Abstract
Objective
To understand the occurrence of atopic dermatitis (AD) in children aged 2 years on exposure to maternal group B streptococcus (GBS) antibiotic prophylaxis (IAP).
Design
Retrospective cohort study of 2909 mother–child pairs.
Setting
Taixing People’s Hospital in Eastern China.
Participants
Term infants born 2018–2019, followed longitudinally from birth to 2 years.
Exposures
The GBS-IAP was defined as therapy with intravenous penicillin G or ampicillin or cefazolin ≥ 4 h prior to delivery to the mother. Reference infants were defined as born without or with other intrapartum antibiotic exposure.
Outcomes
The logistic regression models were employed to analyze the effect of intrapartum GBS prophylaxis on AD in 2-year-old children during delivery. Analysis was a priori stratified according to the mode of delivery and adjusted for relevant covariates.
Results
The cohorts showed that preventive GBS-IAP was potentially associated with increased incidence of AD in children delivered vaginally according to logistic regression models before and after covariate-adjusted treatment (OR: 6.719,95% CI: 4.730–9.544,P < 0.001;aOR: 6.562,95% CI: 4.302–10.008, P < 0.001).
Conclusion
Prophylactic treatment of intrapartum GBS may raise the risk of AD in vaginally delivered children. These findings highlight the need to better understand the risk between childhood AD and current GBS-IAP intervention strategies.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12887-022-03758-5.
Keywords: Group B streptococcus, Intrapartum antibiotic prophylaxis, Atopic dermatitis
Highlights
► Maternal group B streptococcus antibiotic prophylaxis (GBS-IAP) was associated with the occurrence of atopic dermatitis in 2-year-old children with vaginal delivery.
► The findings were significant in vaginal delivery before and after adjusting for multiple covariates.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12887-022-03758-5.
Introduction
Research over the past decades has revealed the emergence of group B Streptococcus (GBS) is the leading cause of neonatal infections in China [1]. Intrapartum antibiotic prophylaxis (IAP) was initially introduced in the 1980s to lower the prevalence of perinatal GBS disease and offered to women with particular obstetric risk factors during parturition [2, 3]. The treatment of IAP has significantly diminished the incidence of neonatal GBS early-onset disease (GBS-EOD) in newborns [1, 4]. However, new research has shown that using maternal antibiotics during pregnancy increases the incidence of atopic dermatitis in offspring [5].
Atopic dermatitis (AD), a chronic and recurrent inflammatory skin disease that commonly occurs in infancy, is clinically characterized by intense itching and eczematous lesions, and its incidence has increased sharply over the past decade in response to lifestyle changes [6]. A multicentric study conducted between January and December 2014 showed that the overall point prevalence of AD in infants reached 30.48% in China [7]. Notably, previous studies evidenced the associations between the occurrence of allergic diseases and gut microbiota after cesarean section in children [8]. Recent reports also evidenced the shifts of neonatal gut microbiota when intrapartum antibiotics are administered [9, 10]. However, whether such antibiotic-mediated effects are related to childhood AD is unknown.
To better understand the association between GBS-IAP and AD in children, a retrospective cohort study was administrated in the present project by analyzing 2909 full-term newborns approximately 2 years old to establish a theoretical basis for formulating GBS intervention strategies in China.
Methods
Ethics approval and consent to participate
The study was approved by the Ethics Committees of Taixing People’s Hospital (Reference txry2018-003) in Jiangsu Province, China. Written informed consents were obtained from the parents of all the enrolled infants before data collection. All methods were carried out in accordance with relevant guidelines and regulations.
Design and setting
The subjects selected pregnant women and full-term newborns delivered in the present hospital from June 2018 to December 2019. A total of 3500 pregnant women were enrolled in the study. Among them, 320 were excluded from miscarriage and induced labor, 271 for incomplete information on mother–child pairs, and incomplete disease records. Finally, 2909 pairs of mother–child that met the criteria were included and divided into two cohorts, i.e. vaginal delivery, and cesarean section according to the mode of delivery.
Population
Healthy infants with a gestational age of > 37 weeks and a birth weight of > 2500 g were included in the study. The following criteria that may impact the exposure or outcome were excluded for the subjects (Fig. 1).
Fig. 1.
Design of study cohorts. The figure describes the process of inclusion and exclusion criteria for the selected pregnant women and infants
Data collection
A questionnaire was used to collect basic information on the pregnant women and newborns, including the data of age, weight, height, parity, mode of delivery, previous GBS colonization, allergies, smoking history, pet ownership, resident place, education level, antibiotic usage, and feeding patterns. A hospital record system was applicated to collect the data on GBS colonization and IAP intervention for pregnant mothers. GBS colonization was determined according to prenatal GBS-PCR.
Exposure
The intrapartum antibiotic prophylaxis (IAP) was defined that pregnant women with positive GBS screening were given antibiotic prophylaxis, by intravenous injection of penicillin G or ampicillin or cefazolin at an interval of ≥ 4 h prior to the labor delivery [11, 12]. All the pregnant women with positive GBS screening in this study received the IAP as recommended by national guidelines during the study period. All other forms of maternal antibiotic therapy were classified as “no GBS-IAP” antibiotic exposure, including non GBS-specific antibiotics, GBS-specific antibiotics administered < 4 h before delivery, and surgical prophylaxis administered to women undergoing cesarean delivery. The definition of exposure was applicated identically for both delivery cohorts. Notably, there was a number of 2.5% and 5.1% population from the vaginal birth C-S group were not received IAP treatment due to the refusion of the family member or other urgent issues. Besides, IAP was also given to those pregnant women with GBS positive on their first parity, although the current screen test was negative. Detail exposure issues were listed in Table 1.
Table 1.
