CD HAS Thai

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com/scientificreports
OPEN Caesarean delivery is associated

with increased blood pressure
in young adult offspring
Amaraporn Rerkasem 1, Sarah E. Maessen 2, Antika Wongthanee3, Sakda Pruenglampoo1,
Ampica Mangklabruks3, Patumrat Sripan1, José G. B. Derraik 1,2,4,5* &
Kittipan Rerkasem 1,6*
We examined the associations between caesarean section (CS) delivery and cardiovascular risk
factors in young adults in Thailand. Participants were 632 offspring from a birth cohort in Chiang Mai
(Northern Thailand), born in 1989–1990 and assessed in 2010 at a mean age of 20.6 years, including 57
individuals (9.0%) born by CS and 575 born vaginally. Clinical assessments included anthropometry,
blood pressure (BP), carotid intima-media thickness, and fasting blood glucose, insulin, and lipid
profile. Young adults born by CS had systolic BP (SBP) 6.2 mmHg higher (p < 0.001), diastolic BP
3.2 mmHg higher (p = 0.029), and mean arterial pressure (MAP) 4.1 mmHg higher (p = 0.003) than
those born vaginally. After covariate adjustments, SBP and MAP remained 4.1 mmHg (p = 0.006) and
2.9 mmHg (p = 0.021) higher, respectively, in the CS group. The prevalence of abnormal SBP (i.e., pre-
hypertension or hypertension) in the CS group was 2.5 times that of those born vaginally (25.0% vs
10.3%; p = 0.003), with an adjusted relative risk of abnormal SBP 1.9 times higher (95% CI 1.15, 2.98;
p = 0.011). There were no differences in anthropometry (including obesity risk) or other metabolic
parameters. In this birth cohort in Thailand, CS delivery was associated with increased blood pressure
in young adulthood.
The proportion of infants born by caesarean sections (CS) worldwide has increased markedly over recent decades,
including in Th ailand1. The reasons for this observed increase are largely unknown, but it is thought that both
practitioner preference and increases in maternal request in well-resourced health systems have contributed to
this trend2. Several studies have shown that compared to individuals born vaginally, those born by CS have an
increased risk of adverse health outcomes, including overweight/obesity and hypertension in childhood, ado-
lescence, and a dulthood3–6. However, these findings are far from universal, with some studies showing no such
associations when CS is e lective7 or for all CS c ases8. A meta-analysis suggested that inadequate adjustment for
confounding effects and publication bias may explain the associations found in many studies, which were typi-
cally small in magnitude9.
While the evidence is far from conclusive, it is postulated that babies born vaginally are exposed to maternal
symbiotic bacteria essential for the long-term development of a healthy gut m icrobiome9,10. One study showed
that the association between maternal pre-pregnancy overweight and early offspring overweight was mediated
by both birth mode and the infant’s gut microbiome, with infants of overweight mothers born by CS at the high-
est risk of obesity11. There are differences in gut microbiome between lean individuals and those with obesity
in both childhood and a dulthood12, and alterations to the gut microbiome have been shown to cause obesity in
an animal m odel13. Furthermore, the gut microbiome has been associated with hypertension in animal models,
and there is evidence that this may also apply to humans14.
In this context, we aimed to examine the associations between CS and long-term cardiometabolic outcomes
in a cohort of young adults in Thailand. To our knowledge, such associations have never been previously exam-
ined in this country.
1
NCD Center of Excellence, Research Institute for Health Sciences, Chiang Mai University, Chiang Mai,
Thailand. 2Liggins Institute, University of Auckland, Auckland, New Zealand. 3Department of Internal Medicine,
Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. 4Department of Women’s and Children’s Health,
Uppsala University, Uppsala, Sweden. 5Department of Endocrinology, Children’s Hospital, Zhejiang University
School of Medicine, Hangzhou, China. 6Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang
Mai, Thailand. *email: j.derraik@auckland.ac.nz; rerkase@gmail.com
Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 1
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www.nature.com/scientificreports/
Figure 1. Flow diagram outlining participants’ recruitment into the Chiang Mai Low Birth Weight
Study (1989–1990) and subsequently to the follow-up study on the offspring (2010).
Methods
This prospective cohort study involved the offspring of mothers from the Chiang Mai Low Birth Weight Study
born in 1989–1990, in Chiang Mai, Northern Thailand15. Briefly, 2184 women were recruited in early pregnancy
(≤ 24 weeks of gestation) from two health centres, Maharaj Nakorn Chiang Mai Hospital and The Maternal-Child
Health Care Center. At the time, these were the only public hospitals providing antenatal care in Chiang Mai
Province15. In 2010, their offspring were recruited for a follow-up study at approximately 20 years of age (Fig. 1)16.
Demographic and clinical data were extracted from the original study database. Demographic data of inter-
est included maternal age, maternal and paternal education levels, family income, and maternal smoking and
alcohol consumption during pregnancy. Clinical data included maternal anthropometry, type of delivery, and
the occurrence of pregnancy-induced hypertension, as well as the offspring’s weight and gestational age at birth.
Birth weights were converted into z-scores as per INTERGROWTH-21st s tandards17. The current education and
smoking status of the offspring were obtained using questionnaires.
Follow-up participants underwent a clinical examination at the Research Institute for Health Science (RIHES),
at Chiang Mai University, after an overnight fast. Participants underwent anthropometric assessments while bare-
foot and wearing light clothing; height was measured on a wall-mounted stadiometer to the nearest 1 mm, and
