Cesarean Delivery on Maternal Request and Common Child Health Outcomes: A Prospective Cohort Study

doi:10.21203/rs.3.rs-689896/v1

Cesarean delivery (CD) versus vaginal delivery was reported to increase the risks of childhood obesity, pneumonia, anemia, and neurobehavioral disorders, but few studies were able to deal with the confounding biases associated with medical conditions indicating cesareans. This prospective cohort study aims to investigate the associations of non-medically indicated CD on maternal request (CDMR) with multiple child health outcomes. Among live-born infants whose mothers participated in a randomized controlled trial on micronutrient supplementation and pregnancy outcomes during 2006-2009 in 5 rural counties in Hebei Province, China, 6972 singletons born by full-term spontaneous vaginal delivery (SVD) and 3626 by CDMR were selected and followed up at 1.5-5 years in 2011. The primary outcome was obesity, defined as a weight-for-height z-score >3. The secondary outcomes included self-reported pneumonia, anemia defined as hemoglobin <110 g/L, and neurobehavioral disorders identified by Child Behavior Checklist and Bayley Scales of Infant Development. Compared with SVD, CDMR was associated with increased risks of obesity (adjusted odds ratio [aOR] 1.41; 95% confidence interval [CI] 1.14-1.75) and anemia (aOR 1.65; 95% CI 1.28-2.12), but not with the risk of pneumonia (aOR 1.16; 95% CI 0.94-1.45) or neurobehavioral disorders (aORs varied from 0.82 to 1.13) in childhood. Conclusion: CD, independent of cesarean indications, is likely associated with childhood obesity and anemia, indicating a need to keep pregnant women informed, especially those seeking CDMR, a need to explore possible improvement on obstetric service, and even a need for main stakeholders to reach a compromise in making a cesarean decision.

Pediatrics

Cesarean delivery on maternal request

children

obesity

pneumonia

anemia

neurobehavioral disorder

Cesarean delivery was reported to associate with some adverse child health outcomes, but confounding biases related to cesarean indications might exist. A further study focusing on non-medically indicated cesarean delivery on maternal request (CDMR) is warranted.

CDMR versus vaginal delivery was associated with increased risks of childhood obesity and anemia, indicating a need for main stakeholders to be informed and a compromise after considering the responsibilities, benefits and potential risks when making a cesarean decision, particularly for CDMR.

Cesarean delivery (CD) is either medically or non-medically indicated. Medically indicated CD is clinically necessary to ensure the safety of mothers and infants, but for non-medically indicated CD, its potential benefits may not outweigh risks. For women who experienced CD, the risks of uterine rupture, abnormal placentation, or stillbirth in their subsequent pregnancy are significantly elevated [1]. In addition, some studies have linked CD to childhood obesity, pneumonia, anemia, and neurobehavioral disorders [2-5], but most of them were unable to distinguish between medically and non-medically indicated CD as compared with vaginal delivery (VD), leading to unavoidable biases associated with medical conditions indicating cesareans. For example, macrosomia not only indicates CD but also increases the risk of offspring obesity, likely confounding the association of CD with offspring obesity [6]. Up to now, whether CD has impacts on child health independent of indications is far from determined. Given the growing use of CD worldwide, particularly what is beyond medical necessity, its impacts on child health are widely concerned [7]. To address this concern, a study focusing on CD on maternal request (CDMR), a full-term singleton CD in the absence of any medical or obstetric indications, is warranted, but few studies have been able to identify CDMR in the current medical coding classification systems [8].

To fill the gap, we conducted a large-scale prospective cohort study in China to investigate the associations of CDMR with multiple adverse child health outcomes that were previously suggested, including obesity, pneumonia, anemia, and some neurobehavioral disorders. The prespecified hypotheses is that CDMR is associated with increased risks of these childhood conditions. The study is highly merited in a public health perspective, not only because these childhood conditions are common and their impacts on health are long-lasting, but also because CDMR is very likely avoidable [9; 10].

Study setting and design

This prospective cohort study was conducted based on a randomized controlled trial implemented in 5 rural counties in Hebei Province, China. In the original trial, a total of 18 775 primiparas with hemoglobin >100 g/L prior to their 20^th gestational week were recruited from May 2006 to April 2009, and randomly assigned to supplement folic acid, iron-folic acid, or multiple micronutrients from early pregnancy to delivery. Study details have been described elsewhere [11]. In 2011, all live singletons with known delivery mode were followed up prospectively for a physical examination, nearly half of children were screened for anemia, and two subgroups were further selected via stratified sampling (Online Resource Text 1) for neurobehavioral assessments. Both the original trial and the follow-up study were approved by the Peking University Health Science Center Institutional Review Board with identifiers of NCT00133744 and NCT01404416 on clinicaltrials.gov, respectively. All participants provided written informed consent.

Exposures, outcomes, and covariates

Delivery mode, the exposure of interest, was defined based on related information in the medical records. The original delivery modes were categorized as spontaneous vaginal delivery (SVD), assisted vaginal delivery (AVD; assisted breech, breech extraction, vacuum extraction, or forceps), elective CD (before the onset of labor), emergency CD (after the onset of labor), or others. For CD, indications were delineated as fetal distress, cephalopelvic disproportionate, breech presentation, transverse lie, maternal complications, previous CD, maternal request, or other factors. To implement the current study, SVD and CDMR (full-term elective CD indicated by maternal request without premature rupture of membranes) were selected from the available population based on abovementioned delivery mode and cesarean indications, as well as gestational age and membrane status [8]. To enhance the comparability of SVD with CDMR, participants in the SVD group were also restricted to full-term births.

