Association of multiple pregnancies with risk of preterm birth in the United States: a retrospective cohort study

Introduction

Preterm birth (PTB) is defined as birth before 37 weeks’ gestation (1,2). Recent data from the National Vital Statistics System (NVSS) showed the percentage of newborns delivered preterm rose 4% in 2021, from 10.09% in 2020 to 10.49% of all births (3). PTB is a major contributor to perinatal mortality and morbidity, representing roughly 35% of deaths in this population (4). Therefore, it is critical to make continued efforts to identify modifiable and preventable risk factors of PTB.

The prevalence of multiple pregnancies (MPs) in the United States (US) has risen substantially in recent years, influenced by factors such as delayed childbearing and advancements in fertility treatments (5). According to NVSS statistics, the birth rate of twins and triplets and higher-order multiple birth rate increased by 2% in 2021 compared to 2020 (3). One possible reason is that mothers are getting older to conceive in the current social environment (6). And another reason is the rising incidence of infertility, leading to more mothers receiving infertility treatment (especially assisted reproductive technology) to become pregnant successfully, which has also led to an increase in MPs. MPs are linked to a heightened risk of morbidity and mortality in both fetuses and infants (7), including an estimated fivefold rise in stillbirth risk and a sevenfold increase in neonatal death risk, primarily due to complications related to PTB (8). In addition, MPs significantly increase costs in the antenatal and neonatal periods, in large part due to the costs associated with preterm (9). The average first-year medical costs in care for preterm infants are 10 times higher than for full-term infants (10), which has greatly increased the financial burden on families and the country.

Common reasons for PTB include pre-eclampsia or eclampsia, as well as intrauterine growth restriction. The risk factors for spontaneous PTB include a previous history of PTB, black race, periodontal disease, maternal sexually transmitted infections, smoking during pregnancy, and a low maternal body mass index (BMI) (1,2,10,11). Most of these studies have focused on singleton pregnancies and PTB, however, studies examining the association between MPs and PTB are limited. Furthermore, previously published studies have only illustrated higher rates of PTB in MPs (5,6,12,13), but they did not specify the risk degree associated with MPs compared to those of single pregnancies. Therefore, real-world studies based on a large sample size in nationwide and combined multi-dimensional variables are essential to clarifying how MPs may lead to PTB. Thus, in this cohort study, we utilized nationwide birth data from the US to investigate the relationship between MPs and the risk of PTB in over 22 million mother-infant pairs. The results of this study may allow us to understand the extent of the risk of PTB in different MPs relative to single pregnancies, and provide reference value for prenatal and perinatal management planning formulation, so as to reduce the risk of PTB in MPs. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2024-518/rc).

Methods

We conducted a retrospective cohort analysis using nationwide birth certificate data from the NVSS, spanning January 2016 to December 2021, which provides the most complete data on births and deaths from 50 states and the District of Columbia in the US. The NVSS represents the oldest and most successful example of intergovernmental data sharing in public health. The collaborative relationships, established standards, and procedures create the framework through which the National Center for Health Statistics (NCHS) collects and disseminates the nation’s official vital statistics. Standardized forms for data collection and model procedures for uniform event registration are developed and recommended for nationwide implementation through cooperative efforts between jurisdictions and the NCHS. The NVSS provides a complete enumeration of vital events (births, deaths, marriages, etc.) across all US registration areas, with national representation. Vital events are registered by law, ensuring near-complete coverage. The data is collected by medical professionals, funeral directors, or hospital staff based on the 2003 revision electronic registration standard to improve timeliness and accuracy, and is filed by healthcare providers. All states and territories are required to adopt the standardized certificates. States transmit data to NCHS, which performs additional validation before national publication to protect respondent confidentiality and assure data quality. No sampling is used for core data collection. In this study, we used birth data, including all 22,669,736 mothers who had a live birth with available data on number of fetuses and gestational age at birth. This study was approved as exempt from review and informed consent requirements by the institutional review board at the Guangzhou Women and Children’s Medical Center because it used public database data. This study was carried out in compliance with the Declaration of Helsinki and its subsequent amendments.