Vol:.(1234567890)
weight using calibrated electronic scales to the nearest 100 g, with both measurements carried out twice to max-
imise accuracy. Their body mass index (BMI) was subsequently calculated, and their BMI status classified as per
World Health Organization standards: underweight/normal weight < 25 kg/m2; overweight ≥ 25 and < 30 kg/m2;
and obesity ≥ 30 kg/m2. Fasting venous blood samples were drawn to measure glucose, insulin, and lipid profile.
The homeostatic model assessment of insulin resistance (HOMA-IR)18 was used to estimate insulin sensitivity.
Blood pressure (BP) was measured at rest in a sitting position using a digital sphygmomanometer on the
left arm (Terumo ES-P311; Terumo Corporation, Tokyo, Japan). Two measurements were taken approximately
5 min apart, and their average value was recorded. Mean arterial pressure (MAP) was calculated from systolic
BP (SBP) and diastolic BP (DBP) as follows:
1
MAP = DBP + (SPB − DBP)
3
Types of abnormal blood pressure were defined as: systolic pre-hypertension, SBP ≥ 130 but < 140 mmHg;
systolic hypertension, SBP ≥ 140 mmHg; diastolic pre-hypertension, DBP ≥ 85 but < 90 mmHg; diastolic hyperten-
sion, DBP ≥ 90 mmHg19. Abnormal SBP and DBP were defined as BP ≥ 130 mmHg and ≥ 85 mmHg, respectively.
Maternal pregnancy-induced hypertension was defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg developed
oman20.
after 20 weeks of gestation without proteinuria, in a previously normotensive w
Carotid intima-media thickness was measured as a marker of atherosclerosis on the right common carotid
artery, using a Philips iE33 ultrasound (Philips Medical Systems, Bothell, WA, USA) and L10-4 MHz linear
array transducer.
Statistical analyses. Demographic, familial, and birth characteristics were compared between the CS and
vaginal delivery groups using Fisher’s exact tests or one-way ANOVA, as appropriate. Continuous outcomes
were initially compared between groups using one-way ANOVAs. Subsequently, these outcomes were compared
using general linear regression models adjusting for important confounders: sex and gestational age at b irth21–23.
Additional confounders were included in these models depending on the outcome of interest: for offspring
height—maternal height was also included; for offspring weight—maternal BMI24,25 and offspring height; for off-
spring BMI—maternal BMI24,25; and for offspring BP—mother’s pregnancy-induced hypertension (yes vs no)26.
The prevalence of obesity, overweight/obesity, and types of abnormal BP were compared between groups
using Fisher’s exact tests. The likelihood of BP abnormalities was assessed using unadjusted generalised linear
models and reported as relative risks. Adjusted relative risks were subsequently estimated using generalised linear
models adjusting for the appropriate confounders described previously (i.e., sex, gestational age at delivery, and
mother’s pregnancy-induced hypertension).
There are well-described sexual dimorphisms in association with early life events, with contrasting effects
on long-term health and disease observed in males and f emales27. Therefore, the interaction between delivery
mode and offspring sex was also examined for all models.
Analyses were performed with SPSS v25 (IBM Corp, Armonk, NY, USA) and SAS v9.4 (SAS Institute, Cary,
NC, USA). All statistical tests were two-tailed, and the significance level was maintained at 5% without adjust-
ments for multiple comparisons, as per Rothman (1990)28.
Ethics approval. The Human Experimentation Committee at the Research Institute for Health Sciences
(RIHES) at Chiang Mai University provided ethical approval for this study (#17/52). All participants (i.e., moth-
ers and offspring) provided verbal and written informed consent. This study was performed following all appro-
priate institutional and international guidelines and regulations for medical research, in line with the Declara-
tion of Helsinki principles.
Results
From the 2184 participants in the original study, 1552 were lost to follow-up, so 632 young adults were recruited
into the follow-up study at a mean age of 20.6 years (Fig. 1). Our study participants were largely similar to the
remainder of the original cohort (Table 1). However, a greater proportion of females was recaptured, and our
participants were slightly lighter at birth (− 0.14 z-score), were born to mothers one year older on average, and
had a median family income 14% lower (Table 1).
Our study population included 575 (91%) individuals born by vaginal delivery and 57 (9.0%) by CS; the lat-
ter included 36 elective and 21 non-elective cases (18 cases with prolonged labour with obstruction and 3 cases
with pregnancy-induced hypertension). Demographic, birth, familial, and lifestyle characteristics were similar
in the two groups (Table 2), except for a higher proportion of males born by CS than vaginally (61% vs 45%;
p = 0.018). All individuals were Thai, and no offspring had been previously diagnosed with hypertension or had
been on antihypertensive medication.
The prevalence of obesity in the CS group was 7.0% compared to 5.2% in young adults born by vaginal
delivery (p = 0.54; Table 3). Adjusted models did not show an increased risk of obesity [aRR 1.26 (0.46, 3.42);
p = 0.65] or overweight and obesity [aRR 1.15 (0.69, 1.91); p = 0.60] in the CS compared to the vaginal delivery
group, respectively.
However, there were marked differences in BP between the two groups (Table 3). Young adults born by CS had
SBP 6.2 mmHg higher (p < 0.001), DBP 3.2 mmHg higher (p = 0.029), and MAP 4.1 mmHg higher (p = 0.003) than
those born vaginally (Table 3). Adjustment for covariates attenuated these differences, particularly for DBP, which
was no longer different between groups (Table 3). Nonetheless, SBP and MAP remained 4.1 mmHg (p = 0.006)
and 2.9 mmHg (p = 0.024) higher, respectively, among young adults born by CS (Table 3).
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Characteristic Levels Lost to follow-up Follow-up study P value