The primary outcome of this study was obesity at 1.5-5.0 years, and the secondary outcomes included pneumonia, anemia, and internalizing (emotional)/externalizing (behavioral)/total problems at 1.5-5.0 years, as well as mental/psychomotor delay at 1.5-2.5 years. Child’s height and weight were measured by trained physicians at township health centers using a tailored height board with precision to the nearest 0.1 cm and an electronic scale (BW-150, UWE, Beijing, China) to the nearest 50 g, respectively. Height boards and scales were periodically calibrated. Obesity was defined as weight-for-height greater than 3 standard deviations above the World Health Organization Child Growth Standards median [12]. Pneumonia was confirmed if the caregiver reported that the child had been diagnosed with pneumonia by hospitals of township level or above. Children’s hemoglobin was tested using a photometric instrument (Model 201; HemoCue). Anemia was defined as hemoglobin <110 g/L. Besides, Child Behavior Checklist (CBCL) and Bayley Scales of Infant Development (BSID) were used to assess the neurobehavioral development. CBCLs were filled out by caregivers and BSID by specialized trained physicians. The clinical range for internalizing/externalizing/total problems in CBCL referred to raw score larger than the 90^th percentile of the normative sample [13]. Children with mental/psychomotor developmental index less than 70 in BSID were perceived to have mental/psychomotor delay [14]. Detailed interpretation of these scores is shown in the Online Resource Text 2.

Most of covariates were extracted from the database of the original trial, including supplements received during pregnancy, maternal age at delivery, education, occupation, gestational age, body mass index (BMI) in the 1^st trimester, gestational weight gain (GWG) rate in the 2^nd/3^rd trimester [15], hemoglobin in mid-pregnancy, level of delivery hospital, child’s gender, and birth weight. Child’s age at the follow-up visit, feeding pattern before 6 months old, and medical insurance status were derived from the follow-up questionnaire.

Statistical analysis

All analyses were performed by R (4.0.3). The P values were considered significant at <0.05 (two-sided). Continuous variables are presented as means and standard deviations or as medians and interquartile ranges, and categorical variables as frequencies and percentages. Differences between the CDMR and the SVD groups were examined using Student’s t-test or Mann-Whitney U test for continuous variables and chi-square test for categorical variables. To study the association of CDMR with mental delay (incidence rate >10%), relative risks (RRs) and their 95% confidence intervals (CIs) were estimated using Poisson regression with robust error variance, while for other outcomes (incidence rate <10%), odds ratios (ORs) and 95% CIs were estimated using multivariable logistic regression. For all outcomes, models were adjusted for maternal age at delivery (year, continuous), education (≤primary, secondary, or ≥high school), occupation (farmer or not), gestational age (week, continuous), BMI in the 1^st trimester (<18.5, 18.5-22.9, 23.0-27.4, or ≥27.5 kg/m², cut-offs for Asians) [16], GWG rate (kg/week, in quintiles), micronutrient supplementation during pregnancy (folic acid, iron-folic acid, or multiple micronutrients), level of delivery hospital (provincial/city, county/district, or township/village level), and medical insurance status (yes or no); child’s gender (male or female), birth weight (g, continuous), age at the follow-up visit (month, continuous), and feeding pattern before 6 months old (exclusive breastfeeding, mixed feeding, or formula feeding). Besides, maternal anemia in mid-pregnancy (yes or no) was additionally adjusted for childhood anemia and neurobehavioral disorders. The proportion of missing information on these covariates was ≤6%. Missing data on GWG rate were first imputed with median and then made into categories. Participants with missing information on maternal anemia, level of delivery hospital, feeding pattern, and medical insurance status were incorporated into the category with the highest proportion.

To examine the robustness of the analyses, we further conducted two sets of sensitivity analyses. First, a complete-case analysis was performed using pairwise deletion on missing covariates. Second, for obesity, pneumonia, and anemia, comparisons of intent were made between full-term planned VD and planned CDMR with covariates imputed, as recommended by the 2006 National Institutes of Health Consensus panel [8]. The original intention for post-labor CD indicated by fetal distress or other factors was presumable VD. Therefore, the planned VD group consisted of SVD, AVD, and this subgroup of post-labor CD at term. Planned CDMR included full-term pre-/post-labor CD indicated by maternal request (Online Resource Fig. 1).

As outlined in Fig. 1, of the 17 748 live singletons in the original trial, 8258 children delivered by SVD at term and 4195 children delivered by CDMR were identified as potential cohort participants. Among them, 960 (7.7%) permanently moved, 78 (0.6%) dropped out, and 19 (0.2%) died prior to the start of this study. Of the remaining, 798 (6.4%) declined to participate. After excluding those without information on outcomes, 10 418 and 10 298 children were finally included in the analyses for obesity and pneumonia. A total of 4758, 2317, and 860 children who had available outcomes remained in the analyses for anemia, CBCL, and BSID, respectively. Maternal and offspring characteristics of the included and the excluded are presented in Online Resource Table 1. The characteristics by delivery mode are shown in Table 1 and Online Resource Table 2. Compared with women undergoing SVD, those undergoing CDMR were more likely to be overweight/obese in the 1^st trimester and deliver in township/village hospitals.

Primary outcome

In this cohort, 6854 (65.8%) children were born by SVD and 3564 (34.2%) by CDMR, among which 397 (3.8%) were obese. Children born by CDMR were more likely to be obese than those born by SVD (4.5% vs 3.5%, P=0.009; crude OR, 1.31; 95% CI, 1.07-1.61; Table 2). After multivariable adjustment, the OR was slightly increased to 1.41 (95% CI, 1.14-1.75).

