Risk of stillbirth after a previous caesarean delivery: A Swedish nationwide cohort study

To investigate the risk of stillbirth in relation to (1) a previous caesarean delivery (CD) compared with those following a vaginal birth (VB); and (2) vaginal birth after caesarean (VBAC) compared with a repeat CD.

also performed in situations when neither the mother nor the fetus is at risk of complications.4][5] Sweden has one of the lowest CD rates in Europe, but the CD rate has also increased over the last two decades from 15.5% in 2000 to almost 18% in 2020, with approximately 83%-88% of the total increase accounting for repeat CD. 6,7 Due to the increased frequency of CD, studies have been conducted to assess the impact of CD on subsequent pregnancy outcomes, 8 particularly the risk of stillbirth 9,10 and preterm birth. 11,12tillbirth, a baby born with no signs of life, is one of the most common serious adverse pregnancy outcomes.Approximately 2 million babies were stillborn at or after 28 weeks of gestation in 2019, with a global rate of 13.9 per 1000 births. 13In highincome countries, stillbirth rates vary widely from 1.3 to 8.8 per 1000 births. 14A systematic review and meta-analysis conducted in 2011 to identify important risk factors for stillbirth in highincome countries reported a 21% increased odds of stillbirth (odds ratio [OR] 1.21; 95% confidence interval [CI] 1.07-1.37) in mothers with a previous CD. 15Similarly, a more recent metaanalysis reported a 23% increased odds of stillbirth following CD (pooled OR 1.23; 95% CI 1.08-1.40). 9Although both reviews reported similar findings, they were limited by high heterogeneity, due in part to variation in the cause and timing of stillbirth.A 2020 Norwegian cohort study also reported a slightly higher odds of stillbirth following CD (adjusted OR [aOR] 1.45; 95% CI 1.22-1.73), 16but the authors did not evaluate the impact of the type of CD on the reported associations. 16Given the increasing rates of CD, a potential association between CD, specifically unnecessary CD, and subsequent stillbirth is of significant concern.
In pregnancies following a CD, birth can be achieved either by a repeat planned CD, known as elective repeat caesarean section or by attempting a vaginal birth (VB), known as vaginal birth after caesarean (VBAC).Limited studies have evaluated perinatal outcomes relating to VBAC, 16,17 and evidence on the association between VBAC and stillbirth is lacking and requires further investigations.For these reasons, we conducted this population-based cohort study to investigate if offspring in deliveries following a previous CD have a higher risk for stillbirth than offspring where the mother had a previous VB.We also examined the risk of stillbirth in women who had a VBAC delivery compared with those who had an elective repeat caesarean section.We hypothesised that women with previous CD have a higher risk of adverse pregnancy outcome compared with those with a previous VB.

| Study design and data sources
In this nationwide population-based cohort study, we used data from the Swedish Medical Birth Register (MBR), covering about 99% of all births in Sweden, and we included women with singleton births between 1 January 1982 and 31 December 2012.
The obstetric history of each woman, including data on comorbidity (such as diabetes, hypertension and cardiovascular diseases), was obtained from the MBR and the Swedish National Patient Register.Data from these registers were linked using a unique Swedish personal identification number. 18All diagnoses and complications during pregnancy or delivery are classified according to the Swedish version of the International Classification of Diseases (ICD), using the ICD-8 until 1986, the ICD-9 (1987 to 1996), and the ICD-10 since 1997.This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (Table S1).

| Study population
The study cohort consisted of women who had their first two births between 1982 and 2012.Women who had a singleton birth with available data on the mode of delivery on the first delivery were included.We excluded records where the first pregnancy was a multiple gestation or resulted in stillbirth.Ethical approval was obtained from the Regional Ethical Review Board in Stockholm.