n 1552 632
Males 876 (56.4%) 292 (46.2%) < 0.001
Sex
Females 676 (43.6%) 340 (53.8%)
Birth weight z-score − 0.32 ± 0.92 − 0.46 ± 0.92 0.001
Gestational age (weeks) 38.8 ± 2.0 39.0 ± 1.7 0.022
Delivery by caesarean section 57 (9.0%) 176 (11.3%) 0.13
Maternal age at childbirth (years) 25.3 ± 4.6 26.3 ± 4.6 < 0.001
Maternal BMI (kg/m2)a 21.51 ± 2.86 21.34 ± 2.51 0.19
Maternal PIHb 40 (2.6%) 25 (4.0%) 0.10
Maternal smoking at pregnancy 14 (0.9%) 5 (0.8%) > 0.99
Maternal alcohol consumption during pregnancy 11 (0.7%) 7 (1.1%) 0.43
Less than high school 1127 (89.2%) 491 (90.3%) 0.56
Maternal educationc
High school or greater 136 (10.8%) 53 (9.7%)
Paternal education
Family income (baht per month)d 2918 [1800, 4500] 2500 [1563, 4200] 0.005
Table 1. Comparisons of demographic and birth characteristics between our study population and the
original study participants who were lost to follow-up. Continuous data are means ± SD or median [quartile
1, quartile 3], as appropriate; categorical data are n (%). BMI body mass index, PIH pregnancy-induced
hypertension. P values that are statistically significant (at p < 0.05) are shown in bold. a BMI recorded at the
first antenatal visit in the original study in 1989–1990. b PIH was defined as a systolic blood pressure ≥ 140
mmHg and/or diastolic blood pressure ≥ 90 mmHg developed after 20 weeks of gestation without proteinuria,
in a previously normotensive woman. c There were missing data on the highest levels of education, so that the
available sample sizes for the Follow-up and Lost to follow-up groups were 544 (86.1%) and 1263 (81.4%) for
maternal education, respectively, and 544 (86.1%) and 1262 (81.3%) for paternal education. d Income recorded
at the time of maternal recruitment to the original study in 1989–1990 (i.e., not adjusted for inflation); the
available sample sizes were 542 (85.8%) for the follow-up group and 1230 (79.3%) for those lost to follow-up.
Compared to young adults born vaginally, the CS group had markedly higher rates of systolic pre-hyper-
tension and systolic hypertension (Table 4). Thus, the prevalence of abnormal BP in the CS group was 2.5 times
that of those born vaginally (25.0% vs 10.3%; p = 0.003), with an adjusted relative risk of 1.85 (95% CI 1.15, 2.98;
p = 0.011) (Table 4). Rates of diastolic BP abnormalities were not different between groups (Table 4). There was
no interaction between group and sex, indicating no sex-specific associations between CS birth and blood pres-
sure (data not shown).
There were no differences in anthropometry, glucose metabolism, lipid profile, or carotid intima-media
thickness between groups (Table 3).
Discussion
This prospective cohort study found that young adults born by CS had higher blood pressure than peers born
vaginally, with nearly twice the likelihood of elevated SBP. Overall, few studies have examined associations
between CS and cardiovascular risk factors in the offspring, and the results have been conflicting. Consistent with
our findings, in a Brazilian birth cohort, young adults born by CS were 1.5 times more likely to have hyperten-
sion than those born vaginally; however, the authors did not report a difference in mean SBP or DBP by birth
mode29. In another Brazilian birth cohort study, SBP was 1.4 mmHg higher, and DBP was 1.1 mmHg higher for
male (but not female) young adults born by C S3. Among Chinese children aged 4–7 years, those born by elective
CS were more likely to have a BP > 90th percentile for age and sex, and had SBP 2.9 mmHg higher than children
born vaginally6. In contrast, however, a study in Dutch children and one in Danish young adults did not observe
an association between CS delivery and blood p ressure4,30.
In our cohort, CS delivery was not associated with the risk of overweight or obesity. The study in Chinese
children reported a small but significant increase in mean BMI in children born after elective C S6, while a study
in Vietnam observed an increased risk of obesity in 8-year-olds born by CS31. Two meta-analyses have reported
greater odds of overweight and obesity after CS delivery32,33. Interestingly, among 3-year-olds in Ireland, the risk
of obesity was 56% greater in those born by emergency CS but not elective CS7. In contrast, the opposite was
reported among Singaporean 1-year-olds, where an increased risk of overweight was observed among those born
by elective CS but not by emergency C S34. There are, however, conflicting findings, and another study in Ireland
found no association between delivery mode and risk of overweight in the first five years of life35. The lack of
consistency between studies may be explained in part by differences in both the prevalence and indications for
CS between different medical systems, as well as sociodemographic differences in study p articipants2. Only 7%
of children in the Dutch cohort were born by CS30, while CS births made up more than a quarter of those in
the Irish c ohorts7,35. Besides, CS infants make up a small proportion of participants in many studies and may
be diverse in terms of their medical histories leading to CS. Notably, a large study in the US on 16,140 siblings
reported that within families, CS delivery was not associated with a higher BMI z-score at 5 years of a ge36. The
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Levels Vaginal birth Caesarean section P value

