Early Human Development 136 (2019) 54–59

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Early Human Development

journal homepage: www.elsevier.com/locate/earlhumdev

Maternal urinary tract infection during pregnancy and long-term infectious T

morbidity of the offspring☆
Ram Cohena, , Gil Gutvirtzb, Tamar Wainstockc, Eyal Sheinerb
⁎

a
The Goldman Medical School at the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
b
Department of Obstetrics and Gynecology, Soroka University Medical Center, Beer-Sheva, Israel
c
Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

ARTICLE INFO ABSTRACT

Keywords: Background: Urinary tract infection (UTI) is a common bacterial infection in pregnant women and is associated
Pregnancy with adverse perinatal outcomes. We sought to investigate the long-term infectious outcomes of children to
UTI mothers who were diagnosed with UTI during their pregnancy.
Fetal Methods: A population-based cohort analysis was conducted at a single tertiary medical center. The study in-
Infectious morbidity
cluded all singleton deliveries between the years 1991–2014, comparing offspring born to mothers diagnosed
Long-term morbidity
with UTI during their pregnancy with those born to non-exposed mothers. Infectious-related hospitalizations of
the offspring up to the age of 18 years were assessed according to a predefined set of ICD-9 codes. A Kaplan-
Meier survival curve was conducted to compare cumulative hospitalization incidence between the groups. A Cox
regression model was used to adjust for confounders.
Results: During the study period, 243,725 deliveries met the inclusion criteria. Of them, 8034 (3.3%) were
exposed to maternal UTI during pregnancy. Infectious-related hospitalizations were significantly prevalent in
offspring to exposed mothers (12.3% vs. 11.0%, OR = 1.125, 95% CI 1.051–1.204, Kaplan-Meier log rank
p < 0.001). In the Cox regression model, while controlling for clinically relevant confounders, maternal UTI
(adjuster HR = 1.240), as well as preterm delivery (adjusted HR = 1.385) and cesarean delivery (adjusted
HR = 1.198) were noted as independent risk factors for long-term infectious morbidity of the offspring.
Conclusions: Maternal UTI in pregnancy may influence offspring susceptibility to pediatric infections, as it was
found to be an independent risk factor for long-term infectious morbidity of the offspring.

1. Introduction the right side) are present, pyelonephritis should be suspected as it is

the most common complication of UTI [3,6], mainly during the second
Pregnancy is a unique state characterized by both physiologic and and third trimesters [7].
immunologic changes. The major changes of the immune system in- In recent studies, untreated UTI during pregnancy was associated
clude activation of the innate system whereas the adaptive system is with adverse maternal and fetal outcomes, including intrauterine
suppressed. Therefore, women are more susceptible to infections during growth restriction (IUGR) and low birth weight, chorioamnionitis and
pregnancy [1–3]. Urinary tract infection (UTI) is among the most preterm delivery (PTD) [1,6,8,9]. Some studies even demonstrated in-
common bacterial infections in pregnant women and is associated with creased perinatal mortality [3,4].
adverse pregnancy outcomes [1,3]. Whether offspring of mothers diagnosed with UTI during pregnancy
The overall incidence of UTIs (acute cystitis and pyelonephritis) suffer long-term consequences is unclear. Some studies found UTI to be
during pregnancy varies between studies between 2.3 and 8% [1,4], associated with developmental delay/mental retardation [10] and even
and as in non-pregnant women, the most common bacteria are Es- childhood epilepsy [11]. Interestingly, in a recent study, maternal
cherichia coli [3,5,6], found in 60% of all positive cultures [6]. The signs genitourinary infection was associated with an increased risk of atten-
and symptoms of UTI include urgency, frequency, dysuria, hematuria tion deficit hyperactivity disorder (ADHD) [12]. There are several
and pyuria. If fever and costovertebral angle tenderness (especially on factors by which UTI could affect the fetus in the long-term. First, the

This study was conducted as part of the requirements for MD degree from the Goldman Medical School at the Faculty of Health Sciences, Ben-Gurion University of
☆

the Negev.
⁎
Corresponding author at: Ben-Gurion University Medical School, Soroka University Medical Center, 151 Izak Rager Ave., Beer-Sheva 84101, Israel.
E-mail address: ramcohen11@gmail.com (R. Cohen).

https://doi.org/10.1016/j.earlhumdev.2019.07.002
Received 15 March 2019; Received in revised form 31 May 2019; Accepted 1 July 2019
0378-3782/ © 2019 Elsevier B.V. All rights reserved.

