Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 261e265

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Taiwanese Journal of Obstetrics & Gynecology

journal homepage: www.tjog-online.com

Original Article

Maternal pregnancy-induced hypertension increases the subsequent

risk of neonatal candidiasis: A nationwide population-based cohort
study
San-Nung Chen a, Peng-Hui Wang b, c, d, e, Ming-Fang Hsieh a, Hsiao-Wen Tsai a, d,
Li-Te Lin a, c, f, *, 1, Kuan-Hao Tsui a, c, g, **, 1
a
Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
b
Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
c
Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan
d
Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
e
Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
f
Department of Nursing, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan
g
Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung County, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Neonatal candidiasis is a leading infectious cause of significant morbidity and mortality in
Accepted 12 June 2018 premature birth mainly due to impaired physical barriers and immature immune system of fetus.
Maternal pregnancy-induced hypertension (PIH) has been reported to be able to disturb the neonatal
Keywords: immune system, which could cause the increased possibility of neonatal infection. Therefore, we
Gestational hypertension hypothesized that maternal PIH may increase the risk of neonatal candidiasis. The aim of this study was
Hypertension in pregnancy
to evaluate whether PIH increased the risk of neonatal candidiasis and identify the predictive risk factors.
Neonatal candidiasis
Materials and methods: Patients with newly diagnosed PIH between January 1, 2000, and December 31,
Preeclampsia
Pregnancy-induced hypertension
2013 were selected from the Taiwan National Health Insurance Research Database (NHIRD). For each
patient in the PIH cohort, 4 subjects without PIH, matched for age and year of delivery, were randomly
selected as the comparison cohort. A Cox proportional regression model was used to estimate the risks of
neonatal candidiasis in both cohorts.
Results: Among the 23.3 million individuals registered in the NHIRD, 29,013 patients with PIH and
116,052 matched controls were identified. Patients with PIH had a higher incidence of neonatal candi-
diasis than did those without PIH. According to the multivariate analysis, PIH (odds ratio [OR] ¼ 2.08, 95%
confidence interval [CI] ¼ 1.11e3.19, p < 0.0228), single parity (OR ¼ 1.91, 95% CI ¼ 1.00e3.65,
p < 0.0499), and preterm birth (OR ¼ 3.57, 95% CI ¼ 1.84e6.93, p ¼ 0.0002) were independent risk factors
for the development of neonatal candidiasis.
Conclusion: Patients who had a history of PIH was associated with an increased risk of having infants
who develop neonatal candidiasis compared with those without PIH. Additionally, preterm birth was an
independent risk factor for the development of neonatal candidiasis.
© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

* Corresponding author. Department of Obstetrics and Gynecology, Kaohsiung Hypertensive disorders during pregnancy, including maternal
Veterans General Hospital, No. 386, Dazhong 1st Rd., Zuoying Dist., Kaohsiung
pregnancy-induced hypertension (PIH), complicate approximately
81362, Taiwan. Fax: þ886 7 3468189.
** Corresponding author. Department of Obstetrics and Gynecology, Kaohsiung 10% of pregnancies worldwide and represent one of the major
Veterans General Hospital, No. 386, Dazhong 1st Rd., Zuoying Dist., Kaohsiung causes of maternal and perinatal morbidity and mortality world-
81362, Taiwan. Fax: þ886 7 3468189. wide [1]. It is generally established that PIH is a syndrome recog-
E-mail addresses: [email protected] (L.-T. Lin), [email protected] nized as the new-onset of hypertension during second half of
(K.-H. Tsui).
1
Both authors contributed equally.
pregnancy with the occurrence of substantial proteinuria [2].

https://doi.org/10.1016/j.tjog.2019.01.017
1028-4559/© 2019 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
262 S.-N. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 261e265