Basic characteristics of the two groups of cohorts
| Basic situation | Vaginal birth (n = 1510) | Cesarean section (n = 1399) | ||||||
|---|---|---|---|---|---|---|---|---|
| No IAP (n = 1346) | GBS-IAP (n = 164) | t/χ 2 | P | No IAP (n = 1279) | GBS-IAP (n = 120) | t/χ 2 | P | |
| Mother’s age (years) | 27.3 ± 3.9 | 27.5 ± 4.1 | -0.379 | 0.414 | 29.0 ± 4.4 | 29.2 ± 4.5 | -0.382 | 0.702 |
| Mother’s BMI (x ± s) | 20.8 ± 1.6 | 21.0 ± 1.5 | -1.094 | 0.274 | 21.0 ± 1.8 | 21.0 ± 1.9 | -0.272 | 0.786 |
| Parity (n, %) | 5.733 | 0.017 | 2.521 | 0.112 | ||||
| One child | 724 (53.8) | 72 (43.9) | 596 (46.5) | 65 (54.1) | ||||
| Second child or more | 622 (46.2) | 92 (56.0) | 683 (53.4) | 55 (45.8) | ||||
| GBS Screening (n, %) | 1206.195 | < 0.001 | 730.014 | < 0.001 | ||||
| Positive | 33 (2.5) | 162 (98.7) | 65 (5.1) | 108 (90.0) | ||||
| Negative | 1313 (97.5) | 2 (1.3) | 1214 (94.9) | 12 (10.0) | ||||
| Mother’s allergy history (n, %) | 128 (9.5) | 12 (7.3) | 0.835 | 0.361 | 110 (8.6) | 14 (11.7) | 1.277 | 0.258 |
| Whether received higher education (n, %) | 1081 (80.3) | 132 (80.5) | 0.003 | 0.957 | 922 (72.1) | 91 (75.8) | 0.770 | 0.380 |
| Gender (man, n, %) | 702 (52.1) | 103 (62.8) | 6.662 | 0.010 | 711 (55.6) | 58 (48.3) | 2.334 | 0.127 |
| Gestational age (weeks x ± s) | 39.5 ± 1.0 | 39.2 ± 1.1 | 1.645 | 0.100 | 39.3 ± 1.0 | 39.4 ± 1.0 | -1.210 | 0.227 |
| Weight of birth (g x ± s) | 3362 ± 396 | 3416 ± 415 | -1.644 | 0.100 | 3462 ± 447 | 3542 ± 473 | -1.850 | 0.065 |
| Feeding method (n, %) | 10.846 | 0.004 | 1.336 | 0.113 | ||||
| Breast feeding | 1060 (78.7) | 138 (84.1) | 963 (75.2) | 96 (80.0) | ||||
| Artificial feeding | 12 (8.9) | 5 (3.0) | 24 (1.8) | 2 (1.7) | ||||
| Mixed feeding | 274 (20.4) | 21 (12.8) | 292 (22.8) | 22 (18.3) | ||||
| Whether used antibiotics in infant (n, %) | 92 (6.8) | 68 (41.4) | 185.044 | < 0.001 | 99 (7.7) | 46 (38.3) | 110.521 | < 0.001 |
| Incidence of atopic dermatitis in 2 years children (n, %) | 150 (11.1) | 75 (45.0) | 140.204 | < 0.001 | 163 (12.7) | 9 (7.5) | 3.370 | 0.185 |
BMI Body mass index, GBS Group B Streptococcus, IAP Intrapartum antibiotic prophylaxis
Outcome
The primary outcome was the occurrence of AD in infants. In this study, a questionnaire was enrolled to collect AD information from family members including the key question "Had the respondent ever been diagnosed with AD by a doctor or specialist?". The diagnostic of AD in infants was obtained by trained clinical staff according to Williams standards, and an infant was confirmed to have AD when > 3 criteria were present. Detailed criteria were listed in Supply Table 1.
Covariates
In addition to the exposure factors and mode of delivery, potential confounding factors that may affect outcomes were screened including genetic and environmental issues [1, 11–14]. A questionnaire was used to collect the covariates information of pregnant women and newborns including age, weight, height, parity, mode of delivery, previous GBS colonization, allergies, smoking history, pet ownership, resident place, education level, antibiotic usage, and feeding patterns. The data sources and definitions of model covariates were listed in Supply Table 1.
Statistical analysis
Initially, chi-square tests and one-way ANOVA were employed for comparison between groups of two cohorts. Then a univariate logistic regression model was performed to analyze the exposure and preselected risk factors for atopic dermatitis in children. To better evaluate the association between maternal IAP and AD in children, a multivariate logistic regression model was enrolled to adjust the confounding factors such as maternal age, maternal allergy history, parity, gestational age, neonatal birth weight, etc. The Data were imported into Epidata 3.0 database. SPSS 22.0 software was used for statistical analysis. The forest plots were drawn with R 4.1.3. Two-sided tests were employed with an inspection level set at α = 0.05.
Results
Overview of the cohorts
A total of 2909 mother–child pairs were included in the cohort study (Table 1). Of these, 1510 cases (52%) were delivered through the vagina and 1399 cases (48%) were by cesarean section. Furthermore, 368 pregnant mothers were screened positive for GBS with a colonization rate of 12.6%, with 284 (9.8%) receiving GBS-IAP, comprising 164 cases from the vaginal group and 120 cases from the cesarean section group.
Characteristics of the cohorts
Multiple characteristics of mother–child pairs were compared between the IAP and non-IAP groups in the two cohorts. As shown in Table 1, characteristics were detected across the vaginal birth cohorts in terms of breastfeeding rates, and antibiotics usage within 72 h after birth (Table 1). In the cohort of vaginal delivery, the IAP group had a higher rate of multipara compared with the control group. Moreover, the prenatal IAP group also had higher GBS-positive rate, frequent maternal breastfeeding, and higher antibiotic use within 72 h of birth in the vaginal delivery cohort (Table 1). In the cohort of cesarean section, significances were observed in the IAP group on primipara, GBS-positive rate, maternal breastfeeding and children were more likely to receive antibiotics use within 72 h after birth in this cohort (Table 1).