Secondary outcomes

The overall prevalence was 4.0% for pneumonia, 6.4% for anemia, 9.7% for internalizing problems, 3.9% for externalizing problems, 4.7% for total problems, 37.4% for mental delay, and 7.9% for psychomotor delay. Compared with SVD, CDMR was associated with a higher risk of anemia in childhood (7.6% vs 5.1%, P<0.001; adjusted OR, 1.65; 95% CI, 1.28-2.12). There was no significant difference when comparing the risk of pneumonia (4.2% vs 3.9%, P=0.50; adjusted OR, 1.16; 95% CI, 0.94-1.45), internalizing problems (8.6% vs 10.6%, P=0.10; adjusted OR, 0.82; 95% CI, 0.61-1.10), externalizing problems (3.5% vs 4.2%, P=0.40; adjusted OR, 0.90; 95% CI, 0.57-1.41), total problems (6.8% vs 7.7%, P=0.40; adjusted OR, 0.91; 95% CI, 0.65-1.26), mental delay (40.4% vs 34.7%, P=0.09; adjusted RR, 1.13; 95% CI, 0.95-1.33), and psychomotor delay (8.7% vs 7.2%, P=0.50; adjusted OR, 1.13; 95% CI, 0.67-1.90) between CDMR and SVD.

Results of the complete-case analysis and the intention-to-treat analysis were similar to those of the main analysis with covariates imputed (Online Resource Table 3 and Table 4).

In this prospective cohort study, non-medically indicated CDMR was associated with increased risks of obesity and anemia, yet did not affect the risk of pneumonia or neurobehavioral disorders in childhood, indicating that CD might be a risk factor for childhood obesity and anemia independent of cesarean indications.

CDMR and childhood obesity

Many observational studies have investigated the association of CD with the risk of childhood obesity, but few of them were able to deal with the potential biases associated with cesarean indications [2; 17]. In this study, we found that CDMR, without any medical indication, labor, or premature rupture of membranes, was associated with a 41% increased risk of obesity in children aged 1.5-5 years compared with SVD, suggesting that CD per se or its accompanying factors might increase the susceptibility for childhood obesity. This is consistent with the result of a previous cohort study, which indicated a borderline significant association (adjusted OR, 1.18; 95% CI, 1.00-1.41) between CDMR and overweight in Chinese children aged 3-7 years [18]. Another longitudinal study restricted to women without known risk factors (maternal overweight/obesity, gestational diabetes, hypertensive disorders, etc.) for CD also reported a significant association (adjusted RR, 1.30; 95% CI, 1.09-1.54) between CD and obesity in offspring followed from age 9-14 to age 20-28 years in the United States [19].

One of the biological mechanisms might be the distinct obesity-related intestinal microbiota profiles resulting from the circumvention of birth canal or the lack of labor, such as the decreased or delayed colonization of Bifidobacteria, Bacteroides, and Collinsella, and the increased quantities of Firmicutes [20-23]. The other potential mechanism revealed by a mouse experiment was that vasopressin, an appetite inhibitor, was less produced in cesarean-delivered offspring than the vaginally-born [24].

CDMR and childhood pneumonia

In this study, children born by CDMR were at a non-significantly increased risk (16%) of pneumonia compared with those born by SVD. This may be due to our insufficient sample size (n = 10 298), because more than 36 214 participants are needed to detect an OR of 1.16 with 80% power when the incidence of pneumonia in the reference group is assumed to be 3.9%. Other studies with sufficient sample size all demonstrated that CD especially elective CD was associated with an elevated risk of childhood respiratory infection (8%-35%) [3; 25-27].

The underlying mechanisms can be summarized as follows: cortisol, a cytokine promoting lung liquid clearance and lung maturation, was less generated in children born by elective CD [28]; the DNA methylation patterns related to immune responses in infants born by CD were different from those born vaginally [29]; the upper respiratory tract microbial profiles in children born by CD were less stable and abundant [30]

CDMR and childhood anemia

A significant increased risk of anemia (65%) was observed in children aged 1.5-5.0 years born by CDMR. This supported the positive association between CDMR and anemia at 40-79 months (adjusted OR=1.18) demonstrated by another Chinese cohort derived from a quite different socioeconomic setting [4]. A previous cohort study found that the iron-related hematological indices (serum ferritin, hemoglobin, red blood cell, and hematocrit) in cord blood were lower in CDMR than in SVD [31]. It is worth mentioning that no association was found between CDMR and anemia at 6 or 12 months in our previous study using the same population [4]. The inconsistency across age might be explained by the following reasons. The exclusion of women with hemoglobin ≤100 g/L at enrollment and the micronutrient supplementation throughout pregnancy might reduce the risk of anemia in early infancy, and narrow the gap of anemia between CDMR and SVD. As was seen in our previous study, the overall anemia prevalence at 6 and 12 months in this cohort was 6.8% and 5.3%, far below that of their peers in another study (26.4% at 6-11 months and 35.3% at 12-17 months) [32]. This gap might expand as children grow when the iron store/hemoglobin bonus endowed from these factors gradually fades, which was verified by the post hoc analysis, suggesting that the probability of anemia decreased as child’s age increased, but the rate of decline was slower for CDMR than for SVD (P<0.001, Online Resource Fig. 2).

The observed higher risk of anemia in CDMR might be attributed to their less placental transfusion at birth because of early cord clamping, lack of utero squeezing and delayed onset of respiration [33]. A study found that the residual blood volume in umbilical cord after clamping was higher in CDMR than in SVD [31]. Notably, when this study was conducted, both groups underwent early cord clamping (<1 minute after birth), but the difference of placental transfusion may be enlarged after the universal implementation of delayed cord clamping (>1 minute after birth), because it is much easier to be followed in VD than in CD [34]. In addition, the gut microbiota has been linked to folate and vitamin B₁₂ metabolism in humans, and iron sensing of intestinal cells in mice, all of which are associated with anemia [35-37]. Whether different profiles of gut microbiota between CD and VD lead to different risks of childhood anemia demands further study.