n 575 57
Age (years) 20.6 ± 0.5 20.5 ± 0.5 0.82
Males 256 (44.5%) 35 (61.4%) 0.018
Sex
Females 319 (55.5%) 22 (38.6%)
Birth weight (g) 2983 ± 425 2939 ± 513 0.46
Birth weight z-score − 0.52 ± 0.91 − 0.67 ± 1.10 0.27
Gestational age (weeks) 39.2 ± 1.6 39.3 ± 2.2 0.70
Maternal age at childbirth (years) 26.2 ± 4.6 26.9 ± 4.5 0.28
Maternal BMI (kg/m2)a 21.31 ± 2.47 21.65 ± 2.96 0.33
Maternal PIHb 22 (3.8%) 3 (5.3%) 0.49
Maternal smoking at pregnancy 4 (0.7%) 1 (1.8%) 0.38
Maternal alcohol consumption during pregnancy 6 (1.0%) 1 (1.8%) 0.49
Maternal educationc
Paternal education
High school or lesser 81 (18.2%) 8 (17.8%) > 0.99
Offspring education
University 363 (81.8%) 37 (82.2%)
Family income (baht per month)d 2500 [1500, 4000] 3200 [1800, 5000] 0.10
Offspring current smoking 63 (10.9%) 10 (17.5%) 0.31
Table 2. Demographic and birth characteristics of the study population according to the mode of delivery.
Continuous data are means ± SD or median [quartile 1, quartile 3], as appropriate; categorical data are n (%).
BMI body mass index, PIH pregnancy-induced hypertension. P values that are statistically significant (at
p < 0.05) are shown in bold. a BMI recorded at the first antenatal visit in the original study in 1989–1990. b PIH
was defined as a systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg developed
after 20 weeks of gestation without proteinuria, in a previously normotensive woman. c There were missing data
on the highest level of education, so that the available sample sizes for the vaginal birth and caesarean section
groups, respectively, were: maternal education [497 (86.4%) and 47 (82.5%)], paternal education [49 (86.4%)
and 47 (82.5%)], and offspring education [444 (77.2%) and 45 (78.9%)]. d Income recorded at the time of
maternal recruitment to the original study in 1989–1990 (i.e., not adjusted for inflation); the available sample
sizes were 495 (86.1%) for the vaginal birth group and 47 (82.5%) for the caesarean section group.
authors, therefore, suggested that unmeasured confounders (such as maternal BMI and sociocultural factors)
likely accounted for the reported associations between CS delivery and increased BMI in many studies36.
Though there is some evidence that exposure to microflora during vaginal birth may lead to more optimal
gut microbiome development in infants, this proposition has been rejected by some authors37. Epigenetics has
also been suggested to play a role in the relationship between CS and cardiovascular outcomes. Methylation of
genes related to the regulation of food responses, glycolysis, and ketone metabolic processes have been reported
to be higher for CS-born infants across the first few days of life, but the consequences of these changes for gene
expression and future health risks are yet to be u nderstood38. Further, the relationship between CS and off-
spring blood pressure is influenced by other maternal factors; in particular, women with either pre-existing or
pregnancy-specific hypertension are more likely to undergo CS and also more likely to have offspring with higher
blood pressure across childhood and a dolescence39. Of note, our blood pressure analyses adjusted for the mother’s
pregnancy-induced hypertension, suggesting that other factors beyond maternal blood pressure are at play.
Our study’s main limitation was the relatively low participation rate (29%) from the original birth cohort at the
20-year follow-up, which might have resulted in some selection bias. For example, at recruitment for the original
study, median income among our follow-up participants was 14% lower than those who were lost. However,
importantly, parents in both groups had similar education levels, with other demographic characteristics also
largely similar. While we recorded information on the offspring’s education, their socioeconomic status was not
formally assessed and therefore not accounted for in our statistical analyses, but data on their mothers indicated
that the CS and vaginal birth groups had similar demographic and lifestyle characteristics. Furthermore, data on
dietary habits that can affect blood pressure (such as salt intake and alcohol consumption) were not recorded.
Vol.:(0123456789)
Unadjusted Adjusted
