Interaction between smoking during pregnancy and gestational diabetes mellitus and the risk of cesarean delivery: evidence from the National Vital Statistics System 2019

Abstract Objective To explore the interaction between smoking during pregnancy (SDP) and gestational diabetes mellitus (GDM) on the risk of cesarean delivery. Methods This retrospective cohort study utilized data from the National Vital Statistics System (NVSS) 2019. The NVSS database provides data on births and deaths as well as maternal characteristics in the United States. The duration of follow-up was 38.74 ± 2.12 weeks. The outcome was the method of delivery, including vaginal and cesarean delivery. The multivariate logistic regression model was adopted to assess the associations of SDP and GDM with the method of delivery. The interaction between SDP and GDM was examined via calculating the relative excess risk of interaction (RERI), the attributable proportion of interaction (API) and the synergy index (S). Subgroup analyses were conducted based on age, race, prepregnancy body mass index (BMI), and primiparity. Results The study included 3352615 puerperae. Compared with women who did not smoke during pregnancy, those who smoked during pregnancy had a significantly higher risk of cesarean delivery [odds ratio (OR)=1.07, 95% confidence intervals (CI): 1.05–1.10, p < 0.001]; women with GDM had a significantly greater risk of cesarean delivery than those without (OR = 1.31, 95%CI: 1.30-1.33, p < 0.001). In contrast to women who did not smoke during pregnancy and did not have GDM, those who smoked during pregnancy and had GDM exhibited an increased risk of a cesarean section (OR = 1.47, 95%CI: 1.40–1.54, p < 0.001). RERI was 0.08 (95%CI: 0.01–0.15), API was 0.06 (95%CI: 0.01–0.10), and S was 1.21 (95%CI: 1.04–1.40) suggested that there was an interaction between SDP and GDM, and it was a synergistic effect. There was a synergism between SDP and GDM in women of non-advanced age (RERI = 0.07, 95%CI: 0.001-0.15; API = 0.05, 95%CI: 0.003–0.10; S = 1.17, 95%CI: 1.001–1.36), in white women (RERI = 0.08, 95%CI: 0.004-0.16; API = 0.05, 95%CI: 0.01–0.10; S = 1.19, 95%CI: 1.02–1.39), in women who were overweight before pregnancy (RERI = 0.13, 95%CI: 0.05–0.21; API = 0.08, 95%CI: 0.04–0.13; S = 1.33, 95%CI: 1.14–1.55), and in primiparae (RERI = 0.20, 95%CI: 0.08–0.31; API = 0.12, 95%CI: 0.06–0.19; S = 1.50, 95%CI: 1.23–1.84). Conclusion SDP and GDM were associated with an increased risk of cesarean delivery, and a synergistic effect existed between SDP and GDM on the risk of cesarean delivery, especially in women of non-advanced age, white women, women who were overweight before pregnancy, and primiparae.


Introduction
Nowadays, one out of every three women in the United States has cesarean delivery, and in some parts of the world, four in five women have this delivery [1].In contrast to spontaneous vaginal delivery, cesarean delivery is related to increases in maternal and neonatal morbidity and mortality [2,3].Complications after cesarean delivery comprise pain, wound separation/infection, urinary tract infection, deep vein thrombosis and infectious thrombophlebitis [3].Newborns delivered by cesarean sections are at risk of changed immune development, increased probability of allergy, atopy and asthma, and decreased intestinal microbiome diversity [4].Therefore, it has become a global consensus to control cesarean section rates and reduce possible health risks [5].
Increasing studies focus on and identify the risk factors of cesarean delivery [6][7][8].Among these factors, smoking during pregnancy (SDP) and gestational diabetes mellitus (GDM) are two modifiable factors that have received a lot of attention.In the United States, 12.7% of adult female reported smoking almost every day in 2019 [9], and about half of women continued smoking at gestation [10,11].Smoking cessation measures have been taken to control SDP [12], but SDP remains prevalent in many countries [10].SDP was reported to increase the risk of cesarean delivery [13,14].In addition, SDP was associated with excessive gestational weight gain (GWG), placenta previa and placental abruption [15][16][17].GDM, the most common metabolic disorder during pregnancy affecting the health of pregnant women, develops in about 15% of pregnant women worldwide [18], and can increase the risk of adverse pregnancy outcomes such as cesarean delivery and macrosomia [19,20].Excessive GWG, placenta previa, placental abruption and macrosomia are important indications and risk factors for cesarean delivery [20].In GDM women, excessive GWG was also associated with a higher cesarean section rate [21], and since SDP was associated with excessive GWG [15,22], we speculated that SDP combined with GDM would further increase the risk of cesarean delivery.Besides, current research has assessed the independent impact of SDP or GDM on cesarean delivery, while the combined effect of SDP and GDM on cesarean delivery is still unknown.
This study aimed to explore the interaction between SDP and GDM on the risk of cesarean delivery, based on the National Vital Statistics System (NVSS) database.Subgroup analyses were further conducted to demonstrate whether and how the interaction varied by age, race, prepregnancy body mass index (BMI), and primiparity in this population-based cohort.