CDMR and childhood neurobehavioral disorders

No significant associations were found between CDMR and neurobehavioral disorders recognized by CBCL or BSID (adjusted ORs varied from 0.82 to 1.13). Results from previous studies were inconsistent: no association (adjusted RR, 0.78; 95% CI, 0.47-1.37) was observed between CD and mental delay in preterm 2-year-olds in a cohort using BSID [38]; two studies using CBCL indicated that children born by CD had higher scores (worse performance) on internalizing problems than those born vaginally [39; 40], whereas another study observed an opposite result [41]. Unlike diagnoses of the other outcomes, scores of these scales were only served as a reference for preliminary screening. The validity of the results is largely dependent on the applicability of the scales to the population, which might lead to the high heterogeneity across studies. To our surprise, the rate of mental delay was as high as 37.4% in this study, but it is consistent with the results revealed by the Rural Education Action Program, which have used BSID to assess early childhood development in rural China for many years [42].

A potential link between delivery mode and offspring neurobehavioral disorders is cortisol, a hormone closely related to cognitive functioning, which was less produced in cesarean-delivered children than those born vaginally when aged 6 months [43]. There were also some intriguing findings in animal experiments. For example, CD has been revealed to underlie alterations in the structure and function of the prefrontal cortex mediated by mitochondrial adaptations, manifesting as behavioral characteristics of psychiatric illness in mice [44]. Additionally, gene expression and cell death in rat/mouse brain varied significantly by delivery mode, but whether these can cause neurobehavioral disorders is undetermined [24].

Strengths and limitations

This study has some strengths. Delicate classification of delivery mode and cesarean indications allowed us to identify CDMR and examine its intrinsic effect on child health. Data on multiple critical covariates facilitated confounding adjustment. All participants were primiparas, eliminating potential confounding caused by birth order or parity-related complications [45]. All information except for breastfeeding and medical insurance status were collected prospectively and the process of data collection and measurements was standardized, which minimized information bias.

This study also has several limitations. We did not have information about antepartum use of antibiotics, neonatal hormone levels, intestinal microbiota, or placenta transfusion, therefore we were unable to explore whether they mediated the association of CDMR with child health. Information on maternal and paternal mental health were unavailable either. Psychiatric illnesses, such as stress-related disorders and mood disorders, were found to be more common in Swedish women giving birth by CDMR during the 5 years before their first delivery [46]. Antenatal maternal anxiety and stress might be associated with child’s neurobehavioral disorders [47; 48]. A potential confounder-socioeconomic status was also unknown, but its potential proxies, such as education, occupation, level of delivery hospital, and medical insurance, were adjusted. Besides, we did not have objective indicators for the diagnosis of pneumonia, but the criteria were simple and consistent across different hospitals. Additionally, we could not rule out the possibility of confounding associated with CDMR-specific characteristics. Studies found that women requested CD mainly because of the fear of labor pain, perceived safety of CD, perceived better quality of life after CD, self-determined timing of birth, etc. [49; 50]. Whether these may bias the associations of interest is unknown. Finally, women in this study were relatively well-nourished (hemoglobin >100 g/L at enrollment and took micronutrient supplements during pregnancy) and had good access to health care, which might limit the generalizability.

Clinical and research implications

Findings in our study suggested that CD might increase the risks of childhood obesity and anemia independent of cesarean indications. It may be better to consider these impacts when deciding the delivery mode so that some unnecessary CD might be avoided. Meanwhile, some preventive strategies could be developed to mitigate the adverse impacts of CD. For example, CDMR was not recommended prior to 39 weeks of gestation to ensure lung maturity [8]; delayed cord clamping and umbilical cord milking were assessed to reduce the risk of offspring anemia [51]; vaginal seeding and probiotics supplementation were investigated to cope with microbiota dysbiosis caused by CD [52; 53]; physical squeeze and administration of corticosteroids before elective CD were tried to imitate physiological environment induced by labor [1]. But these new interventions are in a fledging period, which merit further evaluations.

CD, independent of cesarean indications, is likely associated with childhood obesity and anemia, indicating a strong need for informed decisions on delivery mode, especially for those seeking CDMR. The degree, duration, mechanisms, and countermeasures of the adverse effects of CD on child health demand further investigation.

AVD, assisted vaginal delivery

BMI, body mass index

BSID, Bayley Scales of Infant Development

CBCL, Child Behavior Checklist

CD, cesarean delivery

CDMR, cesarean delivery on maternal request

CI, confidence interval

GWG, gestational weight gain

OR, odds ratio

RR, relative risk

SVD, spontaneous vaginal delivery

VD, vaginal delivery

Funding: This study was funded by the National Basic Research Program of China (973 Program; No. 2007CB5119001) and the National Natural Science Foundation of China (No. 81571517).

Conflicts of interest/Competing interests: All authors have no disclosure of interests to report.

Availability of data and material: Data and material can be acquired by asking for permission from the corresponding author.

Code availability: N/A.

Authors' contributions: Ke-yi Si did the analysis, interpreted the data, and drafted the manuscript. Yu-bo Zhou, Ya-li Zhang, Le Zhang, Zhi-wen Li, Rong-wei Ye, Hong-tian Li, and Jian-meng Liu contributed substantially to the conduction and supervision of the study. Hong-tian Li and Jian-meng Liu designed the study. Jian-meng Liu obtained funding. All authors critically revised the manuscript and gave approval of the publication of the study.