Outcomes Vaginal birth C-section P value Vaginal birth C-section P value
Anthropometry
Height (cm) 163.7 (163.0, 164.4) 164.8 (162.7, 167.0) 0.32 164.3 (163.8, 164.7) 163.9 (162.5, 165.3) 0.59
Weight (kg) 57.3 (56.2, 58.5) 59.5 (55.9, 63.2) 0.25 57.9 (56.9, 59.0) 57.9 (54.6, 61.1) 0.97
BMI (kg/m2)a 21.27 (20.91, 21.62) 21.79 (20.67, 22.91) 0.38 21.33 (20.99, 21.67) 21.54 (20.46, 22.62) 0.71
Underweight/normal
479 (83.9%) 45 (79.0%) 0.57 – –
weight
Overweight 62 (10.9%) 8 (14.0%) – –
Obesity 30 (5.2%) 4 (7.0%) – –
Blood pressureb
Systolic (mmHg) 114.1 (113.0, 115.1) 120.3 (117.1, 123.6) < 0.001 115.9 (113.8, 118.1) 120.0 (116.7, 123.4) 0.006
Diastolic (mmHg) 73.5 (72.7, 74.4) 76.7 (74.0, 79.4) 0.029 75.5 (73.5, 77.5) 77.9 (74.7, 81.1) 0.09
Mean arterial pressure
87.1 (86.3, 87.9) 91.2 (88.6, 93.8) 0.003 89.0 (87.1, 90.9) 91.9 (89.0, 94.8) 0.024
(mmHg)
Atherosclerosis marker
CIMT (mm) 0.439 (0.436, 0.442) 0.443 (0.435, 0.451) 0.38 0.439 (0.436, 0.442) 0.442 (0.434, 0.450) 0.47
Glucose homeostasis
Fasting glucose (mg/dL) 82.7 (82.0, 83.4) 82.8 (80.5, 85.1) 0.97 82.8 (82.1, 83.5) 82.6 (80.3, 84.9) 0.86
Fasting insulin (mIU/L) 7.36 (6.96, 7.78) 7.31 (6.12, 8.73) 0.95 7.29 (6.90, 7.71) 7.46 (6.25, 8.91) 0.80
HOMA-IR 1.51 (1.42, 1.60) 1.51 (1.25, 1.81) 0.99 1.49 (1.41, 1.58) 1.53 (1.27, 1.84) 0.80
Lipid profile
Total cholesterol (mg/dL) 169 (166, 171) 170 (161, 179) 0.70 168 (166, 171) 171 (161, 180) 0.66
HDL (mg/dL) 56 (55, 57) 57 (53, 61) 0.65 56 (55, 57) 58 (54, 61) 0.35
LDL (mg/dL) 96 (93, 98) 96 (88, 104) 0.88 96 (93, 98) 96 (88, 104) 0.88
Triglycerides (mg/dL) 75 (72, 78) 81 (71, 93) 0.27 76 (73, 79) 80 (70, 91) 0.49
Table 3. Anthropometric and cardiometabolic outcomes in a cohort of young adults in Chiang Mai
(Thailand) according to delivery mode. Underweight/normal weight was defined as BMI < 25 kg/m2,
overweight as BMI ≥ 25 but < 30 kg/m2, and obesity as BMI ≥ 30 kg/m2. BMI status data are n (%); all other
data are means, and the respective 95% confidence intervals (CI). Adjusted means are the least-squares
means and respective 95% CI, adjusted for sex and gestational age at delivery, as well as: maternal height for
offspring height; maternal BMI and offspring height for offspring weight; maternal BMI for offspring BMI; and
mother’s pregnancy-induced hypertension (yes vs no) for offspring BP. BMI body mass index, CIMT carotid
intima-media thickness, C-section caesarean section, HDL high-density lipoprotein cholesterol, HOMA-IR
homeostatic model assessment of insulin resistance, LDL low-density lipoprotein cholesterol, RR relative
risk. P values that are statistically significant (at p < 0.05) are shown in bold. a BMI data were not available for
four participants born vaginally. b Systolic and diastolic BP data were missing for 12 and 6 participants born
vaginally, respectively, and for one participant born by C-section.
Also, while our sample size was still relatively large (n = 632), there was a low rate of CS in our cohort (9.0%),
which likely limited our statistical power to detect potential differences between groups, particularly regarding
CS indication (i.e., elective vs emergency). However, the CS rate in our follow-up participants and the original
cohort (10.6%) simply reflected general CS rates in Chiang Mai (and Thailand) at the time. In 1992, 11.3% of
births occurred by CS at the Maharaj Nakorn Chiang Mai H ospital40, with national CS rates of 15.2% across
Thailand41. Nonetheless, our study’s major strength is that, to our knowledge, this is the first investigation to
examine the associations between CS delivery and long-term health in the offspring in Thailand.
In conclusion, our study showed that CS delivery was associated with an increased risk of blood pressure in
young adult offspring in Thailand. With the increasing rates of CS delivery in this country1, further studies are
needed to clarify whether these associations persist in the long-term and the potential underlying mechanisms.
Importantly, it is still unclear whether the observed increase in blood pressure at the age of 20 years will lead to
greater cardiovascular morbidity and mortality.
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BP type Outcome Vaginal birth C-section P value