Outcome of the cohorts
Atopic dermatitis affected 397 (13.6%) of the children in the present cohorts, of which 225 (56.7%) were delivered vaginally and 172 (43.3%) were delivered by cesarean section (Table 1). To be specific, the GBS-IAP group had a higher incidence of atopic dermatitis (45% vs 11.1%) compared with the control group in the vaginal delivery cohort (p < 0.01). However, in cesarean delivery, the presence of AD was not associated with intrapartum GBS-IAP exposure (7.5% vs. 12.7%, p > 0.05).
Analysis of risk factors for atopic dermatitis
A univariate logistic regression model was initially performed to analyze the exposure and preselected risk factors for atopic dermatitis in children. Results showed that children exposed to GBS-IAP had an increased incidence of atopic dermatitis in the vaginal delivery cohort compared to those without GBS-IAP exposure (OR: 6.719, 95% CI: 4.730–9.544, Table 2). Particularly, the vaginal delivery cohort also revealed an association between childhood AD and other factors such as maternal allergy history (OR: 2.357, 95% CI: 1.575–3.527), mixed feeding rate (OR: 1.479, 95% CI: 1.061–2.061), parity (OR: 1.509, 95% CI: 1.134–2.007), and antibiotic usage (OR: 2.544, 95% CI: 1.793–3.609, Table 2). In the cohort of cesarean section, however, only maternal allergy history (OR: 1.721,95% CI: 1.061–2.792) was evidenced to be associated with the incidence of atopic dermatitis while no significance was observed between the GBS-IAP group and control group in 2 years children (OR: 0.555,95% CI: 0.276–1.117, Table 2).
Table 2.
Univariate logistic regression analysis of variables in the cohorts
| Variables | Vaginal delivery | Cesarean section | ||||
|---|---|---|---|---|---|---|
| OR | 95%CI | P | OR | 95%CI | P | |
| No IAP | Reference | Reference | ||||
| GBS-IAP | 6.719 | 4.730–9.544 | < 0.001 | 0.555 | 0.276–1.117 | 0.099 |
| Mothers age | 1.018 | 0.982–1.056 | 0.322 | 0.997 | 0.962–1.034 | 0.873 |
| Mothers without allergic history | Reference | Reference | ||||
| Mothers with allergic history | 2.357 | 1.575–3.527 | < 0.001 | 1.721 | 1.061–2.792 | 0.028 |
| One child | Reference | Reference | ||||
| Second child and more | 1.509 | 1.134–2.007 | 0.005 | 0.906 | 0.658–1.246 | 0.543 |
| Gestational age | 0.696 | 0.607–0.798 | < 0.001 | 1.135 | 0.965–1.335 | 0.127 |
| BMI | 0.976 | 0.894–1.065 | 0.584 | 0.964 | 0.881–1.054 | 0.421 |
| Weight of birth | 1.238 | 0.87–1.762 | 0.236 | 1.159 | 0.816–1.646 | 0.411 |
| Breast feeding | Reference | Reference | ||||
| Artificial feeding | 0.386 | 0.051–2.929 | 0.357 | 2.283 | 0.899–5.795 | 0.082 |
| Mixed feeding | 1.479 | 1.061–2.061 | 0.021 | 1.207 | 0.832–1.753 | 0.321 |
| No antibiotics used within 72 h | Reference | |||||
| Antibiotics used within 72 h | 2.544 | 1.793–3.609 | < 0.01 | 0.741 | 0.417–1.318 | 0.308 |
| No smoking | Reference | Reference | ||||
| Smoking | 1.420 | 0.933–2.161 | 0.102 | 1.012 | 0.593–1.728 | 0.966 |
| No keeping pets | Reference | Reference | ||||
| Keeping pets | 1.140 | 0.849–1.532 | 0.384 | 1.329 | 0.950–1.859 | 0.097 |
P value is for the comparison of the GBS IAP groups among vaginal and caesarean cohorts
OR Odds ratio, BMI Body mass index, GBS Group B Streptococcus, IAP Intrapartum antibiotic prophylaxis
In addition, we combined the cohorts and analyzed the total population as a whole group. Results showed that the key variable of GBS-IAP still influenced the occurrence of AD in infants (aOR: 2.953, 95% CI: 2,154–4.048, P < 0.001, Table 3). Notably, the vaginal delivery (aOR: 1.000) had a higher effect on AD compared with cesarean section (aOR: 0.794, p = 0.045) among the whole population without enrolling IAP as the factor. Then we compared the infant’s AD in those no GBS-IAP received populations according to the modes of delivery. After removing the GBS-IAP factor from the overall population cohort, there were no significant variances in the outcome of AD between the cohorts of vaginal delivery and cesarean section (Tables 4 and 5).
Table 3.
Multivariate logistic regression analysis of variables in the total 2909 mother–child pairs. The effect of GBS-IAP on AD outcomes remained after the vaginal and cesarean cohorts were combined
| Variables | B | Wald | P | aOR | 95%CI | |
|---|---|---|---|---|---|---|
| Mother’s age | -0.006 | 0.188 | 0.664 | 0.994 | 0.965 | 1.023 |
| Breast feeding | 7.937 | 0.019 | 1.000 | |||
| Artificial feeding | 0.117 | 0.073 | 0.787 | 1.124 | 0.483 | 2.613 |
| Mixed feeding | 0.371 | 7.936 | 0.005 | 1.449 | 1.120 | 1.876 |
| Weight of birth | 0.217 | 2.749 | 0.097 | 1.243 | 0.961 | 1.607 |
| Mothers without allergic history | 1.000 | |||||
| Mothers with allergic history | 0.690 | 17.949 | 0.000 | 1.993 | 1.449 | 2.743 |
| No keeping pets | 1.000 | |||||
| Keeping pets | 0.217 | 3.296 | 0.069 | 1.242 | 0.983 | 1.569 |
| One child | 1.000 | |||||
| Second child and more | 0.190 | 2.316 | 0.128 | 1.209 | 0.947 | 1.545 |
| Vaginal delivery | 1.000 | |||||
| Cesarean section | -0.231 | 4.023 | 0.045 | 0.794 | 0.634 | 0.995 |
| No IAP | 1.000 | |||||
| GBS-IAP | 1.083 | 45.273 | 0.000 | 2.953 | 2.154 | 4.048 |
| Gestational age | -0.128 | 5.125 | 0.024 | 0.880 | 0.788 | 0.983 |
| BMI | -0.032 | 0.952 | 0.329 | 0.969 | 0.909 | 1.033 |
| No smoking | 1.000 | |||||
| Smoking | 0.260 | 2.082 | 0.149 | 1.296 | 0.911 | 1.844 |
| No antibiotics used within 72 h | 1.000 | |||||
| Antibiotics used within 72 h | 0.115 | 0.468 | 0.494 | 1.121 | 0.808 | 1.557 |
See Supplementary Table 1 for definition of characteristic variable
aOR Adjusted odds ratio, BMI Body mass index, GBS Group B Streptococcus, IAP Intrapartum antibiotic prophylaxis
Table 4.