Exposure measurement and outcome

Exposure measurement in our study was MPs (twin, triplet, and quadruplet or higher). Information on MPs were collected directly from the medical record in facility worksheet. The primary outcome was the diagnosis of PTB, defined as a gestational age of less than 37 weeks. Gestational age was determined using the obstetric estimate of gestation at delivery, which was directly obtained from the worksheet. Secondary outcomes included extremely PTB (less than 28 weeks gestation), very PTB (28 to 31 weeks gestation), and moderate PTB (32 to 36 weeks gestation).

Covariates

Data on age, race or ethnicity, nativity, pre-pregnancy BMI, maternal education, marital status, and smoking during pregnancy were obtained using the standardized Mother’s Worksheet during birth registration. Information regarding previous PTB, history of cesarean delivery, pre-pregnancy diabetes, pre-pregnancy hypertension, gestational diabetes, gestational hypertension, pre-eclampsia, eclampsia, infertility treatment, prenatal care, and maternal sexually transmitted infections (such as gonorrhea, syphilis, or chlamydia) was sourced from the facility worksheet, which is directly derived from the medical records.

Statistical analysis

We assessed the maternal characteristics and distribution of sociodemographic and according to MPs and PTB, respectively. Comparisons between categorical variables were conducted using Chi-squared (χ²) tests. We calculated the risk of PTB for mothers with MPs (twin, triplet, and quadruplet or higher) with those with single pregnancy, respectively. We also compared the risk of PTB for mothers with any kinds of MPs compared with single pregnancy. The odds ratios (ORs) and 95% confidence intervals (CIs) of PTB were estimated by multivariable logistic regression models. Multinomial logistic regression models were used to calculate ORs and 95% CIs for the subtypes of PTB (i.e., extremely PTB, very PTB, and moderately PTB).

In model 1, we adjusted for maternal age (<25, 25–34, ≥35 years), and race or ethnicity (Hispanic, non-Hispanic White, non-Hispanic Black, non-Hispanic Asian). In model 2, we further adjusted for mother’s nativity (born in the US, born outside the US), maternal education level (less than high school, high school, more than high school), marital status (married, unmarried), previous history of PTB (yes, no), previous history of cesarean (yes, no), pre-pregnancy BMI (underweight, <18.5 kg/m²; normal weight, 18.5–24.9 kg/m²; overweight, 25.0–29.9 kg/m²; obesity, ≥30.0 kg/m²), pre-pregnancy diabetes (yes, no), pre-pregnancy hypertension (yes, no), gestational diabetes (yes, no), gestational hypertension (yes, no), eclampsia (yes, no), infertility treatment (yes, no), smoking during pregnancy (yes, no), prenatal care (yes, no), gonorrhea (yes, no), syphilis (yes, no), and chlamydia (yes, no). The variables mentioned above were selected based on univariate analysis and review of the literature. We used the R² to assess the model fit assessment of model 2.

We performed stratified analyses based on age and race or ethnicity to investigate whether the relationship between MPs and PTB varied across these demographic factors. The P value for interaction was calculated using multivariable logistic regression models that included multiplicative interaction terms.

We performed sensitivity analyses by excluding pregnant women who receive infertility treatment because these women are more likely to have MPs. We performed another sensitivity analysis by excluding pregnant women with gestational complication (gestational diabetes, gestational hypertension, or eclampsia) due to these women are more likely to experience PTB. In addition, due to a woman may had more than one pregnancy over a 6-year period [2016–2021], we further conducted a sensitivity analysis using data from each year. Two-sided P<0.05 were considered statistically significant. All statistical analyses were conducted using IBM SPSS Statistic 27.0.