n 563 56
Normotension 505 (89.7%) 42 (75.0%) 0.005
Pre-hypertension 39 (6.9%) 10 (17.9%)
Systolic BP
Hypertension 19 (3.4%) 4 (7.1%)
RR abnormal BP Reference 2.43 (1.45, 4.06) < 0.001
aRR abnormal BP Reference 1.85 (1.15, 2.98) 0.011
n 569 56
Normotension 486 (85.4%) 47 (83.9%) 0.75
Pre-hypertension 53 (9.3%) 5 (8.9%)
Diastolic BP
Hypertension 30 (5.3%) 4 (7.1%)
RR abnormal BP Reference 1.10 (0.59, 2.07) 0.76
aRR abnormal BP Reference 0.95 (0.51, 1.78) 0.88
Table 4. Rates of blood pressure abnormalities in a cohort of young adults in Chiang Mai (Thailand)
according to delivery mode. Systolic pre-hypertension, SBP ≥ 130 but < 140 mmHg; systolic hypertension,
SBP ≥ 140 mmHg; abnormal systolic BP, SBP ≥ 130 mmHg; diastolic pre-hypertension, DBP ≥ 85
but < 90 mmHg; diastolic hypertension, DBP ≥ 90 mmHg; and abnormal diastolic BP, DBP ≥ 85 mmHg.
Rates data are n (%); RR data are relative risks and the respective 95% confidence intervals (CI); aRR data
are adjusted RR and respective 95% CI, adjusted for sex, gestational age at delivery, and mother’s pregnancy-
induced hypertension (yes vs no). Systolic and diastolic BP data were missing for 12 and 6 participants born
vaginally, respectively, and for one participant born by C-section. aRR adjusted relative risk, BP blood pressure,
C-section caesarean section, RR relative risk. P values that are statistically significant (at p < 0.05) are shown in
bold.
Data availability
The anonymised data on which this manuscript was based could be made available to other investigators upon
bona fide request, and following all the necessary approvals (including ethics) of the detailed study proposal
and statistical analyses plan. Any queries should be directed to Prof Kittipan Rerkasem (rerkase@gmail.com).
Received: 29 April 2020; Accepted: 26 April 2021
References
1. Vogel, J. P. et al. Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two
WHO multicountry surveys. Lancet Glob. Health 3, e260-270. https://doi.org/10.1016/s2214-109x(15)70094-x (2015).
2. Lavender, T., Hofmeyr, G. J., Neilson, J. P., Kingdon, C. & Gyte, G. M. Caesarean section for non-medical reasons at term. Cochrane
Database Syst. Rev. 3, CD004660. https://doi.org/10.1002/14651858.CD004660.pub3 (2012).
3. Horta, B. L., Gigante, D. P., Lima, R. C., Barros, F. C. & Victora, C. G. Birth by caesarean section and prevalence of risk factors for
non-communicable diseases in young adults: a birth cohort study. PLoS ONE 8, e74301. https://doi.org/10.1371/journal.pone.
0074301 (2013).
4. Pluymen, L. P. et al. Cesarean delivery, overweight throughout childhood, and blood pressure in adolescence. J. Pediatr. 179, 111.
e113-117.e113. https://doi.org/10.1016/j.jpeds.2016.08.059 (2016).
5. Yuan, C. et al. 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 (2016).
6. Zhou, Y. B. et al. Association of elective cesarean delivery with metabolic measures in childhood: a prospective cohort study in
China. Nutr. Metab. Cardiovasc. Dis. 29, 775–782. https://doi.org/10.1016/j.numecd.2019.04.007 (2019).
7. Masukume, G. et al. The impact of caesarean section on the risk of childhood overweight and obesity: new evidence from a con-
temporary cohort study. Sci. Rep. 8, 15113. https://doi.org/10.1038/s41598-018-33482-z (2018).
8. Smithers, L. G., Mol, B. W., Jamieson, L. & Lynch, J. W. Cesarean birth is not associated with early childhood body mass index.
Pediatr. Obes. 12, 120–124. https://doi.org/10.1111/ijpo.12180 (2017).
9. Sutharsan, R., Mannan, M., Doi, S. A. & Mamun, A. A. Caesarean delivery and the risk of offspring overweight and obesity over
the life course: a systematic review and bias-adjusted meta-analysis. Clin. Obes. 5, 293–301. https://doi.org/10.1111/cob.12114
(2015).
10. Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body
habitats in newborns. Proc. Natl. Acad. Sci. U. S. A. 107, 11971–11975. https://doi.org/10.1073/pnas.1002601107 (2010).
11. Tun, H. M. et al. Roles of birth mode and infant gut microbiota in intergenerational transmission of overweight and obesity from