Comparison of AD in the no GBS-IAP received population by different modes of delivery
| Outcome | Mode of delivery | Statistical analysis | ||
|---|---|---|---|---|
| Vaginal birth (n = 1346) | Cesarean section (n = 1279) | χ 2 | P | |
| Without atopic dermatitis | 1196 | 1116 | 1.599 | 0.206 |
| With atopic dermatitis | 150 | 163 | ||
Table 5.
Comparison of AD in the no GBS-IAP received population. After removing the GBS-IAP factor from the overall population cohort, cesarean section had no effect on the outcome of AD compared with vaginal delivery
| Variables | B | Wald | P | aOR | 95%CI | |
|---|---|---|---|---|---|---|
| Mother’s age | 0.011 | 0.421 | 0.516 | 1.011 | 0.978 | 1.044 |
| Breast feeding | 8.826 | 0.012 | ||||
| Artificial feeding | 0.540 | 1.534 | 0.215 | 1.717 | 0.730 | 4.036 |
| Mixed feeding | 0.392 | 7.898 | 0.005 | 1.480 | 1.126 | 1.945 |
| Weight of birth | 0.203 | 1.963 | 0.161 | 1.225 | 0.922 | 1.626 |
| Mothers without allergic history | ||||||
| Mothers with allergic history | 0.720 | 16.738 | 0.000 | 2.055 | 1.455 | 2.901 |
| No keeping pets | ||||||
| Keeping pets | 0.268 | 4.348 | 0.037 | 1.308 | 1.016 | 1.683 |
| One child | ||||||
| Second child and more | 0.053 | 0.144 | 0.705 | 1.055 | 0.800 | 1.390 |
| Vaginal delivery | ||||||
| Cesarean section | 0.131 | 1.074 | 0.300 | 1.140 | 0.890 | 1.460 |
| Gestational age | 0.020 | 0.104 | 0.747 | 1.021 | 0.901 | 1.156 |
| BMI | -0.055 | 2.299 | 0.129 | 0.947 | 0.882 | 1.016 |
| No smoking | ||||||
| Smoking | -0.237 | 0.978 | 0.323 | 0.789 | 0.493 | 1.262 |
| No antibiotics used within 72 h | ||||||
| Antibiotics used within 72 h | 0.552 | 8.154 | 0.004 | 1.737 | 1.189 | 2.538 |
See Supplementary Table 1 for definition of characteristic variable
aOR Adjusted odds ratio, BMI Body mass index
Association between the risk factors and atopic dermatitis after adjustment
A multivariate logistic regression model was enrolled to explore the association between the cohorts and atopic dermatitis after covariates adjustment. The adjusted results revealed that the vaginal delivery cohort still had a higher occurrence of atopic dermatitis in children with GBS-IAP exposure (adjusted OR: 6. 562, 95% CI: 4.302–10.008, Table 6, Fig. 2). On the contrary, no significant risk factors were identified for atopic dermatitis in children without GBS-IAP exposure delivered by cesarean section (adjusted OR: 0.560, 95% CI: 0.271–1.155, Table 6, Fig. 2). In addition, the vaginal delivery cohort also witnessed the association between childhood AD and other factors in the multivariate logistic regression model including maternal allergy history (adjusted OR: 2.642, 95% CI: 1.699–4.109), mixed feeding rate (adjusted OR: 1.844, 95% CI: 1.281–2.655), and gestational age (adjusted OR: 0.758, 95% CI: 1.003–2.701) that relate to childhood AD. However, only maternal allergy history was evidenced to be associated with the occurrence of childhood AD in the cesarean section cohort (adjusted OR: 1.646, 95% CI: 1.003–2.701, Table 6, Fig. 2).
Table 6.
Multivariate logistic regression analysis of variables in the cohorts
| Variables | Vaginal delivery | Cesarean section | ||||
|---|---|---|---|---|---|---|
| aOR | 95%CI | P | aOR | 95%CI | P | |
| No IAP | Reference | Reference | ||||
| GBS-IAP | 6.562 | 4.302–10.008 | < 0.001 | 0.562 | 0.271–1.155 | 0.116 |
| Mothers age | 0.994 | 0.953–1.036 | 0.769 | 1.011 | 0.969–1.055 | 0.614 |
| Mothers without allergic history | Reference | Reference | ||||
| Mothers with allergic history | 2.642 | 1.699–4.109 | 0.000 | 1.645 | 1.003–2.701 | 0.049 |
| One child | Reference | Reference | ||||
| Second child and more | 1.495 | 1.074–2.081 | 0.017 | 0.986 | 0.664–1.472 | 0.954 |
| Gestational age | 0.758 | 0.653–0.879 | 0.000 | 1.172 | 0.977–1.4 | 0.087 |
| No smoking | Reference | Reference | ||||
| Smoking | 1.282 | 0.782–2.101 | 0.324 | 1.169 | 0.675–2.057 | 0.564 |
| BMI | 0.966 | 0.879–1.061 | 0.470 | 0.961 | 0.877–1.053 | 0.397 |
| Breast feeding | Reference | Reference | ||||
| Artificial feeding | 0.203 | 0.025–1.628 | 0.133 | 2.245 | 0.865–5.78 | 0.097 |
| Mixed feeding | 1.844 | 1.281–2.655 | 0.001 | 1.187 | 0.809–1.734 | 0.384 |
| No antibiotics used within 72 h | Reference | Reference | ||||
| antibiotics used within 72 h | 1.234 | 0.795–1.915 | 0.348 | 0.851 | 0.472–1.564 | 0.619 |
| No keeping pets | Reference | Reference | ||||
| Keeping pets | 1.276 | 0.92–1.77 | 0.144 | 1.282 | 0.905–1.831 | 0.161 |
See Supplementary Table 1 for definition of characteristic variable
aOR Adjusted odds ratio, BMI Body mass index, GBS Group B Streptococcus, IAP Intrapartum antibiotic prophylaxis
Fig. 2.