Among other clinical manifestations accompanying PIH, it has been to the study endpoints, which were defined as the onset of a
reported that visual disturbances, headaches, epigastric pain, and neonatal candidiasis (ICD-9-CM: 771.7), death within 28 days
the development of edema are the most common. There are several after birth, or the end of the study period. The flow chart of the
risk factors that could account for increased likelihood of devel- study design is shown in Fig. 1.
oping PIH, including multiple pregnancy, maternal age younger The pregnancy and baseline characteristics, including age, par-
than 20 or older than 40, diabetes and obesity [3]. Moreover, the ity, gestational age, gestational number, delivery mode and major
risk of PIH is increased 2-fold in women with first-degree relative comorbidities, were obtained. The major comorbidities in this
with a medical history of the disorder, and even 7-fold if PIH study included diabetes mellitus (DM) (ICD-9-CM: 250), hyper-
complicated previous pregnancy [3]. tension (HTN) (ICD-9-CM: 401e405), dyslipidemia (ICD-9-CM:
Pathogenesis of early PIH involves impaired placentation and 272), coronary artery disease (CAD) (ICD-9-CM: 410e414), chronic
secondary complications due to poor placentation, which are obstructive pulmonary disease (COPD) (ICD-9-CM: 491.2, 493.2,
probably evoked by placental hypoxia and hypoxia reperfusion, 496), chronic kidney disease (CKD) (ICD-9-CM: 585, 403), and
resulting in a damaged syncytium and limited fetal growth [4]. cerebrovascular disease (ICD-9-CM: 430e437).
Several mechanisms may account for the link between relatively
hypoxic placenta and the maternal syndrome, including altered pro- Statistical analysis
angiogenic and anti-angiogenic factor balance, metabolic changes,
increased maternal oxidative stress and endothelial dysfunction and The distributions of the pregnancy and baseline characteristics
impaired immune response. A recent meta-analysis demonstrated between the PIH and matched groups were compared using Stu-
the association between elevated preeclampsia and elevated circu- dent's t-test for continuous variables and the chi-squared test for
lating levels of TNF-alpha, IL-6 and IL-10 in the third trimester of categorical variables. Univariate and multivariate Cox proportional
pregnancy [5]. Impaired inflammatory response may errand in- hazards regression models were used to estimate odds ratios (ORs)
fections, including infection with Candida species [4], which has and 95% confidence intervals (CIs) of neonatal candidiasis. The
been associated with significant increased risk of complications, multivariate model was adjusted for age, parity, gestational age,
such as neurodevelopmental impairment, heart and kidney disor- gestational number, cesarean section, and common comorbidities,
ders, and mortality [6,7]. A recent study demonstrated that maternal including DM, HTN, CAD, dyslipidemia, COPD, CKD, and cerebro-
PIH was one the main risk factors for candidiasis [8]. However, the vascular disease. All statistical analyses were conducted using
small sample size limited the strength of the evidence and additional Statistical Analysis Software (SAS) version 9.4 (SAS Institute, Inc.,
studies are needed to further investigate such potential relation. The Cary, NC, USA). Comparisons with two-tailed p value of less than
aim on this study was to investigate the association between 0.05 were considered statistically significant.
maternal PIH and the risk of neonatal candidiasis in a population-
based retrospective cohort study.

Patients and methods

Data sources

The Taiwan National Health Insurance program was launched

since 1995 and the National Health Research Institute in Taiwan
established the National Health Insurance research database
(NHIRD). The data for the current study were extracted from the
Taiwan NHIRD, which covers more than 99% of the 23 million
Taiwanese residents. The International Classification of Diseases,
Ninth Revision, Clinical Modification (ICD-9-CM) was used for the
disease record system. The source data were encrypted to protect
privacy, and the data were accessed anonymously. This study was
approved by the Institutional Review Board of the Kaohsiung
Veteran's General Hospital (VGHKS15-EM4-01).

Study design and participants

Using a retrospective population-based cohort study design,

we identified two cohorts, PIH and matched groups, who were
aged 20e50 years between January 1, 2000, and December 31,
2013. The PIH group was defined as a new diagnosis of PIH based
on ICD-9-CM codes 642.3e642.6, which can be divided into
gestational hypertension (ICD-9-CM codes 642.3x), mild pre-
eclampsia (ICD-9-CM codes 642.4x), severe preeclampsia (ICD-9-
CM codes 642.5x), and eclampsia (ICD-9-CM codes 642.6x). To
ensure the validity of PIH diagnosis, only patients with inpatient
hospitalization were included. The index date for the patients in
the PIH group was the date of their first diagnosis of PIH. For
each patient with PIH, four insured enrollees, who did not have a
history of PIH and were matched for age and year of delivery,
were randomly retrieved from the NHIRD and included as the
matched group. All subjects were followed from the index date Fig. 1. Flow chart of the study design. PIH, pregnancy-induced hypertension.
 S.-N. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 261e265 263