mother to offspring. JAMA Pediatr. 172, 368–377. https://doi.org/10.1001/jamapediatrics.2017.5535 (2018).
12. Castaner, O. et al. The gut microbiome profile in obesity: a systematic review. Int. J. Endocrinol. 2018, 4095789. https://doi.org/10.
1155/2018/4095789 (2018).
13. Ridura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214. https://
doi.org/10.1126/science.1241214 (2013).
14. Li, J. et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 5, 14. https://doi.org/10.1186/
s40168-016-0222-x (2017).
15. Chiang Mai Low Birth Weight Study Group. The risk factors of low birth weight infants in the northern part of Thailand. J. Med.
Assoc. Thail. 95, 358–365 (2012).
16. Rerkasem, K. et al. Higher Alu methylation levels in catch-up growth in twenty-year-old offsprings. PLoS ONE 10, e0120032.
https://doi.org/10.1371/journal.pone.0120032 (2015).
Vol.:(0123456789)
17. Papageorghiou, A. T. et al. The INTERGROWTH-21st fetal growth standards: toward the global integration of pregnancy and
pediatric care. Am. J. Obstet. Gynecol. 218, S630–S640. https://doi.org/10.1016/j.ajog.2018.01.011 (2018).
18. Wallace, T. M., Levy, J. C. & Matthews, D. R. Use and abuse of HOMA modeling. Diabetes Care 27, 1487–1495. https://doi.org/10.
2337/diacare.27.6.1487 (2004).
19. Mancia, G. et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of
arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J. Hyper-
tens. 31, 1281–1357. https://doi.org/10.1097/01.hjh.0000431740.32696.cc (2013).
20. Jeyabalan, A. & Heazell, A. Management of isolated hypertension in pregnancy. In Hypertension in Pregnancy, Cambridge Clinical
Guides (eds. Heazell, A., Norwitz, E., Kenny, L. & Baker, P.) 79–96 (Cambridge University Press, 2010).
21. Markopoulou, P., Papanikolaou, E., Analytis, A., Zoumakis, E. & Siahanidou, T. Preterm birth as a risk factor for metabolic syn-
drome and cardiovascular disease in adult life: a systematic review and meta-analysis. J. Pediatr. 210, 69.e65-80.e65. https://doi.
org/10.1016/j.jpeds.2019.02.041 (2019).
22. Mathai, S. et al. Insulin sensitivity and β-cell function in adults born preterm and their children. Diabetes 61, 2479–2483. https://
doi.org/10.2337/db11-1672 (2012).
23. Skudder-Hill, L., Ahlsson, F., Lundgren, M., Cutfield, W. S. & Derraik, J. G. B. Preterm birth is associated with increased blood
pressure in young adult women. J. Am. Heart Assoc. 8, e012274. https://doi.org/10.1161/JAHA.119.012274 (2019).
24. Catalano, P. M. Obesity and pregnancy—the propagation of a viscous cycle?. J. Clin. Endocrinol. Metab. 88, 3505–3506. https://
doi.org/10.1210/jc.2003-031046 (2003).
25. Catalano, P. M. & Shankar, K. Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother
and child. BMJ 356, j1. https://doi.org/10.1136/bmj.j1 (2017).
26. Palmsten, K., Buka, S. L. & Michels, K. B. Maternal pregnancy-related hypertension and risk for hypertension in offspring later in
life. Obstet. Gynecol. 116, 858–864. https://doi.org/10.1097/AOG.0b013e3181f3a1f9 (2010).
27. Gabory, A., Roseboom, T. J., Moore, T., Moore, L. G. & Junien, C. Placental contribution to the origins of sexual dimorphism in
health and diseases: sex chromosomes and epigenetics. Biol. Sex Differ. 4, 5. https://doi.org/10.1186/2042-6410-4-5 (2013).
28. Rothman, K. J. No adjustments are needed for multiple comparisons. Epidemiology 1, 43–46 (1990).
29. Ferraro, A. A. et al. Cesarean delivery and hypertension in early adulthood. Am. J. Epidemiol. 188, 1296–1303. https://doi.org/10.
1093/aje/kwz096 (2019).
30. Hansen, S. et al. Birth by cesarean section in relation to adult offspring overweight and biomarkers of cardiometabolic risk. Int. J.
Obes. 42, 15–19. https://doi.org/10.1038/ijo.2017.175 (2018).
31. Lavin, T. & Preen, D. B. Investigating caesarean section birth as a risk factor for childhood overweight. Child. Obes. 14, 131–138
https://doi.org/10.1089/chi.2017.0034 (2018).
32. Li, H. T., Zhou, Y. B. & Liu, J. M. The impact of cesarean section on offspring overweight and obesity: a systematic review and