Results

This study involved 22,669,736 mothers who gave birth to live infants. The mean [standard deviation (SD)] age was 29.05 (5.8) years; 5,365,989 (23.7%) mothers identified as Hispanic, 11,680,688 mothers (51.5%) as non-Hispanic White, 3,269,219 (14.4%) as non-Hispanic Black, and 1,418,537 (6.3%) as non-Hispanic Asian (Table 1). Among the mothers, 732,289 (3.2%) were twin pregnancy, 19,573 (0.1%) were triplet pregnancy, and 1,066 (<0.1%) were quadruplet or higher pregnancy. Among the newborns, 2,683,587 (11.8%) were categorized as PTB.

The rate of PTB was 10.2% (2,242,028 of 21,916,808 births), 57.6% (422,097 of 732,289), 94.2% (18,446 of 19,573), and 95.3% (1,016 of 1,066) for women with single, twin, triplet and quadruplet or higher, respectively. In addition, MPs had higher very and extremely PB rate (18.9% in twin, 38.4% in triplet, and 77.9% in quadruplet or higher) compared with single pregnancy (15.2%).

Higher rates of twin, triplet, and quadruplet or higher pregnancies were found among mothers with age 25–34 years [e.g., twin: 434,466 (3.3%) vs. age <25 years, 118,093 (2.2%)], the Black women [135,277 (4.1%) vs. the White women, 402,563 (3.4%)], women with higher education [higher than high school, 486,600 (3.5%) vs. high school, 165,122 (2.9%)], women who were married [426,412 (3.5%) vs. unmarried, 240,038 (2.9%)], women who not smoked during pregnancy [685,306 (3.2%) vs. yes, 43,408 (3.1%)], women with previous history of preterm [41,398 (5.2%) vs. no, 690,248 (3.2%)], women with history of cesarean [128,825 (3.7%) vs. no, 602,821 (3.1%)], or women who received prenatal care [698,325 (3.2%) vs. not, 11,964 (2.9%)] (Table 1). Table S1 listed the population characteristics based on PTB and PTB subcategories.

In the all population, mothers who with MPs had an increased risk of PTB compared with mothers with single pregnancy. The adjusted OR of PTB was 12.03 (95% CI: 11.97–12.10) for twin, 139.08 (95% CI: 130.43–148.30) for triplet, 161.17 (95% CI: 118.80–218.65) for quadruplet or higher, and 12.51 (95% CI: 12.44–12.58) for any kinds of MPs after adjustment for age, race or ethnicity, nativity, education, marital status, previous history of PTB and cesareans, infertility treatment, pre-pregnancy BMI, pre-pregnancy diabetes, pre-pregnancy hypertension, gestational hypertension, gestational diabetes, eclampsia, smoking during pregnancy, chlamydia, gonorrhea, syphilis, and prenatal care (Table 2). In addition, we subdivided PTB into three degrees: moderately, very, and extremely PTB. We identified a significant association among all three kinds of MPs evaluated with moderate, severe, and extreme PTB. The adjusted OR of moderately PTB was 11.43 (95% CI: 11.36–11.49) for twin, 102.00 (95% CI: 95.53–108.91) for triplet, and 41.24 (95% CI: 29.50–57.65) for quadruplet or higher; the adjusted OR of very PTB was 14.11 (95% CI: 13.94–14.29) for twin, 374.22 (95% CI: 348.26–402.10) for triplet, and 806.36 (95% CI: 586.99–1,107.69) for quadruplet or higher; the adjusted OR of extremely PTB was 15.22 (95% CI: 14.99–15.46) for twin, 313.30 (95% CI: 288.88–339.79) for triplet, and 1,017.26 (95% CI: 733.29–1,411.18) for quadruplet or higher. Significant associations of any kinds of MPs with three kinds of degree of PTB were also found. The adjusted OR of moderately, very and extremely PTB were 11.76 (95% CI: 11.69–11.82), 15.40 (95% CI: 15.22–15.59) and 16.42 (95% CI: 16.18–16.67) for any MPs (Table 2), respectively.