Forest plot for multivariate logistic regression analysis of outcomes. Blue square represents vaginal delivery and red symbol represents cesarean section. See Supplementary Table 1 for definition of characteristic variable. OR, odds ratio
Discussion
Previous studies have shown an association between postnatal antibiotic exposure and allergic disease in children, while fewer cases of atopic dermatitis were of concern in the context of presumed prenatal antibiotic use. Although there have been previous reports evaluating the association between antibiotic administration during pregnancy and atopic dermatitis in children, the association remains controversial [15–17]. A European cohort report conducted in 2019 revealed a positive association between antenatal antibiotic use and the appearance of AD in the first year of rural-born children [18]. Simultaneously, a prospective birth cohort in China also demonstrated that maternal antibiotic exposure was significantly associated with AD in postnatal childhood [5]. However, a recent meta-analysis claimed that no significant evidence that maternal antibiotic exposure in late pregnancy increases the risk of AD in infants [19].
To better explore the relationship between antibiotic exposure during pregnancy and the risk of atopic dermatitis in children, a retrospective cohort analysis was administrated in this study that identified that vaginal delivery significantly increased the AD risk in children exposed to GBS-IAP. Previous research reported that delivery mode had a greater impact on the establishment of neonatal gut microbiota after birth [13, 20]. Microbiota development was affected in infants born vaginally exposed to IAP for up to 6 months [21]. Specifically, exposure to IAP may change the microenvironment of colonized gut microbiota, leading to a reduction in commensal bacteria but the persistence of pathogenic microorganisms [22]. In the present study, we assumed that the GBS-IAP exposure might result in the disruption of gut microbiota and further influence the course of allergic diseases such as atopic dermatitis processes in childhood. GBS-IAP interventions are usually administered 4 h before delivery, which overlaps with the establishment of gut microbes in the first colonized neonate [17]. Such overlaps may affect the dysregulation of the gut microbiota throughout the neonatal period, and into infancy [23, 24].
Contrary to the cohort of vaginal delivery, no significant incidence of AD was observed in infants with IAP exposure at the time of cesarean delivery. Similar results were observed in previous studies which examined the associations between cesarean delivery and AD. Renz-Polster et al. reported that infants born via C-section without premature rupture of the membranes exhibit a reduction of AD compared with vaginal delivery [25]. Similarly, Kim et al. witnessed a decreased risk of AD among children born via planned C-section [26]. In addition, Rechard et al. demonstrated that the cesarean section was not associated with atopic dermatitis in 4-year-old children in a large cohort in the USA [27]. Such C-section delivery without exposure to maternal microbiome showed no relation to infants’ AD, and was neither affected by intrapartum antibiotics, breastfeeding, missing data, familial factors nor other indications [27]. Furthermore, another study also showed that delivery by cesarean section may cause food allergy in children, but not atopic dermatitis [28], which explained why the colonization of infant gut microbiome was less affected by cesarean section than vaginally born children.
In our study, we collected information on early postnatal antibiotic prophylaxis and postpartum feeding patterns. Our results showed that no significance of risk factors was observed in cesarean mothers compared with the vaginal delivery cohort, consistent with previous studies. This may be explained by the role of gut microbiota perturbation in the dysregulation of immune response and related allergic disorders [29, 30]. Specifically, infants born by vaginal delivery established the microbial communities that resemble maternal vaginal microbiota, whereas CS-delivered newborns obtained those non-maternal bacteria from the hospital environment [31]. Such delayed colonization of beneficial bacteria via CS delivery appeared to be the risk factors that predisposed infants to allergic manifestations. In addition, cesarean section may also affect maturation of immune system by altering stress levels at birth [29]. In contrast to the release of cortisol in fetal circulation with uterine contractions and fetal hypoxia during vaginal delivery, neonates delivered by CS lack the compounds for the maturation of the immune system [29]. This delayed immune maturation may contribute to the occurrence of AD. However, atopic dermatitis is the heterogeneous disorder that involved complex immune responses, environmental exposures, and barrier defects. We agreed with the previous study that an accurate association of CS on AD is unlikely to be revealed by alterations in the gut microbiota in observational studies like ours [28]. Further research is required to illustrate the risk factors of AD by CS delivery.
However, among the studies that evaluated the association between antibiotic administration during pregnancy and allergic disease in infants, Lee et al. and Timm et al. reported a significant connection between prenatal antibiotic exposure and AD in Korean and Danish cohorts [32, 33]. Those children born by cesarean section showed a superior impact on the occurrence of AD. This may be explained by the fact that maternal diseases such as asthma were one of the risk factors for atopic dermatitis, and mothers with asthma were recommended for cesarean section [32]. In this study, only a small proportion (7.3% to 11.7%) of the enrolled pregnant women were reported to have allergy history. After excluding maternal disease bias, we adjusted for AD-related variables and not observed a significant association between the infants’ AD in cesarean mothers who received GBS-IAP.