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R. Cohen, et al. Early Human Development 136 (2019) 54–59

presence of an infecting organism, which by itself is sufficient to cause and the differences were evaluated by chi-square for general associa-
fetal damage due to various metabolic by-products, colonization, or tions. For the comparison of continuous variables with normal dis-
other bacterial activity [13]. This damage can also extend to years after tribution, a student t-test was used, while for comparing cumulative
delivery. For example, a study by Keski-Nisula et al. suggested that hospitalization incidences over time among the study groups, we used
intrauterine bacterial growth was associated with respiratory illness Kaplan–Meier survival curves. In the survival analysis and for a given
among the offspring at the age of 15 to 17 years [14]. Another possible individual, only the first admission with infectious-related condition
provocative factor was found at the cellular level. The maternal and the was included. The differences between the curves were evaluated with
fetal immune responses, evoked by the infection, may disrupt fetal the log-rank test.
development via direct effects of cytokines [13]. A Cox regression model, adjusting for confounding and clinically
To the best of our knowledge, there are no studies to date that in- significant variables, including maternal age, maternal diabetes (pre-
vestigate long-term infectious morbidity in offspring of mothers with gestational and gestational), maternal hypertensive disorders of preg-
UTI in pregnancy. In this large population-based study, we sought to nancy (chronic hypertension, gestational or preeclampsia with or
investigate the long-term (up to the age of 18) infectious outcomes of without severe features), preterm delivery, induced labor and cesarean
children to mothers who were diagnosed with UTI during their preg- delivery, was used to establish an independent association between
nancy, compared with children who were born to non-exposed mothers. maternal UTI in pregnancy and future incidence of infectious-related
hospitalizations of the offspring, while deliveries of non-exposed mo-
2. Methods thers were considered as reference. All analyses were two-sided, and a
p-value of ≤0.05 was considered statistically significant.
In this population-based retrospective cohort study, all singleton
deliveries between 1991 and 2014 were included. The study is based on 3. Results
a large non-selective population data, as it was conducted at Soroka
University Medical Center (SUMC), which is the largest birth center in During the study period, 243,725 deliveries in SUMC met the in-
the country and the sole tertiary medical center in the Negev (southern clusion criteria. Of them, 8034 (3.3%) were in mothers that were di-
Israel). It compared deliveries of mothers who were diagnosed with UTI agnosed with UTI during pregnancy. Maternal characteristics for both
during pregnancy and mothers who were not. The study has been groups are presented in Table 1. Mothers who were exposed to UTI
performed in accordance with the ethical standards of the 1964 during their pregnancy were older and had higher rates of diabetes
Declaration of Helsinki and its later amendments (Helsinki Declaration mellitus (pre-gestational or gestational) and hypertension (chronic,
1975, revision 2013), and was approved by the institutional review gestational or preeclampsia). Table 2 compares pregnancy outcomes
board (SUMC IRB Committee). between the two groups. Mean birthweight was lower in the UTI-ex-
The primary exposure for offspring was maternal UTI, diagnosed posed group and rates of low birth weight infants and preterm de-
during pregnancy based on positive urine culture (detection of liveries (< 37, < 34, < 32 weeks' gestation and also indicated PTDs)
≥100,000 colony forming unit (CFU)/ml in a single voided mid-stream infants were higher. SGA rates were higher in the non-exposed group.
urine). Common practice in Israel for prenatal care include a urine Cesarean delivery rate was higher among the UTI group. Hospitaliza-
analysis in each trimester of pregnancy and when clinically warranted. tion rates and the long-term infectious morbidities of the offspring are
The diagnosis was performed either in the hospital or out of the hos- presented in Table 3. The incidence of neonatal, otorhinolaryngological
pital. In this study, UTI included lower UTI, meaning acute cystitis di- (ENT) and respiratory infections was significantly higher in children
agnosis – symptomatic women diagnosed with positive urine culture. from the maternal UTI group while systemic febrile syndromes was
Multiple pregnancies and fetuses with congenital anomalies were ex- found in lower rates compared with the non-exposed group. All other
cluded. Perinatal mortality cases were excluded from the long-term infectious morbidities rates were comparable between the groups. The
analysis. total infectious-related hospitalizations rate was significantly higher in
The comparison conducted was between children born to UTI-ex- the group of children born to UTI exposed mothers (12.3% vs. 11.0%,
posed and non-exposed mothers. Adverse perinatal outcomes assessed OR = 1.125, 95% CI 1.051–1.204, p < 0.001). In the Kaplan–Meier
included low birthweight (LBW, defined as birthweight < 2500 g.), survival curve (Fig. 1), children born to mothers who had UTI during
small for gestational age (SGA), preterm delivery their pregnancy showed a significantly higher cumulative incidence of
(< 37, < 34, < 32 weeks' gestation and also indicated PTDs), and ce- infectious-related hospitalizations, as compared with children born to
sarean delivery rates. Infectious-related Hospitalizations of the off- non-UTI exposed mothers (log rank p < 0.001). The higher incidence
spring up to the age of 18 years were assessed using diagnoses that were of infectious-related hospitalizations was seen throughout the neonatal
pre-defined by a set of ICD-9 codes presented in the Supplementary period and early childhood (up to 5 years of age) (Fig. 2a) and later in
Table (Table 5). Follow-up was terminated if any of the following oc- life, up to 18 years (Fig. 2b) (log rank p < 0.001 and p = 0.049, re-
curred: hospitalization involving infectious morbidity, the child spectively).
reached the age of 18, hospitalization resulting in death or the end of
the study period. Table 1
Two databases were cross-linked and merged, in order to collect the Maternal characteristics of the study population.
data of the study, based on patients' ID number. The first database was
Maternal characteristic UTI in pregnancy No UTI in P value
the computerized perinatal database of the obstetrics and gynecology (n = 8034) pregnancy
department, containing maternal and neonatal information recorded (n = 235,691)
immediately following delivery by an obstetrician. The second was the
Maternal age 28.7 ± 5.729 28.14 ± 5.826 < 0.001
computerized pediatric hospitalization database of SUMC (“Demog-
(mean ± SD)
ICD9”), which includes demographic information and ICD-9 codes for Parity group < 0.001
all medical diagnoses made during hospitalizations in the SUMC pe- 1 2447 (30.5%) 55,068 (23.4%)
diatric departments. 2–4 4332 (53.9%) 120,204 (51.0%)
5+ 1255 (15.6%) 60,366 (25.6%)
Hypertensive disorders 452 (5.6%) 11,804 (5.0%) 0.013
2.1. Statistical analysis Diabetesb 480 (6.0%) 11,684 (5.0%) < 0.001