Study design and population
This retrospective cohort study utilized data from the NVSS 2019.The NVSS database provides data on births and deaths as well as maternal characteristics in 50 states, New York City, District of Columbia, and 5 territories (Puerto Rico, Virgin Islands, Guam, American Samoa, and Northern Mariana Islands) of the United States [23].The approval of the Institutional Review Committee was waived because NVSS data were de-identified.The study included women (1) aged �18 years old, (2) with an assessment of GDM, (3) with complete information on smoking before and during pregnancy, and (4) with an assessment of methods of delivery in the NVSS database.Women (1) diagnosed with prepregnancy diabetes, (2) with multifetal pregnancies or stillbirths or (3) with missing information on key covariates were excluded.The deadline for follow-up was December 2019.The duration of follow-up was 38.74 ± 2.12 weeks.

Variables
The outcome variable in this study was the method of delivery, which included vaginal delivery and cesarean delivery.The main study variables were SDP and GDM.The question in the NVSS asked for the number of cigarettes (or packs) smoked in the three trimesters of pregnancy.All entries reporting packs of cigarettes were converted to the corresponding number of cigarettes (1 pack ¼ 20 cigarettes).If the mother reported smoking in any of the three trimesters of pregnancy, she was classified as a smoker (smoked anytime during pregnancy); otherwise, she was classified as a nonsmoker.Information on gestational diabetes was collected from the medical record of the mother.If the mother's medical record indicated a diagnosis of glucose intolerance that required treatment during this pregnancy, she was reported as having GDM [24].The covariates were age of the mother at the time of pregnancy [<35 years (non-advanced age), �35 years (advanced age)], race (white, black, Asian, other), educational level (junior high school or below, senior high school, college or more, unknown), marital status (married, unmarried, unknown), smoking status before pregnancy (nonsmoker, 1-10 cigarettes, 11-20 cigarettes, �21 cigarettes), weight gain during pregnancy (pounds), gestational age (weeks), prepregnancy BMI [<18.5 kg/m 2 (underweight), 18.5-24.9kg/m 2 (normalweight), �25.0 kg/m 2 (overweight)], primipara (yes, no), eclampsia (yes, no), prepregnancy hypertension (yes, no), gestational hypertension including preeclampsia (yes, no), chorioamnionitis (yes, no), assisted reproductive treatment (yes, no), previous preterm birth (yes, no), previous cesarean section (yes, no), fetal distress (yes, no), malposition (yes, no), and macrosomia (yes, no).