| Mode of birth
Mode of birth was categorised into VB and CD.We further subclassified this as follows: (1) spontaneous VB (reference group), (2) assisted VB (vacuum/forceps), (3) pre-labour CD (before the onset of labour), (4) in-labour CD (after the onset of labour) and ( 5) unspecified CD, where data on the type of CD were not available.The variable was defined in this way to assess the effect of specific types of mode of birth in the first birth on the risk of stillbirth in the second pregnancy.
Then we considered mode of birth in both first and second births to assess the impact of VBAC on the risk of stillbirth, in which mode of birth was grouped as follows: (1) repeat CD (CD in both pregnancies, [reference group]), (2) VBAC, (3) first VB and subsequent CD, and (4) VB in both pregnancies.It should be noted that mode of delivery recorded in the MBR is the 'final' mode of delivery, which may differ from the woman's intended mode of delivery.For example, a woman may attempt a trial of labour after a CD and fail, ending up with an in-labour CD.Hence, our study groups represent a good reflection of what happens in 'realworld' situations.

| Outcome
The outcome of interest was stillbirth (antepartum and intrapartum fetal death).We used data from the Swedish MBR to identify stillbirths in the second pregnancy.This was defined as fetal death after 28 completed weeks of gestation (until June 2008) and fetal death after 22 completed weeks of gestation since July 2008.
We classified stillbirth into explained and unexplained stillbirth using an adapted version of the ReCoDe (RElevant COndition at DEath) classification system.The ReCoDe classification system is designed in a hierarchical manner to organise relevant clinical conditions associated with death in utero.It contains nine main categories, starting from A (conditions affecting the fetus) to I (unclassified), and each category is divided into several subgroups. 19These categories include a wide range of clinical conditions related to the fetus, the placenta, the mother and intrapartum conditions.On the other hand, unexplained cases are divided into two subcategories; cases with irrelevant conditions despite information or cases lacking available information. 19e used the diagnosis variables from the MBR and Swedish National Patient Register to classify stillbirth according to the underlying conditions of the ReCoDe classification system.All diseases and complications during pregnancy or delivery were classified according to the Swedish version of ICD codes.In addition, small for gestational age (SGA) was defined as a birthweight below 2 standard deviations of the population mean birthweight adjusted for sex-specific and gestational age distributions or according to ICD codes (codes are shown in Table S2).

| Statistical analysis
Maternal and birth characteristics are presented according to stillbirth and mode of delivery (Tables S3-S5) using frequency and percentages for categorical variables or mean with standard deviation for continous variables.Logistic regression models were performed to evaluate all associations using crude OR and aOR, along with 95% CI.First, we estimated the odds of stillbirth in the second birth following a CD in the first delivery, compared with the outcome of second deliveries following a previous VB.Second, we expanded the exposure variable to evaluate the impact of specific types of mode of delivery, specifically pre-labour CD and in-labour CD, on the associations.Finally, in a third model, we considered the mode of delivery in the first and second births to estimate the odds of stillbirth in women with a VBAC compared with women with a repeat CD.
Adjusted models included maternal age, BMI, smoking, education, country of origin, year of delivery, comorbidities (diabetes, chronic hypertension, cardiovascular disease) and pregnancy-related disorders (gestational diabetes, gestational hypertension and pre-eclampsia) in the first pregnancy.We added a missing data category to control for missing data on BMI and smoking.
We undertook subgroup analysis based on ReCoDe classification categories, including a specific cause of stillbirth for explained stillbirths (cases with a known condition for death).We conducted separate analyses for causes of death restricted to stillbirths caused by: lethal congenital anomaly, SGA/fetal growth restriction, any cord issue, placental abruption, any placental abnormalities, any maternal conditions, uterine rupture and intrapartum asphyxia/birth trauma.We additionally evaluated the association between a previous CD and explained stillbirth (including any relevant condition), unexplained stillbirth (including cases without relevant condition) and, finally, relevant versus no relevant condition (Table S7).
We performed sensitivity analyses according to birth defects, pre-eclampsia, gestational diabetes, preterm birth, SGA and time period.We also calculated the population attributable fraction (details are shown in Appendix S1, page 2).
Statistical analyses were performed using Stata version 16.1 (StataCorp, College Station, TX, USA), and all tests were two-sided with a 5% significance level.