Statistical analysis was performed using the SPSS package 23rd ed. a
Including chronic hypertension, gestational hypertension and pre-eclampsia.
(IBM/SPSS, Chicago, IL). Categorical data are shown in counts and rates b
Including pre-gestational and gestational diabetes.

55

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R. Cohen, et al. Early Human Development 136 (2019) 54–59

Table 2
Pregnancy outcomes for deliveries of women with and without UTI in preg-
nancy.
Pregnancy outcome UTI in pregnancy No UTI in pregnancy p value UTI in pregnancy
(n = 8034) (n = 235,691)

Gestational age (in 38.84 ± 2.01 39.11 ± 1.987 < 0.001

weeks)
Small for 317 (3.9%) 10,978 (4.7%) 0.003
gestational age
(SGA)
Preterm delivery
< 37 weeks 736 (9.2%) 16,023 (6.8%) < 0.001
< 34 weeks 157 (2.0%) 3180 (1.3%) < 0.001 No UTI in pregnancy
< 32 weeks 106 (1.3%) 2325 (1.0%) 0.003
Indicated 223 (30.3%) 3475 (21.7%) < 0.001
Birthweight 3183.35 ± 519.513 3206.28 ± 510.935 < 0.001
Low birth weight 631 (7.9%) 15,811 (6.7%) < 0.001
(LBW)a
Cesarean section 1367 (17.0%) 31,680 (13.4%) < 0.001

a
LBW < 2500 g.