Ethics approval: Both the original trial and the follow-up study were approved by the Peking University Health Science Center Institutional Review Board (date of approval: 31 March 2011; approval number: IRB00001052-11024) and registered on clinicaltrials.gov with identifiers of NCT00133744 and NCT01404416, respectively.

Consent to participate: All participants provided written informed consent to participate in the study.

Consent for publication: All participants provided consent for publication.

Acknowledgments: We thank health workers who have contributed to the conduction of the study in 5 counties (Fengrun, Mancheng, Laoting, Xianghe, and Yuanshi in Hebei Province, China).

1. Sandall J, Tribe RM, Avery L, Mola G, Visser GH, Homer CS, Gibbons D, Kelly NM, Kennedy HP, Kidanto H, et al. (2018) Short-term and long-term effects of caesarean section on the health of women and children. Lancet 392:1349-1357. https://doi.org/10.1016/S0140-6736(18)31930-5

2. Keag OE, Norman JE, Stock SJ (2018) Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: Systematic review and meta-analysis. PLoS Med 15:e1002494. https://doi.org/10.1371/journal.pmed.1002494

3. Haataja P, Korhonen P, Ojala R, Hirvonen M, Korppi M, Gissler M, Luukkaala T, Tammela O (2018) Hospital admissions for lower respiratory tract infections in children born moderately/late preterm. Pediatr Pulmonol 53:209-217. https://doi.org/10.1002/ppul.23908

4. Li HT, Trasande L, Zhu LP, Ye RW, Zhou YB, Liu JM (2015) Association of cesarean delivery with anemia in infants and children in 2 large longitudinal Chinese birth cohorts. Am J Clin Nutr 101:523-529. https://doi.org/10.3945/ajcn.114.092585

5. Zhang T, Sidorchuk A, Sevilla-Cermeño L, Vilaplana-Pérez A, Chang Z, Larsson H, Mataix-Cols D, Fernández de la Cruz L (2019) Association of cesarean delivery with risk of neurodevelopmental and psychiatric disorders in the offspring: A systematic review and meta-analysis. JAMA Netw Open 2:e1910236. https://doi.org/10.1001/jamanetworkopen.2019.10236

6. Zhou LS, He GP, Zhang JP, Xie RH, Walker M, Wen SW (2011) Risk factors of obesity in preschool children in an urban area in China. Eur J Pediatr 170:1401-1406. https://doi.org/10.1007/s00431-011-1416-7

7. Boerma T, Ronsmans C, Melesse DY, Barros AJD, Barros FC, Juan L, Moller A-B, Say L, Hosseinpoor AR, Yi M, et al. (2018) Global epidemiology of use of and disparities in caesarean sections. Lancet 392:1341-1348. https://doi.org/10.1016/s0140-6736(18)31928-7

8. National Institute of Health (2006) NIH State-of-the-Science Conference Statement on cesarean delivery on maternal request https://consensus.nih.gov/2006/cesareanstatement.pdf. Accessed 17 Jun 2021

9. Kassebaum N, Kyu HH, Zoeckler L, Olsen HE, Thomas K, Pinho C, Bhutta ZA, Dandona L, Ferrari A, Ghiwot TT, et al. (2017) Child and adolescent health from 1990 to 2015: Findings from the global burden of diseases, injuries, and risk factors 2015 study. JAMA Pediatr 171:573-592. https://doi.org/10.1001/jamapediatrics.2017.0250

10. Begum T, Saif-Ur-Rahman KM, Yaqoot F, Stekelenburg J, Anuradha S, Biswas T, Doi SA, Mamun AA (2021) Global incidence of caesarean deliveries on maternal request: A systematic review and meta-regression. BJOG 128:798-806. https://doi.org/10.1111/1471-0528.16491

11. Liu JM, Mei Z, Ye R, Serdula MK, Ren A, Cogswell ME (2013) Micronutrient supplementation and pregnancy outcomes: Double-blind randomized controlled trial in China. JAMA Intern Med 173:276-282. https://doi.org/10.1001/jamainternmed.2013.1632

12. World Health Organization. Obesity and overweight https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 18 Apr 2021

13. Achenbach T, Rescorla LA (2000) Manual for the ASEBA Preschool Forms & Profiles. University of Vermont, Research Center for Children, Youth, & Families, Burlington,VT

14. Yi S (1995) Manual for Chinese revision of Bayley Scales of Infant Development. Hunan Medical University Press, Changsha, China

15. Yin S, Zhou Y, Li H, Cheng Z, Zhang Y, Zhang L, Liu J, Liu J (2020) Association of gestational weight gain rate with infant anaemia in China: A birth cohort study. Br J Nutr 124:1285-1292. https://doi.org/10.1017/S0007114520002354

16. WHO Expert Consultation (2004) Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 363:157-163. https://doi.org/10.1016/S0140-6736(03)15268-3

17. Kuhle S, Tong OS, Woolcott CG (2015) Association between caesarean section and childhood obesity: A systematic review and meta-analysis. Obes Rev 16:295-303. https://doi.org/10.1111/obr.12267

18. Li H, Ye R, Pei L, Ren A, Zheng X, Liu J (2014) Caesarean delivery, caesarean delivery on maternal request and childhood overweight: A Chinese birth cohort study of 181 380 children. Pediatr Obes 9:10-16. https://doi.org/10.1111/j.2047-6310.2013.00151.x

19. Yuan C, Gaskins AJ, Blaine AI, Zhang C, Gillman MW, Missmer SA, Field AE, Chavarro JE (2016) Association between cesarean birth and risk of obesity in offspring in childhood, adolescence, and early adulthood. JAMA Pediatr 170:e162385. https://doi.org/10.1001/jamapediatrics.2016.2385