| R E SU LTS
During the study period (1982-2012), 1 771 700 singleton births from 885 850 women were identified as eligible participants (Figure S1).Of the 885 850 women in the cohort, 2428 had a stillbirth in the second pregnancy (2292 were antepartum stillbirths and 136 were intrapartum stillbirths), resulting in a rate of 2.7 per 1000 births.Women who had a stillbirth in their second pregnancy were older, more likely to be smokers, had higher BMI and had higher rates of chronic hypertension and diabetes, but lower gestational age compared with women who had a live birth in their second pregnancy (Table 1).The ReCoDe classification system indicated that fetal causes accounted for approximately 27% of the total stillbirths and the SGA/fetal growth restriction was the most frequent factor (21.2%, Table 2).The second most frequent cause was placental abruption (5.5%), followed by intrapartum asphyxia (4.4%).
The demographic characteristics of women and their babies according to mode of delivery are shown in Tables S3-S5.In first pregnancy, 117 114 (13.2%) mothers had a CD, while 768 736 (86.7%) had a VB.In the second pregnancy, almost half (53.6%) of the women with a previous CD also had a CD in their subsequent pregnancy compared with 46.3% of women who had a VBAC.While 5.4% of mothers who had a VB in their first pregnancy had a CD in their subsequent pregnancy.
Table 3 presents the crude and adjusted OR of the association between CD in the first pregnancy and the risk of subsequent stillbirth.After adjusting for potential confounders, mothers with a previous CD had higher odds for antepartum stillbirth (aOR 1.35; 95% CI 1.21-1.51),intrapartum stillbirth (aOR 1.67; 95% CI 1.09-2.53)and any stillbirth (aOR 1.37; 95% CI 1.23-1.52)compared with mothers with a previous VB.
Analyses by type of CD in the first pregnancy showed increased odds of any subsequent stillbirth in women with a pre-labour CD (aOR 1.31; 95% CI 1.09-1.58)and in-labour CD (aOR 1.36; 95% CI 1.19-1.55),compared with women with a previous VB (Table 4).The odds of antepartum stillbirth were similarly higher in mothers with a previous   4).
No association was found between VBAC and intrapartum stillbirth (aOR 0.99; 95% CI 0.48-2.06)(Table S6).Similar results were found when VBAC was grouped according to type of CD in the second pregnancy into: (1) VB after pre-labour CD and (2) VB after in-labour CD.Neither type of CD was associated with intrapartum stillbirth (Table S10).
On the other hand, women who had a CD after VB had an increased odds for both antepartum stillbirth (aOR 2.50; 95% CI 1.92-3.25)and intrapartum stillbirth (aOR 3.01; 95% CI 1.67-5.43)compared with women who had a repeat CD (Table S6).However, in the subgroup analyses by types of CD, the increased odds of antepartum and intrapartum stillbirth were only observed in women who had in-labour CD after VB (aOR 3.67; 95% CI 2.76-4.89and aOR 5.86; 95% CI 3.20-10.7,respectively, Table S10), suggesting that increased risk of stillbirth could be a result of complications during birth.
The results from the subgroup analysis by cause of stillbirth according to ReCoDe classification (Table S7) suggested that maternal conditions (aOR 1.78; 95% CI 1.31-2.42)and intrapartum asphyxia (aOR 2.04; 95% CI 1.41-2.97)have a significant impact on the association between CD and subsequent stillbirth.However, the results of other causes did not reach statistical significance (Table S7).Additionally, we found 69% increased odds of explained stillbirth, with any known relevant condition (OR 1.69; 95% CI 1.46-1.94),but almost no effect for the unexplained cases (OR 1.08; 95% CI 0.92-1.27).We also found that the risk of unexplained stillbirth differed with gestational age.In an additional analysis of restricted gestational age of 34 weeks or more (n = 872 351), the odds of unexplained stillbirth were 1.18 (95% CI 1.00-1.38),but this was attenuated after adjusting for confounding factors to 1.11 (95% CI 0.94-1.30).
Results from sensitivity analyses were similar to the main findings (Appendix S1, pages 1 and 2, Tables S8 and S9).The population attributable fraction associated with previous CD was 0.049, meaning that CD in the first pregnancy accounted for approximately 5% of all subsequent stillbirths in the studied population.