Statistical analysis
Measurement data were tested for normality using the Kolmogorov-Smirnov test, and measurement data of normal distribution were reported as mean ± standard deviation (Mean ± SD), and the independent-samples t test was used for comparisons between groups.Nonnormally distributed measurement data were shown by median and quartile [M (Q 1 , Q 3 )], and the Mann-Whitney U test was applied for comparisons between groups.Enumeration data were described as the number of cases and the composition ratio [n (%)], and the Chi-square test was adopted for between-group comparisons.Missing data were classified as unknown.
The participants were divided into women who underwent vaginal delivery and cesarean delivery.The univariate logistic regression model was used to explore factors related to the method of delivery (confounding factors), taking the method of delivery as the outcome variable, and all other variables were included in the model (Supplementary Table 1).The univariate and multivariate logistic regression models were adopted to further assess the associations between SDP and the method of delivery and between GDM and the method of delivery, and whether there was an interaction between SDP and GDM: Model 1 was a univariate model; Model 2 was a multivariate model adjusted for age, race, educational level, and marital status; Model 3 was a multivariate model adjusted for age, race, educational level, marital status, previous preterm birth, and previous cesarean section; Model 4 was a multivariate model adjusted for age, race, educational level, marital status, smoking status before pregnancy, weight gain during pregnancy, gestational age, prepregnancy BMI, primipara, eclampsia, prepregnancy hypertension, gestational hypertension, chorioamnionitis, assisted reproductive treatment, previous preterm birth, previous cesarean section, fetal distress, malposition, and macrosomia.Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.To evaluate the interaction between SDP and GDM, the participants were divided into four groups according to SDP and GDM status, and the interaction was examined via calculating the relative excess risk of interaction (RERI), the attributable proportion of interaction (API) and the synergy index (S) together with their 95% CIs.If the 95% CI of the RERI and API contained 0, and the 95% CI of S contained 1, there was no additive interaction.Subgroup analyses were conducted based on age, race, prepregnancy BMI, and primiparity to illustrate if and how the interaction between them on the method of delivery varied by age, race, prepregnancy BMI, and primiparity.
All statistical tests were two-sided, and p < 0.05 denoted statistical significance.Python 3.9 (Python Software Foundation, Delaware, USA) was used for data cleaning, and SAS 9.4 (SAS Institute Inc., Cary, NC, USA) was employed for statistical analyses and interaction tests.

Participant characteristics
The methods of delivery in 1729 puerperae were missing, and the rate of loss to follow-up was 0.05%.Finally, 3352615 puerperae were included in this study.The flow chart of participant selection is shown in Figure 1.Of the included women, 2337796 (69.73%) had a vaginal delivery (vaginal delivery group), and 1014819 (30.27%) had cesarean delivery (cesarean delivery group).For women with vaginal delivery, 2071062 (88.59%) did not smoke during pregnancy and did not have GDM, 134274 (5.74%) did not smoke during pregnancy and had GDM, 124990 (5.35%) smoked during pregnancy and did not have GDM, and 7470 (0.32%) smoked during pregnancy and had GDM.For women with cesarean delivery, 861431 (84.89%) did not smoke during pregnancy and did not have GDM, 89245 (8.79%) did not smoke during pregnancy and had GDM, 58594 (5.77%) smoked during pregnancy and did not have GDM, and 5549 (0.55%) smoked during pregnancy and had GDM.There was a significant difference in SDP and GDM status between women with vaginal delivery and cesarean delivery (p < 0.001).Significant differences were also found in SDP, GDM, age, race, educational level, marital status, smoking status before pregnancy, weight gain, gestational age, prepregnancy BMI, primipara, eclampsia, prepregnancy hypertension, gestational hypertension, chorioamnionitis, assisted reproductive treatment, previous preterm birth, previous cesarean section, fetal distress, malposition, and macrosomia between the vaginal delivery and cesarean delivery groups (all p < 0.001).The cesarean delivery group had significantly more women with GDM or SDP than the vaginal delivery group.Women with vaginal delivery were significantly younger than those with cesarean delivery.Table 1 presents the basic characteristics of the participants.

Associations of SDP and GDM with cesarean delivery
After controlling for age, race, educational level, marital status, smoking status before pregnancy, weight gain during pregnancy, gestational age, prepregnancy BMI, primipara, eclampsia, prepregnancy hypertension, gestational hypertension, chorioamnionitis, assisted reproductive treatment, previous preterm birth, previous cesarean section, fetal distress, malposition, and macrosomia, compared with women who did not smoke during pregnancy, those who smoked during pregnancy had a significantly higher risk of cesarean delivery (OR ¼ 1.07, 95%CI: 1.05-1.10,p < 0.001); women with GDM had a significantly greater risk of cesarean delivery than those without (OR ¼ 1.31, 95%CI: 1.30-1.33,p < 0.001) (Table 2).