The antimicrobials administered in this study were narrow-spectrum antibiotics, which may lead to changes in the composition and diversity of gut microbiota during the perinatal period. After therapy with the narrow-spectrum penicillin, Nogacka and Aloisio found a decrease in symbiotic bacteria but an increase in pathogen abundance in infants [34, 35]. Taipianen revealed that the effect size of IAP was comparable to that caused by postnatal antibiotics in newborn infants [36]. When narrow-spectrum antibiotics were given to pregnant women, the effects on the newborn gut microbiota were comparable to when broad-spectrum antibiotics were given directly to neonates. Moreover, Cox reported that postnatal administration of low-dose penicillin induces metabolic changes and affects the ileal expression of immune-related genes [37].
Other genetic and environmental factors, such as the history of family allergic disease, climate change, passive smoking, pet ownership, and other confounding factors, were believed to be connected with the incidence of atopic dermatitis [38]. To better adjust the logistic regression model, these indicators, initially screened by univariate logistic regression, were selected for multivariate regression analysis. The adjusted results showed that maternal history of allergic disease and IAP exposure was an independent risk factor. Parental allergic disease may affect skin barrier function and immune homeostasis, leading to a variety of immunological abnormalities [39]. Other studies have reported that pet ownership and smoking may be linked with the development of atopic dermatitis in children, however, this was not found in our study [40–42].
There are some limitations to this study. First, this study was a retrospective analysis but relied on parental feedback on a diagnosis of atopic dermatitis. To better reduced the recall bias caused by parental feedback, we designed this unified questionnaire, with clear definitions and objective standards for every measurement indicator. Second, we trained the investigator to fully understand the purpose and connotation of each question with the essential skills of collecting information. Third, we obtained the outcome information parallelly for both exposed and non-exposed populations via the same methodology to reduce the shortcomings of retrospective studies. In addition, the lack of detailed information on the parents was noticed, including a family history of allergies, and smoking history. Finally, given to the low rates of GBS colonization in this region, the smaller population receiving GBS-IAP may have influenced the outcome. Therefore, a prospective large-sample study will be established to collect the feces of newborns after IAP intervention and send for metagenome sequence. A longitudinal study will be conducted to investigate the impact of IAP on children to better understand the risks and benefits of the current GBS-IAP intervention strategies.
Conclusion
GBS-IAP intervention for pregnant mothers significantly increased the incidence of AD in children aged 2 years in vaginal delivery.
Supplementary Information
Additional file 1: Supply Table 1. Information, data sources and definitions of model covariates.
Acknowledgements
Not applicable.
Authors’ contributions
ZH and RJ designed and organized the performance of the study; DX and YX guided and instructed the data analysis. ZH and RJ performed the study, collected and analyzed the data; LH, XK, ZC, WY and ZB participated in the table and figure analysis. ZH and RJ wrote the manuscript. DX and YX revised the manuscript. The author(s) read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on a reasonable request.
Declarations
Ethics approval and consent to participate
The study was approved by the Ethics Committees of Taixing People’s Hospital (Reference txry2018-003) in Jiangsu Province, China. Written informed consents were obtained from the parents of all the enrolled infants before data collection. All methods were carried out in accordance with relevant guidelines and regulations.
Consent for publication
Not applicable.
Competing interests
The authors declare no conflicts of interest.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Zhang Hong and Ren Jing contributed equally to this work.
Contributor Information
Ding Xin, Email: dingxin@suda.edu.cn.
Yin Xiaoping, Email: ryyxp123@163.com.
References
- 1.Zhu Y, Huang J, Lin XZ, Chen C. Group B streptococcus colonization in late pregnancy and invasive infection in neonates in China: a population-based 3-year study. Neonatology. 2019;115(4):301–309. doi: 10.1159/000494133. [DOI] [PubMed] [Google Scholar]
- 2.Hasperhoven GF, Al-Nasiry S, Bekker V, Villamor E, Kramer B. Universal screening versus risk-based protocols for antibiotic prophylaxis during childbirth to prevent early-onset group B streptococcal disease: a systematic review and meta-analysis. BJOG. 2020;127(6):680–691. doi: 10.1111/1471-0528.16085. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Braye K, Ferguson J, Davis D, Catling C, Monk A, Foureur M. Effectiveness of intrapartum antibiotic prophylaxis for early-onset group B Streptococcal infection: an integrative review. Women Birth. 2018;31(4):244–253. doi: 10.1016/j.wombi.2017.10.012. [DOI] [PubMed] [Google Scholar]