| Main findings
In the present study, we assessed the association between CD and subsequent stillbirth, and the impact of VBAC on stillbirth using data from the Swedish MBR.The results show that women with a previous CD had an increased risk of subsequent stillbirth by 37%, and the risk was similar for both pre-labour CD (31% increase) and in-labour CD (36% increase).Pre-labour CD was associated with subsequent intrapartum stillbirth, but not in-labour CD.However, we did not find enough evidence of increased odds for intrapartum stillbirth in women who had a VBAC (compared with women who had a repeat CD).

| Strengths and limitations
The strengths of the present study include the use of national register-based data and the ability to make a linkage between registers, which minimises risk of selection bias.As this is one of the largest studies investigating the risk of stillbirth following a previous CD, we were also able to conduct several subgroup and sensitivity analyses.We further classify stillbirth based on timing into antepartum and T A B L E 3 Odds ratios with 95% CI for stillbirth in the second pregnancy of 117 114 mothers who had a caesarean delivery in the first pregnancy compared with 768 736 mothers who had a vaginal birth in the first pregnancy.intrapartum stillbirth, well into explained and unexplained stillbirths.We restricted the analyses to singletons because CD and pregnancy complications related to stillbirth are more common in multiple gestations. 20We also restricted the analyses to mothers who had live births in their first pregnancy because women with a history of stillbirth have an almost five times higher risk of subsequent stillbirth. 21We used a data set of the first two births per woman in Sweden over three decades between 1982 and 2012; however, we acknowledge this as a limitation of the current study because there have been changes in obstetric practices in the past 40 years.We attempted to address this limitation by conducting a sensitivity analysis, where we restricted the cohort to the time period from July 2008 to December 2012 (to evaluate whether change in stillbirth definition had any impact on the reported associations) the results showed that all CD were associated with an increased odds of antepartum stillbirth and intrapartum stillbirth.When we further evaluated this according to CD types, only pre-labour CD was associated with subsequent intrapartum stillbirth, meaning that our results were consistent over the last three decades and unlikely to be influenced by changes in definitions of stillbirth.Limitations to the study include the possibility of misclassification for data on the clinical conditions (explaining cause of stillbirth) as data on some conditions, such as vasa praevia, were only available in ICD-9 and ICD-10.Other limitations were related to unmeasured confounders, as this is an observational study.

| Implications (in light of other evidence)
Our finding regarding the increased risk for subsequent stillbirth in pregnancies with a previous CD is consistent with several other studies. 16,22,23,24,25,26However, most of the previous studies had inconsistencies and weaknesses in the methods and statistical analysis.For example, most studies did not exclude stillbirth from the first birth, which is strongly associated with subsequent stillbirth. 21ur findings agree with those from a recent Norwegian cohort study of 294 598 singleton second births, which reported a 33% increased odds of antepartum stillbirth (aOR 1.33; 95% CI 1.08-1.63)and an 84% increased odds of intrapartum stillbirth (aOR 1.84; 95% CI 1.00-3.38), 16although the timing of CD was not considered in this study.
When analysed by cause of fetal death, excess risk was apparent for unexplained stillbirth from 34 weeks of gestation as previously observed. 10,24It should be noted however that both studies failed to adjust for maternal comorbidities and our results attenuated to almost no effect in the adjusted model.
We found no increased odds of intrapartum stillbirth in women who had VBAC compared with those with repeat CD.It must be acknowledged however that there were few cases of intrapartum stillbirth (n = 13) in women who had a VBAC.To our knowledge, none of the previous studies assessed the risk of stillbirth while adjusting for potential confounders in women who had a VBAC, possibly because T A B L E 4 Odds ratios with 95% CI of the associations between mode of delivery in the first pregnancy and stillbirth in the subsequent pregnancy.of rarity of this event.Findings from a review meta-suggested a higher rate of perinatal mortality in women who had a VBAC compared with a planned repeat CD (0.13% versus 0.05%), but no data were reported on stillbirth. 17wo studies reported inconsistent results for the association between perinatal death and neonatal death in women with a first CD undergoing VBAC. 27,28Smith et al. assessed the risk of perinatal mortality, including intrapartum stillbirth and neonatal death, using a large Scottish registry data set of 313 238 singleton births and reported 11 times greater odds (aOR 11.7; 95% CI 1.4-101.6)compared with women with a repeat CD. 27 However, the reported CI were very wide, and the authors did not adjust for maternal comorbidities.The second study by O'Neill et al. 28 evaluated the risk of neonatal and infant death in women with a VBAC compared with women with a repeat CD using data from the Danish registry, including 61 626 births.The authors reported no increased odds of late neonatal death (aOR 0.97; 95% CI 0.22-4.32)or infant death (aOR 1.12; 95% CI 0.79-1.59). 28ur analysis demonstrates that maternal conditions (including hypertensive disorders of pregnancy) and intrapartum asphyxia have a significant impact on the association between CD and subsequent stillbirth.This provides information that could formulate a causal hypothesis for the observed association.A case-control study found that the uterine artery Doppler waveform between 18 and 22 weeks of gestation is more likely to be notched (14.5% versus 6%, p < 0.001) and have a higher average pulsatility index (1.25 versus 1.16, p < 0.02) in women who had an elective CD compared with a VB. 29 Notably, women who had a previous CD also have a higher incidence of pre-eclampsia. 30,31Further research is required to further our understanding of a causal relationship between CD and stillbirth; these studies suggest that investigation of impaired placental blood flow merits further exploration.