Interaction between SDP and GDM on cesarean delivery
In contrast to women who did not smoke during pregnancy and did not have GDM, those who smoked during pregnancy and had GDM exhibited an increased risk of a cesarean section after adjusting for age, race, educational level, marital status, smoking status before pregnancy, weight gain during pregnancy, gestational age, prepregnancy BMI, primipara, eclampsia, prepregnancy hypertension, gestational hypertension, chorioamnionitis, assisted reproductive treatment, previous preterm birth, previous cesarean section, fetal distress, malposition, and macrosomia (OR ¼ 1.47, 95%CI: 1.40-1.54,p < 0.001).RERI was 0.08 (95%CI: 0.01-0.15),API was 0.06 (95%CI: 0.01-0.10),and S was 1.21 (95%CI: 1.04-1.40)suggested that there was an interaction between SDP and GDM, and it was a synergistic effect (Table 3).

Discussion
To our knowledge, the current study first investigated the interaction between SDP and GDM on cesarean delivery and demonstrated that SDP and GDM were associated with an increased risk of cesarean delivery, and there was a synergistic effect between and GDM on the risk of cesarean delivery, especially in women of non-advanced age, white women, women who were overweight before pregnancy, and primiparae.These findings may help clinicians identify women at a high risk of cesarean delivery, and provide references for lifestyle intervention and health management during pregnancy, so as to prevent and control the risk of cesarean delivery.
A prior review showed that smoking over 10 cigarettes a day was related to a higher rate of cesarean delivery [25].Phelan reported that smokers had a greater rate of cesarean sections than nonsmokers (21.9% vs 17.8%), which could be attributed to fetal distress [26].SDP increases the risk of fetal compromise during delivery in women with uncomplicated fullterm singleton pregnancies, leading to an increase in the rate of cesarean or instrumental delivery [14].Consistently, we also found that SDP was associated with an increased risk of cesarean delivery.The underlying reasons may be that women who smoked during pregnancy were at higher risk of placenta previa [16].Nicotine in these women had a vasoconstrictive effect on uterine circulation.Increasing the effective surface area of gas exchange appeared to be an approach to deal with relative hypoxia.The placenta with increased areas was more likely to cover the internal ostium of the cervix, resulting in placenta previa [27].Cigarette smoking was also correlated with an elevated prevalence of placental abruption [28], which led to a higher rate of cesarean delivery [29].Additionally, we confirmed the association between GDM and the risk of cesarean delivery.According to a study by Ye et al. [19], the odds of cesarean delivery were increased in women with GDM.GDM brought many risks to pregnant women and their children, like preeclampsia, macrosomia, and a consequent cesarean section [30,31].Likewise, women with GDM were reported to have a higher likelihood of developing cesarean delivery, especially primary cesarean delivery [32][33][34].Maternal hyperglycemia may lead to fetal overgrowth and neonatal overweight at birth, which may cause higher odds of cesarean sections; for another, women with GDM may affect clinical decision-making, because of elevated incidences of abnormal delivery, birth trauma and fetal distress, which may raise the risk of cesarean delivery [32].
Further, this study revealed synergy between SDP and GDM on the risk of cesarean delivery.Our results showed that there was 0.09 relative excess risk due to the additive interaction, 6% of cesarean delivery exposed to both SDP and GDM was attributable to the additive interaction, and the risk of cesarean delivery in GDM smokers during pregnancy was 1.22 times as high as the sum of risks in the participants exposed to a single risk factor alone.A potential explanation was that SDP exerted a negative influence on the control of blood glucose during pregnancy, through insulin resistance and impaired glucose hemostasis [35].SDP could directly affect insulin-mediated glucose uptake as well as pancreatic b-cell function and insulin secretion [36].The acute effects on glucose homeostasis may result from the reduced gastric emptying of smokers [37].Besides, nicotine can reduce insulin release by directly activating nicotine receptors on pancreatic islet cells [38].In view of the respective impacts of SDP and GDM and the synergistic effect between SDP and GDM on cesarean delivery, women should be encouraged to quit smoking and to monitor and control blood glucose during pregnancy.Interestingly, subgroup analyses based on age, race, prepregnancy BMI, and primiparity demonstrated that a synergistic effect existed between SDP and GDM on the risk of cesarean delivery in women of nonadvanced age, white women, women who were overweight before pregnancy, and primiparae.Thus, the above subpopulations should be counseled on the synergistic effect of SDP and GDM, and stop smoking and have glycemic control when exposed to them.Of note, other subpopulations should also pay attention to the adverse effects of SDP and GDM, and make lifestyle adjustments, when needed, to prevent and lower the risk of cesarean delivery.
As regards the strengths of this study, a large, nationally representative sample was included (n ¼ 3,352,615).The interaction of SDP and GDM on the risk of cesarean delivery was identified for the first time, adjusting for potential confounding factors.The live birth data of the NVSS in one year were selected for analysis, which could effectively avoid the possible heterogeneity in the practice patterns of delivery schemes in different years.Some limitations should be noted when interpreting the results.First, this study focused on singleton pregnancy, which may not be extrapolated to multiple pregnancies that may have a higher cesarean section rate.Second, maternal comorbidities may be underreported, and some indications for cesarean delivery (e.g.fetal head and current pelvic disproportion, placental abruption, and infection of the reproductive tract) are not recorded in the database.Failure to exclude the effect of these confounding factors would overestimate the effect of SDP and GDM on cesarean delivery.The NVSS database also does not have specific information on treatment, such as the status of blood pressure control preeclampsia, whether pregnant women with GDM are under glycemic control by medication, and the status of glycemic control, which may influence our results.Third, this study was performed based on the American population, with limited generalizability.