- 4.Brigtsen AK, Jacobsen AF, Dedi L, Melby KK, Espeland CN, Fugelseth D, Whitelaw A. Group B Streptococcus colonization at delivery is associated with maternal peripartum infection. PLoS One. 2022;17(4):e0264309. doi: 10.1371/journal.pone.0264309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Gao X, Yan Y, Zeng G, Sha T, Liu S, He Q, Chen C, Li L, Xiang S, Li H, Tan S, Yan Q. Influence of prenatal and early-life exposures on food allergy and eczema in infancy: a birth cohort study. BMC Pediatr. 2019;19(1):239. doi: 10.1186/s12887-019-1623-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387(10023):1109–1122. doi: 10.1016/S0140-6736(15)00149-X. [DOI] [PubMed] [Google Scholar]
- 7.Guo Y, Zhang H, Liu Q, Wei F, Tang J, Li P, Han X, Zou X, Xu G, Xu Z, Zong W, Ran Q, Xiao F, Mu Z, Mao X, Ran N, Cheng R, Li M, Li C, Luo Y, Meng C, Zhang X, Xu H, Li J, Tang P, Xiang J, Shen C, Niu H, Li H, Shen J, Ni C, Zhang J, Wang H, Ma L, Bieber T, Yao Z. Phenotypic analysis of atopic dermatitis in children aged 1–12 months: elaboration of novel diagnostic criteria for infants in China and estimation of prevalence. J Eur Acad Dermatol Venereol. 2019;33(8):1569–1576. doi: 10.1111/jdv.15618. [DOI] [PubMed] [Google Scholar]
- 8.Akagawa S, Kaneko K. Gut microbiota and allergic diseases in children. Allergol Int. 2022;71(3):301–309. doi: 10.1016/j.alit.2022.02.004. [DOI] [PubMed] [Google Scholar]
- 9.Corvaglia L, Tonti G, Martini S, Aceti A, Mazzola G, Aloisio I, Di Gioia D, Faldella G. Influence of intrapartum antibiotic prophylaxis for group B Streptococcus on gut microbiota in the first month of life. J Pediatr Gastroenterol Nutr. 2016;62(2):304–308. doi: 10.1097/MPG.0000000000000928. [DOI] [PubMed] [Google Scholar]
- 10.Bokulich NA, Chung J, Battaglia T, Henderson N, Jay M, Li H, Lieber AD, Wu F, Perez-Perez GI, Chen Y, Schweizer W, Zheng X, Contreras M, Dominguez-Bello MG, Blaser MJ. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med. 2016;8(343):343ra82. doi: 10.1126/scitranslmed.aad7121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Puopolo KM, Lynfield R, Cummings JJ, Hand I, Adams-Chapman I, Poindexter B, Stewart DL, Aucott SW, Goldsmith JP, Mowitz M, Watterberg K. Management of infants at risk for group B streptococcal disease [published correction appears in Pediatrics. 2019;144(4):] Pediatrics. 2019;144(2):e20191881. doi: 10.1542/peds.2019-1881. [DOI] [PubMed] [Google Scholar]
- 12.Nair IS. Prevention of group B streptococcal early-onset disease in newborns: ACOG Committee Opinion, Number 797. Obstet Gynecol. 2020;135(2):e51–72. doi: 10.1097/AOG.0000000000003334. [DOI] [PubMed] [Google Scholar]
- 13.Han P, Gu J-Q, Li L-S, Wang X-Y, Wang H-T, Wang Y, Chang C, Sun J-L. The association between intestinal bacteria and allergic diseases—cause or consequence? Front Cell Infect Microbiol. 2021; 284. 10.3389/fcimb.2021.650893. [DOI] [PMC free article] [PubMed]
- 14.Williams HC, Burney PG, Hay RJ, et al. The U.K. Working Party’s diagnostic criteria for atopic dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994;131(3):383–396. doi: 10.1111/j.1365-2133.1994.tb08530.x. [DOI] [PubMed] [Google Scholar]
- 15.Mubanga M, Lundholm C, D’Onofrio BM, Stratmann M, Hedman A, Almqvist C. Association of early life exposure to antibiotics with risk of atopic dermatitis in Sweden. JAMA Netw Open. 2021;4(4):e215245. doi: 10.1001/jamanetworkopen.2021.5245. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Baron R, Taye M, der Vaart IB, Ujčič-Voortman J, Szajewska H, Seidell JC, Verhoeff A. The relationship of prenatal antibiotic exposure and infant antibiotic administration with childhood allergies: a systematic review. BMC Pediatr. 2020;20(1):312. doi: 10.1186/s12887-020-02042-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Dhudasia MB, Spergel JM, Puopolo KM, Koebnick C, Bryan M, Grundmeier RW, Gerber JS, Lorch SA, Quarshie WO, Zaoutis T, Mukhopadhyay S. Intrapartum group B streptococcal prophylaxis and childhood allergic disorders. Pediatrics. 2021;147(5):e2020012187. doi: 10.1542/peds.2020-012187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Metzler S, Frei R, Schmaußer-Hechfellner E, von Mutius E, Pekkanen J, Karvonen AM, Kirjavainen PV, Dalphin JC, Divaret-Chauveau A, Riedler J, Lauener R, Roduit C, PASTURE/EFRAIM study group Association between antibiotic treatment during pregnancy and infancy and the development of allergic diseases. Pediatr Allergy Immunol. 2019;30(4):423–433. doi: 10.1111/pai.13039. [DOI] [PubMed] [Google Scholar]
- 19.Huang FQ, Lu CY, Wu SP, Gong SZ, Zhao Y. Maternal exposure to antibiotics increases the risk of infant eczema before one year of life: a meta-analysis of observational studies. World J Pediatr. 2020;16(2):143–151. doi: 10.1007/s12519-019-00301-y. [DOI] [PubMed] [Google Scholar]
- 20.Akagawa S, Tsuji S, Onuma C, Akagawa Y, Yamaguchi T, Yamagishi M, Yamanouchi S, Kimata T, Sekiya SI, Ohashi A, Hashiyada M. Effect of delivery mode and nutrition on gut microbiota in neonates. Ann Nutr Metab. 2019;74(2):132–139. doi: 10.1159/000496427. [DOI] [PubMed] [Google Scholar]
- 21.Garcia VR. Impact of intrapartum antibiotic prophylaxis for group B Streptococcus on the term infant gut microbiome: a state of the science review. J Midwifery Womens Health. 2021;66(3):351–359. doi: 10.1111/jmwh.13245. [DOI] [PubMed] [Google Scholar]
- 22.Vangay P, Ward T, Gerber JS, Knights D. Antibiotics, pediatric dysbiosis, and disease. Cell Host Microbe. 2015;17(5):553–564. doi: 10.1016/j.chom.2015.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Shao Y, Forster SC, Tsaliki E, Vervier K, Strang A, Simpson N, Kumar N, Stares MD, Rodger A, Brocklehurst P, Field N, Lawley TD. Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth. Nature. 2019;574(7776):117–121. doi: 10.1038/s41586-019-1560-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, Gordon JI. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402):222–227. doi: 10.1038/nature11053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Renz-Polster H, David MR, Buist AS, Vollmer WM, O’Connor EA, Frazier EA, Wall MA. Caesarean section delivery and the risk of allergic disorders in childhood. Clin Exp Allergy. 2005;35(11):1466–1472. doi: 10.1111/j.1365-2222.2005.02356.x. [DOI] [PubMed] [Google Scholar]