20. Musso G, Gambino R, Cassader M (2010) Obesity, diabetes, and gut microbiota: The hygiene hypothesis expanded? Diabetes Care 33:2277-2284. https://doi.org/10.2337/dc10-0556

21. Dogra S, Sakwinska O, Soh SE, Ngom-Bru C, Bruck WM, Berger B, Brussow H, Lee YS, Yap F, Chong YS, et al. (2015) Dynamics of infant gut microbiota are influenced by delivery mode and gestational duration and are associated with subsequent adiposity. mBio 6:e02419-02414. https://doi.org/10.1128/mBio.02419-14

22. Murata C, Gutierrez-Castrellon P, Perez-Villatoro F, Garcia-Torres I, Enriquez-Flores S, de la Mora-de la Mora I, Fernandez-Lainez C, Werner J, Lopez-Velazquez G (2020) Delivery mode-associated gut microbiota in the first 3 months of life in a country with high obesity rates: A descriptive study. Medicine (Baltimore) 99:e22442. https://doi.org/10.1097/MD.0000000000022442

23. Stinson LF, Payne MS, Keelan JA (2018) A critical review of the bacterial baptism hypothesis and the impact of cesarean delivery on the infant microbiome. Front Med (Lausanne) 5:135. https://doi.org/10.3389/fmed.2018.00135

24. Castillo-Ruiz A, Mosley M, Jacobs AJ, Hoffiz YC, Forger NG (2018) Birth delivery mode alters perinatal cell death in the mouse brain. Proc Natl Acad Sci U S A 115:11826-11831. https://doi.org/10.1073/pnas.1811962115

25. Kristensen K, Henriksen L (2016) Cesarean section and disease associated with immune function. J Allergy Clin Immunol 137:587-590. https://doi.org/10.1016/j.jaci.2015.07.040

26. Kristensen K, Fisker N, Haerskjold A, Ravn H, Simoes EA, Stensballe L (2015) Caesarean section and hospitalization for respiratory syncytial virus infection: A population-based study. Pediatr Infect Dis J 34:145-148. https://doi.org/10.1097/INF.0000000000000552

27. Peters LL, Thornton C, de Jonge A, Khashan A, Tracy M, Downe S, Feijen-de Jong EI, Dahlen HG (2018) The effect of medical and operative birth interventions on child health outcomes in the first 28 days and up to 5 years of age: A linked data population-based cohort study. Birth 45:347-357. https://doi.org/10.1111/birt.12348

28. Martelius L, Janer C, Suvari L, Helve O, Lauerma K, Pitkanen O, Andersson S (2013) Delayed lung liquid absorption after cesarean section at term. Neonatology 104:133-136. https://doi.org/10.1159/000351290

29. Irestedt L, Lagercrantz H, Hjemdahl P, Hagnevik K, Belfrage P (1982) Fetal and maternal plasma catecholamine levels at elective cesarean section under general or epidural anesthesia versus vaginal delivery. American Journal of Obstetrics and Gynecology 142:1004-1010. https://doi.org/10.1016/0002-9378(82)90783-9

30. Bosch A, Levin E, van Houten MA, Hasrat R, Kalkman G, Biesbroek G, de Steenhuijsen Piters WAA, de Groot PCM, Pernet P, Keijser BJF, et al. (2016) Development of upper respiratory tract microbiota in infancy is affected by mode of delivery. EBioMedicine 9:336-345. https://doi.org/10.1016/j.ebiom.2016.05.031

31. Liao Z, Zhou Y, Liu A, Li H, Peters RL, Liu J (2021) Association of cesarean delivery on maternal request with neonatal iron stores at birth. Eur J Clin Nutrhttps://doi.org/10.1038/s41430-021-00874-w

32. Shang Y, Li J, Yan C, Pei J, Li X, Liu J, Huo X (2011) [Prevalence of anemia and related impact factors at 6-35 months in rural Hebei] (in Chinese). Chinese Journal of Women and Children Health:161-164.

33. Zhou YB, Li HT, Zhu LP, Liu JM (2014) Impact of cesarean section on placental transfusion and iron-related hematological indices in term neonates: A systematic review and meta-analysis. Placenta 35:1-8. https://doi.org/10.1016/j.placenta.2013.10.011

34. Liu LY, Feinglass JM, Khan JY, Gerber SE, Grobman WA, Yee LM (2017) Evaluation of introduction of a delayed cord clamping protocol for premature neonates in a high-volume maternity center. Obstet Gynecol 129:835-843. https://doi.org/10.1097/AOG.0000000000001987

35. Engevik MA, Morra CN, Roth D, Engevik K, Spinler JK, Devaraj S, Crawford SE, Estes MK, Kalkum M, Versalovic J (2019) Microbial metabolic capacity for intestinal folate production and modulation of host folate receptors. Front Microbiol 10:2305. https://doi.org/10.3389/fmicb.2019.02305

36. Hill MJ (1997) Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev 6 Suppl 1:S43-45. https://doi.org/10.1097/00008469-199703001-00009

37. Deschemin JC, Noordine ML, Remot A, Willemetz A, Afif C, Canonne-Hergaux F, Langella P, Karim Z, Vaulont S, Thomas M, et al. (2016) The microbiota shifts the iron sensing of intestinal cells. FASEB J 30:252-261. https://doi.org/10.1096/fj.15-276840

38. Obican SG, Small A, Smith D, Levin H, Drassinower D, Gyamfi-Bannerman C (2015) Mode of delivery at periviability and early childhood neurodevelopment. Am J Obstet Gynecol 213:578 e571-574. https://doi.org/10.1016/j.ajog.2015.06.047