The Cox regression model, shown in Table 4, presents the associa-

tion between maternal UTI during pregnancy and the long-term risk for
infectious-related hospitalizations in children (up to the age of
18 years). As can be seen, maternal UTI during pregnancy (adjusted HR
1.240, 95% CI 1.164–1.322, p < 0.001), as well as preterm delivery Fig. 1. Kaplan-Meier survival curve demonstrating the cumulative incidence of
(adjusted HR 1.385, 95% CI 1.326–1.445, p < 0.001), induced labor hospitalizations involving infectious morbidity in children to UTI exposed and
(adjusted HR 1.090, 95% CI 1.061–1.120, p < 0.001), and cesarean non-exposed mothers.
delivery (adjusted HR 1.198, 95% CI 1.158–1.240, p < 0.001), were
significant and independent risk factors for long-term infectious-related at an increased risk for infectious-related hospitalizations compared
hospitalization of the offspring. with children born to non-exposed mothers. It is noteworthy that ad-
ditional two risk factors were identified in our cohort for long-term
4. Discussion infectious morbidity of the offspring, in accordance with other reports:
preterm delivery [29,30] and cesarean delivery [31].
In this study, we sought to extend the knowledge about the long- There are several mechanisms by which UTI could affect the fetus in
term consequences for the offspring whose mother was diagnosed with the long-term, including various metabolic by-products, colonization,
UTI during pregnancy, since they are the most common bacterial in- or other bacterial activity [13]. Also, the maternal and the fetal immune
fections in pregnant women [1,3]. We found that children born to responses, evoked by the infection, may disrupt fetal development via
mothers who were diagnosed with UTI during their pregnancy had an direct effects of cytokines [13]. Velten et al. found that inflammation
increased risk for neonatal and pediatric infectious morbidity, including in-utero was an independent and potent modulator of lung develop-
ENT and respiratory infections. The rates were higher both during the ment, leading to disruption of alveolarization and microvascular de-
neonatal period (and up to 5 years of age) (Fig. 2a), and during the later velopment [15]. The studies above might be helpful for explaining the
years (Fig. 2b). Similarly, other infectious categories that were assessed respiratory illnesses and increased risk for respiratory infections found
had a tendency towards higher rates in the maternal UTI group al- in our study. Specifically, a link between maternal UTI in pregnancy
though they were not statistically significant, probably due to a small and the development of future child respiratory morbidity has been
number of cases. As a result, the children of UTI-exposed mothers were previously reported in the literature [13–16]. An increased rate of

Table 3
Long-term infectious morbidities in children (up to the age of 18 years) born to mothers with and without UTI in pregnancy.
Infectious morbidity UTI in pregnancy No UTI in pregnancy Odds ratio 95% confidence interval p value
(n) (n)

Bacteremia/septicemia 4 (0.0%) 186 (0.1%) 0.630 0.234–1.696 0.356

Bacterial infections 14 (0.2%) 319 (0.1%) 1.286 0.753–2.197 0.356
CNS infections 17 (0.2%) 538 (0.2%) 0.925 0.571–1.500 0.753
ENT infections 146 (1.8%) 3444 (1.5%) 1.246 1.054–1.473 0.010
GI infections 117 (1.5%) 3897 (1.7%) 0.877 0.729–1.056 0.166
Invasive bacterial infections 5 (0.1%) 247 (0.1%) 0.593 0.244–1.437 0.241
Neonatal infections 33 (0.4%) 635 (0.3%) 1.524 1.073–2.164 0.018
Ophthalmic infections 28 (0.3%) 699 (0.3%) 1.174 0.804–1.714 0.406
Orthopedic infections 17 (0.2%) 360 (0.2%) 1.384 0.850–2.252 0.189
Respiratory infections 541 (6.8%) 12,907 (5.5%) 1.244 1.138–1.360 < 0.001
Skin infections 52 (0.6%) 1954 (0.8%) 0.778 0.590–1.025 0.074
Systemic febrile syndromes 6 (0.1%) 513 (0.2%) 0.342 0.153–0.765 0.006
Urological infections 51 (0.6%) 1583 (0.7%) 0.943 0.713–1.248 0.682
Viral infections 77 (1.0%) 2006 (0.9%) 1.125 0.895–1.415 0.311
Total hospitalizations 981 (12.3%) 25,889 (11.0%) 1.125 1.051–1.204 0.001

Some of the diagnoses in Table 3 may overlap between patients.