- 26.Kim HI, Nam S, Park Y, Jung YJ, Kim HY, Kim KW, Sohn MH, Kim YH, Lee JH, Hong SJ, Kwon JY. Cesarean section does not increase the prevalence of allergic disease within 3 years of age in the offsprings. Obstet Gynecol Sci. 2019;62(1):11–18. doi: 10.5468/ogs.2019.62.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Richards M, Ferber J, Chen H, Swor E, Quesenberry CP, Li DK, Darrow LA. Caesarean delivery and the risk of atopic dermatitis in children. Clin Exp Allergy. 2020;50(7):805–814. doi: 10.1111/cea.13668. [DOI] [PubMed] [Google Scholar]
- 28.Papathoma E, Triga M, Fouzas S, Dimitriou G. Cesarean section delivery and development of food allergy and atopic dermatitis in early childhood. Pediatr Allergy Immunol. 2016;27(4):419–424. doi: 10.1111/pai.12552. [DOI] [PubMed] [Google Scholar]
- 29.Cho CE, Norman M. Cesarean section and development of the immune system in the offspring. Am J Obstet Gynecol. 2013;208(4):249–254. doi: 10.1016/j.ajog.2012.08.009. [DOI] [PubMed] [Google Scholar]
- 30.Siggers RH, Thymann T, Jensen BB, Mølbak L, Heegaard PM, Schmidt M, Buddington RK, Sangild PT. Elective cesarean delivery affects gut maturation and delays microbial colonization but does not increase necrotizing enterocolitis in preterm pigs. Am J Physiol Regul Integr Comp Physiol. 2008;294(3):R929–R938. doi: 10.1152/ajpregu.00705.2007. [DOI] [PubMed] [Google Scholar]
- 31.Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107(26):11971–11975. doi: 10.1073/pnas.1002601107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Timm S, Schlünssen V, Olsen J, Ramlau-Hansen CH. Prenatal antibiotics and atopic dermatitis among 18-month-old children in the Danish National Birth Cohort. Clin Exp Allergy. 2017;47(7):929–936. doi: 10.1111/cea.12916. [DOI] [PubMed] [Google Scholar]
- 33.Lee SY, Yu J, Ahn KM, Kim KW, Shin YH, Lee KS, Hong SA, Jung YH, Lee E, Yang SI, Seo JH, Kwon JW, Kim BJ, Kim HB, Kim WK, Song DJ, Jang GC, Shim JY, Lee SY, Kwon JY, Choi SJ, Lee KJ, Park HJ, Won HS, Yoo HS, Kang MJ, Kim HY, Hong SJ. Additive effect between IL-13 polymorphism and cesarean section delivery/prenatal antibiotics use on atopic dermatitis: a birth cohort study (COCOA) PLoS One. 2014;9(5):e96603. doi: 10.1371/journal.pone.0096603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Nogacka A, Salazar N, Suárez M, Milani C, Arboleya S, Solís G, Fernández N, Alaez L, Hernández-Barranco AM, de Los Reyes-Gavilán CG, Ventura M, Gueimonde M. Impact of intrapartum antimicrobial prophylaxis upon the intestinal microbiota and the prevalence of antibiotic resistance genes in vaginally delivered full-term neonates. Microbiome. 2017;5(1):93. doi: 10.1186/s40168-017-0313-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Aloisio I, Quagliariello A, De Fanti S, Luiselli D, De Filippo C, Albanese D, Corvaglia LT, Faldella G, Di Gioia D. Evaluation of the effects of intrapartum antibiotic prophylaxis on newborn intestinal microbiota using a sequencing approach targeted to multi hypervariable 16S rDNA regions. Appl Microbiol Biotechnol. 2016;100(12):5537–5546. doi: 10.1007/s00253-016-7410-2. [DOI] [PubMed] [Google Scholar]
- 36.Tapiainen T, Koivusaari P, Brinkac L, Lorenzi HA, Salo J, Renko M, Pruikkonen H, Pokka T, Li W, Nelson K, Pirttilä AM, Tejesvi MV. Impact of intrapartum and postnatal antibiotics on the gut microbiome and emergence of antimicrobial resistance in infants. Sci Rep. 2019;9(1):10635. doi: 10.1038/s41598-019-46964-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, Kim SG, Li H, Gao Z, Mahana D, Zárate Rodriguez JG, Rogers AB, Robine N, Loke P, Blaser MJ. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158(4):705–721. doi: 10.1016/j.cell.2014.05.052. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Brown S, Reynolds NJ. Atopic and non-atopic eczema. BMJ. 2006;332(7541):584–588. doi: 10.1136/bmj.332.7541.584. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Guo Y, Li P, Tang J, Han X, Zou X, Xu G, Xu Z, Wei F, Liu Q, Wang M, Xiao F, Zong W, Shen C, Li J, Liu J, Luo Y, Chang J, Sheng N, Dong C, Zhang D, Dai X, Zhou J, Meng C, Niu H, Shi X, Zhang X, Xiang J, Xu H, Ran Q, Zhou Y, Li M, Zhang H, Cheng R, Gao X, Wang H, Gu H, Ma L, Yao Z. Prevalence of atopic dermatitis in Chinese children aged 1–7 ys. Sci Rep. 2016;6:29751. doi: 10.1038/srep29751. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160(1):1–9. doi: 10.1111/j.1365-2249.2010.04139.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Langan SM, Flohr C, Williams HC. The role of furry pets in eczema: a systematic review. Arch Dermatol. 2007;143(12):1570–1577. doi: 10.1001/archderm.143.12.1570. [DOI] [PubMed] [Google Scholar]
- 42.Fotopoulou M, Iordanidou M, Vasileiou E, Trypsianis G, Chatzimichael A, Paraskakis E. A short period of breastfeeding in infancy, excessive house cleaning, absence of older sibling, and passive smoking are related to more severe atopic dermatitis in children. Eur J Dermatol. 2018;28(1):56–63. doi: 10.1684/ejd.2017.3165. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Additional file 1: Supply Table 1. Information, data sources and definitions of model covariates.
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on a reasonable request.