39. Sirvinskiene G, Zemaitiene N, Jusiene R, Markuniene E (2016) Predictors of emotional and behavioral problems in 1-year-old children: A longitudinal perspective. Infant Ment Health J 37:401-410. https://doi.org/10.1002/imhj.21575

40. Kelmanson IA (2013) Emotional and behavioural features of preschool children born by caesarean deliveries at maternal request. Eur J Dev Psychol 10:676-690. https://doi.org/10.1080/17405629.2013.787024

41. Li HT, Ye R, Achenbach TM, Ren A, Pei L, Zheng X, Liu JM (2011) Caesarean delivery on maternal request and childhood psychopathology: A retrospective cohort study in China. BJOG 118:42-48. https://doi.org/10.1111/j.1471-0528.2010.02762.x

42. Yue A, Shi Y, Luo R, Chen J, Zhang J, Medina A, Kotb S (2017) China’s invisible crisis: cognitive delays among rural toddlers and the absence of modern parenting. The China Journal:50-78.

43. Martinez LD, Glynn LM, Sandman CA, Wing DA, Davis EP (2020) Cesarean delivery and infant cortisol regulation. Psychoneuroendocrinology 122:104862. https://doi.org/10.1016/j.psyneuen.2020.104862

44. Taylor-Giorlando M, Scheinost D, Ment L, Rothman D, Horvath TL (2019) Prefrontal cortical and behavioral adaptations to surgical delivery mediated by metabolic principles. Cereb Cortex 29:5061-5071. https://doi.org/10.1093/cercor/bhz046

45. Black M, Bhattacharya S, Philip S, Norman JE, McLernon DJ (2015) Planned cesarean delivery at term and adverse outcomes in childhood health. JAMA 314:2271-2279. https://doi.org/10.1001/jama.2015.16176

46. Sydsjö G, Möller L, Lilliecreutz C, Bladh M, Andolf E, Josefsson A (2015) Psychiatric illness in women requesting caesarean section. BJOG 122:351-358. https://doi.org/10.1111/1471-0528.12714

47. Van den Bergh BR, Mulder EJ, Mennes M, Glover V (2005) Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: Links and possible mechanisms. A review. Neurosci Biobehav Rev 29:237-258. https://doi.org/10.1016/j.neubiorev.2004.10.007

48. Matvienko-Sikar K, Cooney J, Flannery C, Murphy J, Khashan A, Huizink A (2021) Maternal stress in the first 1000 days and risk of childhood obesity: A systematic review. J Reprod Infant Psychol 39:180-204. https://doi.org/10.1080/02646838.2020.1724917

49. Long Q, Kingdon C, Yang F, Renecle MD, Jahanfar S, Bohren MA, Betran AP (2018) Prevalence of and reasons for women's, family members', and health professionals' preferences for cesarean section in China: A mixed-methods systematic review. PLoS Med 15:e1002672. https://doi.org/10.1371/journal.pmed.1002672

50. Jenabi E, Khazaei S, Bashirian S, Aghababaei S, Matinnia N (2020) Reasons for elective cesarean section on maternal request: A systematic review. J Matern Fetal Neonatal Med 33:3867-3872. https://doi.org/10.1080/14767058.2019.1587407

51. Katheria AC, Truong G, Cousins L, Oshiro B, Finer NN (2015) Umbilical cord milking versus delayed cord clamping in preterm infants. Pediatrics 136:61-69. https://doi.org/10.1542/peds.2015-0368

52. Korpela K, Helve O, Kolho KL, Saisto T, Skogberg K, Dikareva E, Stefanovic V, Salonen A, Andersson S, de Vos WM (2020) Maternal fecal microbiota transplantation in cesarean-born infants rapidly restores normal gut microbial development: A proof-of-concept study. Cell 183:324-334 e325. https://doi.org/10.1016/j.cell.2020.08.047

53. Garcia Rodenas CL, Lepage M, Ngom-Bru C, Fotiou A, Papagaroufalis K, Berger B (2016) Effect of formula containing lactobacillus reuteri dsm 17938 on fecal microbiota of infants born by cesarean-section. J Pediatr Gastroenterol Nutr 63:681-687. https://doi.org/10.1097/MPG.0000000000001198

Table 1 Maternal and offspring characteristics by mode of delivery in obesity analysis

Characteristics	SVD (n=6854)	CDMR (n=3564)	P value^a
Maternal Details
Age at delivery, year, median (IQR)	22.8 (3.0)	22.9 (3.2)	0.008
Gestational age, week, mean (SD)	39.9 (1.2)	39.8 (1.2)	<0.001
Education, No. (%)			<0.001
≤Primary	1069 (15.6)	664 (18.6)
Secondary	5694 (83.1)	2833 (79.5)
≥High school	91 (1.3)	67 (1.9)
Occupation, No. (%)			0.05
Farmer	6326 (92.3)	3249 (91.2)
Others	528 (7.7)	315 (8.8)
BMI in the 1^st trimester, kg/m², No. (%)			<0.001
<18.5	683 (10.0)	253 (7.1)
18.5-22.9	4615 (67.3)	2109 (59.2)
23.0-27.4	1408 (20.5)	982 (27.6)
≥27.5	148 (2.2)	220 (6.2)
GWG rate in the 2^nd/3^rd trimester, kg/week, mean (SD)	0.43 (0.17)	0.46 (0.18)	<0.001
Missing, No. (%)	225 (3.3)	81 (2.3)
Supplementation during pregnancy, No. (%)			0.90
Folic acid	2269 (33.1)	1193 (33.5)
Iron-folic acid	2317 (33.8)	1197 (33.6)
Multiple micronutrients	2268 (33.1)	1174 (32.9)
Level of delivery hospital, No. (%)			<0.001
Provincial/city	538 (7.8)	212 (5.9)
County/district	5253 (76.6)	2588 (72.6)
Township/village	1063 (15.5)	763 (21.4)
Missing	0 (0)	1 (0.03)
Medical insurance, No. (%)			0.01
Yes	6074 (88.6)	3215 (90.2)
No	767 (11.2)	342 (9.6)
Missing	13 (0.2)	7 (0.2)
Offspring Details
Male	3543 (51.7)	1845 (51.8)	>0.999
Birth weight, g, No. (%)			0.001
<2500	84 (1.2)	19 (0.5)
2500-3999	6770 (98.8)	3545 (99.5)
Apgar score at 1 minute, No. (%)			<0.001
0-7	93 (1.4)	9 (0.3)
8-10	6758 (98.6)	3555 (99.7)
Missing	3 (0.04)	0 (0)
Feeding pattern before 6 months, No. (%)			0.90
Exclusive feeding	5659 (82.6)	2957 (83.0)
Mixed feeding	966 (14.1)	497 (13.9)
Formula feeding	216 (3.2)	107 (3.0)
Missing	13 (0.2)	3 (0.1)
Age at the follow-up visit, month, No. (%)			<0.001
18-29	921 (13.4)	735 (20.6)
30-35	1550 (22.6)	929 (26.1)
36-41	1287 (18.8)	695 (19.5)
42-47	1856 (27.1)	746 (20.9)
48-60	1240 (18.1)	459 (12.9)