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R. Cohen, et al. Early Human Development 136 (2019) 54–59

UTI in pregnancy

No UTI in pregnancy

UTI in pregnancy

No UTI in pregnancy

Fig. 2. Kaplan-Meier survival curve demonstrating the cumulative incidence of hospitalizations involving infectious morbidity in children to UTI exposed and non-
exposed mothers, divided into two subgroups by the age of 5 years of the offspring.

respiratory illness in children beyond the neonatal period was found in complications such as preterm delivery and low birthweight [18,19].
a study by Algert and associates, which showed that fetal exposure to Nevertheless, antibiotic treatment given to pregnant women may also
maternal UTI was associated with an increased risk of childhood re- affect their growing fetus and its immune system. Recent studies sug-
spiratory morbidity admissions [16]. gested that the antibiotic treatment given to mothers during pregnancy
While infection by itself can provoke later morbidity, the use of may affect the maternal microbiota the fetus is exposed to, resulting in
antibiotics in pregnancy also merits attention. Treating UTI in preg- a change in its future respiratory and gut microbiota and can even cause
nancy is recommended by most guidelines [17]. It has been shown that dysbiosis (microbial imbalance) in the fetus [20]. It was also shown that
treating UTI and even asymptomatic bacteriuria reduces pregnancy these alternations can persist over several months and may have long-

57

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R. Cohen, et al. Early Human Development 136 (2019) 54–59

Table 4 aspects of the mother and family of the offspring, which can be im-
Cox regression model for the association between UTI in pregnancy and off- portant factors that might contribute to infectious morbidity.
spring long-term infectious morbidity. The main strength of our study is its large non-selective population-
Variables Adjusted HR 95%CI P-value based cohort, reassuring that our numbers can probably be extrapolated
for the general population. In conclusion, maternal UTI in pregnancy
Min Max may influence offspring susceptibility to pediatric infections, as it was
found to be an independent risk factor for long-term infectious mor-
UTI 1.240 1.164–1.322 < 0.001
Maternal age 0.992 0.990–0.994 < 0.001 bidity of the offspring. Our findings expand the knowledge about the
Diabetes mellitus 1.034 0.979–1.091 0.230 impact of maternal UTI on future child health.
Hypertensive disorders 0.943 0.893–0.996 0.036 Supplementary data to this article can be found online at https://
Preterm delivery 1.385 1.326–1.445 < 0.001
doi.org/10.1016/j.earlhumdev.2019.07.002.
Induced labor 1.090 1.061–1.120 < 0.001
Cesarean section 1.198 1.158–1.240 < 0.001
Funding/support

This research did not receive any specific grant from funding
lasting functional effects with an impact on disease risk later in life agencies in the public, commercial, or not-for-profit sectors.
[20]. Nogacka et al. have shown that intrauterine antimicrobial pro-
phylaxis can change the microbiota of the offspring, and some of these Disclosures
alternations remain for up to 3 months of age [21]. Similarly, studies
made in Denmark, regarding the short and long-term effect of anti- Financial Disclosures: No financial disclosures.
biotics on the fetus' gut microbiota, concluded that intrauterine and Ram Cohen wrote the first draft of the manuscript. No honorarium,
prenatal antibiotics may lead to alternations in the vaginal micro- grant, or other form of payment was given to anyone to produce the
biological ecology of the pregnant mother and are associated with short manuscript.
and long-term effects of the neonate [22]. It is not surprising to find an
association between the gut and the lung microbiota. Even though they Declaration of Competing Interest
are separate organs, with different environments and functions, they
share the same embryonic origin and are part of a shared mucosal Declaration of interest: None.
immune system named the gut–lung axis [23]. Studies have shown that Financial Disclosures: No financial disclosures. No honorarium,
the gut–lung axis influences immune responses both locally and at grant, or other form of payment was given to anyone to produce the
distant sites. Accordingly, dysbiosis in the fetus was linked to altera- manuscript.
tions in immune responses and to disease development in the lungs
[23]. These changes in the immune system of the evolving fetus as a References
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