Results using a design of comparison cohort over a 28-day follow-up period

of neonate. A higher incidence of neonatal candidiasis was observed
Characteristics of the study population among patients who had PIH than those in the control group. After
adjustment for covariates, PIH remained independently associated
The demographic characteristics and history of comorbidities in with an increased risk for developing neonatal candidiasis. More-
patients with PIH and matched subjects were demonstrated in over, preterm birth was an independent risk factor of neonatal
Table 1. A total of 145,065 participants were enrolled in this study, candidiasis.
including 29,013 subjects with PIH and 116,052 subjects as a Neonatal candidiasis has emerged as one of the leading cause of
matched cohort. The corresponding average ages of the PIH and late-onset infection in most neonatal intensive care units and is
matched cohorts were 30.96 and 30.83 years, respectively. In both associated with significant morbidity and mortality in the neo-
cohorts, most patients were aged 30 years (56.29%). The PIH nates. Neonatal candidiasis developed in 2.6%e16.7% of very low
cohort included a significantly higher percentage of single parity, birth weight infants (VLBW, less than 1500 g) and 5.5%e20% of
preterm birth, multiple births and cesarean section than the extremely low birth weight infants (ELBW, less than 1000 g)
matched cohort. Additionally, compared with the comparison [6,9,10]. The crude mortality related to neonatal candida infection
group, the PIH group exhibited a higher prevalence of DM, HTN, ranged from 10% to 54% [10e12]. Long-term neurodevelopmental
dyslipidemia, CAD, COPD, CKD, and cerebrovascular disease. impairments, including cerebral palsy, blindness, hearing impair-
ment, cognitive deficits, and periventricular leukomalacia occurs in
Incidence and risk factors of neonatal candidiasis nearly 60% of survivors [12,13]. C. albicans was reported the most
common pathogen of neonatal candidemia, followed by C. para-
The incidence of neonatal candidiasis was higher in PIH group psilosis [10]. Extreme prematurity is the strongest risk factor for
(0.69‰) than in matched cohort group (0.29‰). Table 2 presented developing neonatal candidiasis. Additionally, prolonged endotra-
the univariate and multivariate Cox proportional analyses. After cheal intubation, presence of central venous catheters, total
adjustment for age, parity, gestational age, gestational number, parenteral nutrition, administration of broad-spectrum antibiotics,
cesarean section and comorbidities, patients who experienced PIH and prolonged antibiotic therapy duration were associated with an
exhibited a 2.08-fold higher risk of neonatal candidiasis compared increased risk for the development of neonatal candidiasis [6,13,14].
to those without PIH (95% CI ¼ 1.11e3.91, p ¼ 0.0228). Furthermore, However, fluconazole prophylaxis, reduced use of broad-spectrum
single parity (OR ¼ 1.91, 95% CI ¼ 1.00e3.65, p ¼ 0.0499) and antibiotics, empirical antifungal therapy, and improved care of
preterm birth (OR ¼ 3.57, 95% CI ¼ 1.84e6.93, p ¼ 0.0002) were central venous catheters have contributed to the decreased inci-
independently correlated with an increased risk for the develop- dence of invasive candidiasis [15e17].
ment of neonatal candidiasis. Neonatal candidiasis generally occurs after the first 2 weeks of
life in the extreme prematurity of infants. Premature neonates are
Discussion predisposed to develop invasive candidiasis after colonized by
Candida after birth. Candida species are yeast that frequently
We present a population-based, retrospective cohort study to colonize skin, the gastrointestinal tract, and the female genitouri-
determine the risk of neonatal candidiasis in patients with PIH by nary tract [18] Premature infants, particularly those of VLBW, have a
poor skin barrier with few cornified layers and deficient dermal
proteins and is characterized by less skin functionality. Those could
Table 1 lead to an increased risk for skin damage and increased perme-
Baseline characteristics of patients with pregnancy-induced hypertension and
ability to exogenous agents and infection [19,20]. Furthermore, due
comparison cohort.
to an intrinsic immaturity of the enteric nervous system, the
Parameters PIH (n ¼ 29,013) Comparison p value motility of the small intestine is less organized in premature infants
cohort
than in term infants. This immature motility results in impaired
(n ¼ 116,052)
function of intestinal mucosal barrier and intestinal immune
n % n %
network, which makes premature neonates particularly susceptible
Age, years, mean ± SD 30.96 ± 5.04 30.84 ± 5.01 e to infection [21]. In addition, marked leukopenia of monocytes,
<30 12,681 43.71 50,724 43.71 granulocytes and lymphopenia of CD4þ T cells, CD8þ T cells, natural
30 16,332 56.29 65,328 56.29
Parity <0.0001
killer cells, and B cells were observed in preterm infants compared
1 17,819 61.42 67,437 58.11 to full-term infants [22,23]. The maturation of anti-microbial re-
2 11,194 38.58 48,615 41.89 sponses develops asynchronously in preterm neonates [24]. These
Gestational age <0.0001 also play a pivotal role in the increased frequency of infections in
Term 22,553 77.73 110,597 95.30
these neonates. Taken together, premature neonates show an
Preterm 6460 22.27 5455 4.70
Gestational number <0.0001 increased susceptibility to neonatal candidiasis, conceivably related
Singleton 27,316 94.15 113,949 98.19 to their defective physical barriers and immature immune system.
Multiple 1697 5.85 2103 1.81 Our study demonstrated that preterm neonates exhibited a 3.57-
Cesarean section <0.0001 fold increase in the incidence rate of neonatal candidiasis
Yes 21,574 74.36 42,288 36.44
No 7439 25.64 73,764 63.56
compared to term neonates (95% CI ¼ 1.84e6.93, p ¼ 0.0002).
Comorbidities The effect of PIH could be involved in the fetus because the
Diabetes mellitus 112 0.39 69 0.06 <0.0001 bioactive factors induced by placental ischemia might cross the
Hypertension 266 0.92 85 0.07 <0.0001 placental barrier into the fetal circulation [25,26]. It seems likely
Dyslipidemia 99 0.34 90 0.08 <0.0001
that maternal PIH could cause significant fetal immune system
Coronary artery disease 26 0.09 71 0.06 0.0938
COPD 36 0.12 66 0.06 <0.0001 derangements. CD4/CD8 T-cell ratio is significantly lower in fetuses
Chronic kidney disease 187 0.64 158 0.14 <0.0001 born to PIH mothers than fetuses born to healthy mothers [27e29].
Cerebrovascular disease 54 0.19 87 0.07 <0.0001 Neonates born to PIH mothers had decreased percentage of regu-
COPD, chronic obstructive pulmonary disease; PIH, pregnancy-induced hyperten- latory T cells and CD 8 þ 28þ T cells (cytotoxic) lymphocytes and
sion; SD, standard deviation. increased percentage CD 8 þ 28  T cells (suppressor) lymphocytes
264 S.-N. Chen et al. / Taiwanese Journal of Obstetrics & Gynecology 58 (2019) 261e265