Conclusion
SDP and GDM were associated with an increased risk of cesarean delivery, and a synergistic effect existed between SDP and GDM on the risk of cesarean delivery, especially in women of non-advanced age, white women, women who were overweight before pregnancy, and primiparae.Future studies are warranted to verify these findings.

Figure 1 .
Figure 1.Flow chart of participant selection.NVSS: the National Vital Statistics System.

Table 1 .
Basic characteristics of the participants.
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Table 2 .
Associations of SDP and GDM with cesarean delivery.
Model 2: a multivariate model adjusted for age, race, educational level, and marital status.Model 3: a multivariate model adjusted for age, race, educational level, marital status, previous preterm birth, and previous cesarean section.Model 4: a multivariate model adjusted for age, race, educational level, marital status, smoking status before pregnancy, weight gain during pregnancy, gestational age, prepregnancy BMI, primipara, eclampsia, prepregnancy hypertension, gestational hypertension, chorioamnionitis, assisted reproductive treatment, previous preterm birth, previous cesarean section, fetal distress, malposition, and macrosomia.SDP: smoking during pregnancy; GDM: gestational diabetes mellitus; BMI: body mass index; Ref: reference; OR: odds ratio; CI: confidence interval.

Table 3 .
Interaction between SDP and GDM on cesarean delivery.
Model 2: a multivariate model adjusted for age, race, educational level, and marital status.Model 3: a multivariate model adjusted for age, race, educational level, marital status, previous preterm birth, and previous cesarean section.Model 4: a multivariate model adjusted for age, race, educational level, marital status, smoking status before pregnancy, weight gain during pregnancy, gestational age, prepregnancy BMI, primipara, eclampsia, prepregnancy hypertension, gestational hypertension, chorioamnionitis, assisted reproductive treatment, previous preterm birth, previous cesarean section, fetal distress, malposition, and macrosomia.SDP: smoking during pregnancy; GDM: gestational diabetes mellitus; BMI: body mass index; RERI: relative excess risk of interaction; API: attributable proportion of interaction; S: synergy index; Ref: reference; OR: odds ratio; CI: confidence interval.