| CONCLUSIONS
The findings of this study reinforce that a previous CD is associated with an increased risk of subsequent stillbirth, with the greatest risk for subsequent intrapartum stillbirth in women who had a previous pre-labour CD.The association could be explained, to some extent, by underlying maternal and intrapartum conditions.These findings might help women and healthcare providers to reach optimal decisions regarding mode of delivery.Considering the important public health consequences of stillbirth, further large-scale studies are needed to confirm findings of the present study, particularly to evaluate the association between VBAC and intrapartum stillbirth, as this will strengthen the current recommendations for the management of pregnancy following CD.

AU T HOR C ON T R I BU T ION S
ASK and AEPH conceived the study, SAK and ASK prepared the data and conducted the statistical analysis.SAK drafted the manuscript with support from AEPH, ASK, MK and KK.All co-authors critically revised the manuscript, and have given approval of the submitted version.

C ON F L IC T OF I N T E R E S T S TAT E M E N T
None declared.

DATA AVA I L A BI L I T Y S TAT E M E N T
The data that support the findings of this study cannot be made freely available because they are subject to secrecy in accordance with the Swedish Public Access to Information and Secrecy Act.Data are, however, available from the authors upon reasonable request and with permission from the Swedish Central Ethical Review Board (kansli@cepn.se).Requests for data can be made to the Department of Medical Epidemiology and Biostatistics in Karolinska Institutet (internservice@meb.ki.se).

T A B L E 1
Maternal characteristics and infant characteristics in the second pregnancy.
None.Open access funding provided by IReL.F U N DI NG I N FOR M AT ION AEPH is supported by Tommy's charity via Centre funding to the University of Manchester, and the KK is supported by the Swedish Research Council (Vetenskapsrådet 2018-00932 GOING-FWD).
Classification of stillbirth according to the ReCoDe (Relevant Condition at Death) system.
Abbreviations: CD, caesarean delivery; VB, vaginal birth.aThisincludes pre-eclampsia and gestational hypertension.T A B L E 2 c This includes chronic kidney disease and cardiovascular disease.pre-CD(aOR 1.24; CI 1.02-1.50)and in-labour CD (aOR 1.36; 95% CI 1.19-1.55),compared with mothers with a previous VB.However, the risk of intrapartum stillbirth was higher in the pre-labour CD group (aOR 2.72; 95% CI 1.51-4.91)than the in-labour CD group (aOR 1.35; 95% CI 0.76-2.40),although this was not statistically significant for the latter group.Additionally, there was no statistically significant association between subsequent stillbirth and previous instrumental VB (Table
a b Includes both antepartum and intrapartum stillbirth.