Abbreviations: SVD, spontaneous vaginal delivery; CDMR, cesarean delivery on maternal request; BMI, body mass index; GWG, gestational weight gain; IQR, interquartile range; SD, standard deviation.

Percentages may not add up to 100% due to rounding.

^a Comparisons between groups were made by Student’s t-test for gestational age and GWG rate, Mann-Whitney U test for maternal age, and chi-square test for other variables.

Table 2 Crude and adjusted odds ratios for multiple child health outcomes by mode of delivery

Outcomes	Delivery Mode	No. of Events/No. of Children (%)	Crude OR (95% CI)	Adjusted OR (95% CI)^a	Adjusted OR (95% CI)^b
Obesity	SVD	237/6854 (3.5)	1 [Reference]	1 [Reference]	1 [Reference]
Obesity	CDMR	160/3564 (4.5)	1.31 (1.07-1.61)^e	1.36 (1.10-1.69)^e	1.41 (1.14-1.75)^e
Pneumonia	SVD	267/6855 (3.9)	1 [Reference]	1 [Reference]	1 [Reference]
Pneumonia	CDMR	144/3443 (4.2)	1.08 (0.88-1.32)	1.14 (0.92-1.41)	1.16 (0.94-1.45)
Anemia	SVD	120/2341 (5.1)	1 [Reference]	1 [Reference]	1 [Reference]
Anemia	CDMR	183/2417 (7.6)	1.52 (1.20-1.92)^e	1.60 (1.25-2.06)^c,e	1.65 (1.28-2.12)^c,e
Internalizing Problems	SVD	133/1257 (10.6)	1 [Reference]	1 [Reference]	1 [Reference]
Internalizing Problems	CDMR	91/1060 (8.6)	0.79 (0.60-1.05)	0.81 (0.60-1.08)^c	0.82 (0.61-1.10)^c
Externalizing Problems	SVD	53/1257 (4.2)	1 [Reference]	1 [Reference]	1 [Reference]
Externalizing Problems	CDMR	37/1060 (3.5)	0.82 (0.54-1.26)	0.88 (0.56-1.38)^c	0.90 (0.57-1.41)^c
Total Problems	SVD	97/1257 (7.7)	1 [Reference]	1 [Reference]	1 [Reference]
Total Problems	CDMR	72/1060 (6.8)	0.87 (0.64-1.20)	0.91 (0.65-1.26)^c	0.91 (0.65-1.26)^c
Mental Delay	SVD	155/447 (34.7)	1 [Reference]	1 [Reference]	1 [Reference]
Mental Delay	CDMR	167/413 (40.4)	1.17 (0.98-1.39)^d	1.14 (0.96-1.36)^c^,^d	1.13 (0.95-1.33)^c,d
Psychomotor Delay	SVD	32/447 (7.2)	1 [Reference]	1 [Reference]	1 [Reference]
Psychomotor Delay	CDMR	36/413 (8.7)	1.24 (0.75-2.03)	1.15 (0.68-1.93)^c	1.13 (0.67-1.90)^c

Abbreviations: SVD, spontaneous vaginal delivery; CDMR, cesarean delivery on maternal request; OR, odds ratio; CI, confidence interval.

^aAdjusted for maternal age at delivery (year, continuous), education (≤primary, secondary, or ≥high school), occupation (farmer or not), gestational age (week, continuous), body mass index in the 1^st trimester (<18.5, 18.5-22.9, 23.0-27.4, or ≥27.5 kg/m²), gestational weight gain rate in the 2^nd/3^rd trimester (kg/week, in quintiles), and micronutrient supplementation (folic acid, iron-folic acid, or multiple micronutrients); child’s gender (male or female), birth weight (g, continuous), age at the follow-up visit (month, continuous), and feeding pattern before 6 months old (exclusive breastfeeding, mixed feeding, or formula feeding).

^b Additionally adjusted for level of delivery hospital (provincial/city, county/district, or township/village level) and medical insurance status (yes or no).

^cAdditionally adjusted for maternal anemia in mid-pregnancy (yes or no).

^d Relative risk was estimated using Poisson regression with robust error variance because the rate of mental delay was >10%.

^e P<0.01.

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Cesarean Delivery on Maternal Request and Common Child Health Outcomes: A Prospective Cohort Study

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