitis

and fetal infection but with some degree of controversy.

27-31

Panwar C, et al. mentioned that maternal WBC >12,000/

could predict EONS with a sensitivity of 67.2% and

a specicity of 77.5% but without achieving statistical

signicance.

However, Mayuka WAB, et al. concluded

that maternal WBC >12,000 /mm

was signicantly

associated with neonatal sepsis.

Our goal was to nd

parameters associated with EONS, but we did not notice

any signicant relationship between maternal hematological

parameters and EONS. One possible explanation is

that leukocytosis in PPROM mothers was the result of

corticosteroids injections and not infection.

Many studies

have advocated the usefulness of an elevated Neutrophils/

Lymphocytes (N/L) ratio to predict adverse outcomes

in PPROM and is associated with chorioamnionitis

and EONS in preterm babies.

30,35,36

Contradicting this

suggestion, the N/L ratio in our study was not signicantly

associated with EONS in PPROM. Future studies that

can control the eect of corticosteroids might show the

true relationship between leukocytosis, chorioamnionitis,

and neonatal sepsis.

e strength of this study was that it found more

information about maternal hematological parameters

and EONS, about which there is relatively little knowledge.

However, it was limited by its retrospective nature, low

power in subgroup analysis and incomplete data of some

parameters. More prospective studies should be carried

out to eliminate these limitations.

CONCLUSION

In conclusion, the incidence of EONS in pregnant

women with PPROM before 34 weeks of gestation was

24%, indicating a decrease over time. Excessive maternal

weight gain, extremely preterm at admission and low birth

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weight are associated with increased incidence of EONS,

which aects the well-being of babies born prematurely.

From this study, some maternal hematologic parameters

may not reveal any risk factors of EONS. A regular check

of some parameters to guide the management of PPROM

cases should be considered.

ACKNOWLEDGEMENTS

e authors gratefully acknowledge Dr.Supasaek

Virojanapa and Julaporn Pooliam for assistance with

statistical analysis.

No conict of interest

is study passed the requirements of the ethical

committee at SIRB, COA no. Si 106/2019.

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