Table 2
Analyses of risk factors for neonatal candidiasis among the patients with pregnancy-induced hypertension and comparison cohort.

Univariate analysis Multivariate analysisa

OR (95% CI) p value OR (95% CI) p value

PIH
Yes vs. No 2.36 (1.36e4.09) 0.0024 2.08 (1.11e3.91) 0.0228
Age, years
30 vs. <30 1.69 (0.95e3.00) 0.0733 1.46 (0.81e2.63) 0.2145
Parity
1 vs. 2 2.21 (1.19e4.13) 0.0126 1.91 (1.00e3.65) 0.0499
Gestational age
Preterm vs. Term 4.71 (2.63e8.45) <0.0001 3.57 (1.84e6.93) 0.0002
Gestational number
Singleton vs. Multiple 3.80 (1.51e9.54) 0.0045 2.02 (0.73e5.56) 0.1744
Cesarean section
Yes vs. No 1.14 (0.67e1.97) 0.6273

CI, confidence interval; OR, odds ratio; PIH, pregnancy-induced hypertension.

a
Adjusted for age, parity, gestational age, gestational number, cesarean section, and comorbidities, including diabetes mellitus, hypertension, dyslipidemia, coronary artery
disease, chronic kidney disease, chronic obstructive pulmonary disease, and cerebrovascular disease.

in comparison with neonates born to healthy women [27,28]. In In conclusion, this study showed that maternal PIH significantly
addition, maternal PIH is associated with a higher percentage of NK increase the incidence of neonatal candidiasis. Moreover, preterm
cells in umbilical cord blood of babies compared to normotensive birth is another important independent risk factor for neonatal
mothers [27,30]. Neonates born to mothers with PIH have a higher candidiasis.
alternative complement pathway activity and monocyte activation
than those born to mothers without PIH [31,32]. The alterations in Conflicts of interest statement
the immunological parameters of neonates born to PIH mothers can
be associated with fetal hypoxia [33] induced by placental ischemia. None.
Taken together, impairment of fetal immune system induced by
maternal PIH may result from fetal hypoxia induced by placenta
Submission declaration and verification
ischemia and may result in the increased possibility of neonatal
infection. The present study showed that a 2.08-fold increase in the
All the authors declare that we have not submitted this work for
incidence rate of neonatal candidiasis in the patients with PIH
publication elsewhere.
compared to those without PIH (95% CI ¼ 1.11e3.91, p ¼ 0.0228). An
8-year retrospective study conducted by Celebi et al. showed that
presence of maternal pre-eclampsia was one of the main predis- Acknowledgments
posing factors for neonatal candidemia with C. parapsilosis [8].
However, further studies are needed to confirm the results. This study was supported by grants (VGHKS15-EM4-01) from
This study showed that single parity seemed to be an indepen- Kaohsiung Veterans General Hospital and the Taiwan Health Pro-
dent risk factor for developing neonatal candidiasis. The study motion Administration. We are grateful for use of the National
conducted by Fievet et al. revealed that maternal parity influenced Health Insurance Research Database provided by Statistic Center of
the absolute numbers and activation status of cord blood antigen- Department of Health and Welfare. The interpretations and con-
presenting cells which is associated with neonatal innate immune clusions contained herein do not represent those of the Bureau of
responses [34]. However, no other literature proposed the similar Health Promotion, Taiwan.
result. Therefore, more studies are required to verify this finding.
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