meta-analysis. Int. J. Obes. 37, 893–899. https://doi.org/10.1038/ijo.2012.195 (2013).
33. Darmasseelane, K., Hyde, M. J., Santhakumaran, S., Gale, C. & Modi, N. Mode of delivery and offspring body mass index, over-
weight and obesity in adult life: a systematic review and meta-analysis. PLoS ONE 9, e87896. https://d oi.o
rg/1 0.1 371/j ourna l.p
one.
0087896 (2014).
34. Cai, M. et al. Association of elective and emergency cesarean delivery with early childhood overweight at 12 months of age. JAMA
Netw. Open 1, e185025. https://doi.org/10.1001/jamanetworkopen.2018.5025 (2018).
35. Masukume, G. et al. Association between caesarean section delivery and obesity in childhood: a longitudinal cohort study in
Ireland. BMJ Open 9, e025051. https://doi.org/10.1136/bmjopen-2018-025051 (2019).
36. Rifas-Shiman, S. L. et al. Association of cesarean delivery with body mass index z score at age 5 years. JAMA Pediatr. 172, 777–779.
https://doi.org/10.1001/jamapediatrics.2018.0674 (2018).
37. Stinson, L. F., Payne, M. S. & Keelan, J. A. A critical review of the bacterial baptism hypothesis and the impact of cesarean delivery
on the infant microbiome. Front. Med. 5, 135. https://doi.org/10.3389/fmed.2018.00135 (2018).
38. Almgren, M. et al. Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health?.
Am. J. Obstet. Gynecol. 211, 502.E501-502.E508. https://doi.org/10.1016/j.ajog.2014.05.014 (2014).
39. Staley, J. R. et al. Associations of blood pressure in pregnancy with offspring blood pressure trajectories during childhood and
adolescence: findings from a prospective study. J. Am. Heart Assoc. 4, e001422. https://doi.org/10.1161/jaha.114.001422 (2015).
40. Charoenboon, C., Srisupundit, K. & Tongsong, T. Rise in cesarean section rate over a 20-year period in a public sector hospital in
northern Thailand. Arch. Gynecol. Obstet. 287, 47–52. https://doi.org/10.1007/s00404-012-2531-z (2013).
41. Hanvoravongchai, P., Letiendumrong, J., Teerawattananon, Y. & Tangcharoensathien, V. Implications of private practice in public
hospitals on the cesarean section rate in Thailand. Hum. Resour. Dev. J. 4, 1–11 (2000).
Acknowledgements
This research was supported by Chiang Mai University and Health Systems Research Institute.
Author contributions
A.M., A.R., A.W., K.R., and S.P. conceived and performed the original follow-up study; J.G.B.D., K.R., P.S., and
A.R. conceived this study; A.W., P.S., and J.G.B.D. compiled the data, which were analyzed by J.G.B.D. and P.S.;
A.R., J.G.B.D., S.E.M., and K.R. wrote the manuscript, which was critically revised by A.M., A.W., P.S., and S.P.;
all authors have approved this version of the manuscript and agree with its submission.
Funding
Open access funding provided by Uppsala University. The original follow-up study was supported by Chiang
Mai University and the Health System Research Institute (Thailand).
Competing interests
The authors declare no competing interests.
Additional information
Correspondence and requests for materials should be addressed to J.G.B.D. or K.R.
Reprints and permissions information is available at www.nature.com/reprints.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and
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OPEN Caesarean delivery is associated

Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 1

Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 2

Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 3

Characteristic Levels Lost to follow-up Follow-up study P value

Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 4

Levels Vaginal birth Caesarean section P value

Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 5

Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 6

BP type Outcome Vaginal birth C-section P value

Received: 29 April 2020; Accepted: 26 April 2021

Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 7

Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 8

© The Author(s) 2021

Scientific Reports | (2021) 11:10201 | https://doi.org/10.1038/s41598-021-89438-3 9

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