In the stratified analyses by age, significant associations with PTB were observed for MPs in all age groups. The adjusted OR for any MPs was 14.24 (95% CI: 14.06–14.43), 13.25 (95% CI: 13.15–13.34), and 10.01 (95% CI: 9.89–10.12) among mothers younger than age 25, 25–34, and 35 years or older, respectively (Table 3). We also found MPs increased the risk of PTB among Hispanic (OR, 8.55; 95% CI: 8.45–8.65), non-Hispanic White (OR, 13.53; 95% CI: 13.45–13.62), non-Hispanic Black (OR, 9.52; 95% CI: 9.41–9.64), and non-Hispanic Asian (OR, 11.71; 95% CI: 11.42–12.01) mothers. Due to the small sample size of quadruplet or higher in Asian mothers, leading to the results were less stable (Table 4).

The results were robust in the sensitivity analyses that excluded pregnant women who received infertility treatment (Table S2). The sensitivity analyses, which included additional adjustments for pregnancy complications, produced comparable results (Table S3). Furthermore, the associations remained consistent in sensitivity analyses utilizing one year of data from 2016 to 2021 (refer to Table S4).

Discussion

By analyzing data from a national population of over 22 million women in the US, we identified a significant association between MPs and PTB. This relationship was consistent across various age, racial, and ethnic groups, and the results remained robust in sensitivity analyses.

A Previous study reported that approximately 60% of twin were born prematurely in developed countries (12), which was consistent with our results (57.6%). However, most studies focus on twin pregnancy and PTB, and researches on the association of triplets or higher and PTB are sparse, which may be limited by the low incidence of triplets or higher and thus the small sample size. In this study, we found the women with triplets and quadruplets had extremely high rates of PTB—94.2% and 95.3%, respectively. Consistent with our findings, Razavi et al. (14) reported that the PTB in triplet was 96.0% (88 cases). In addition, the rate of very PTB (from 11.7% in twin to 44.8% in quadruplets or higher) and extremely PTB (from 7.2% in twin to 33.1% in quadruplets or higher) showed a significantly increasing trend with the increase of the number of fetuses.

The direct potential mechanisms between MPs and PTB remain to be elucidated. However, MPs lead to PTB may due to their own characteristics and the pregnancy-related complications caused by them (8,13). In twin pregnancy, chorionicity is an important factors that contribute to the development of PTB (15). Compared with dichorionic twin, monochorionic diamniotic twin are at higher risk of PTB. The preterm of monochorionic diamniotic twin may associated with twin-to-twin transfusion syndrome, selective intrauterine growth restriction (16) and twin anemiaepolycythemia sequence (17). However, the study on chorionicity in triplets or higher is lacking. In terms of complications secondary to MPs, the frequency of uterine contractions may be a potential factor, showing that twin had higher frequency of uterine contractions compared to singletons, however, there was no difference between PTB and full-term (18). Another complication is amniotic fluid (AF) sludge which is a risk factor for PTB. A study found that twin pregnancies (78 cases) had higher prevalence of AF sludge than singleton pregnancies (34.6% vs. 22.6%) (19). In addition, women with MPs are more like to experience gestational diabetes mellitus, hypertensive disorders of pregnancy, hemorrhage, and cesarean delivery, these diseases are closely associated with PTB (20-26).

This research has important clinical and public health implications. MPs significantly increases the risk of PTB compared with single pregnancy. More than half of mothers with MPs are at risk of PTB, which may increase the fetal and infant morbidity and mortality. Mothers received infertility treatment are more likely to have MPs and have significantly higher rates of PTB. This phenomenon raises the question of whether mothers undergoing infertility treatment (especially assisted reproductive technology) should opt for a single pregnancy in order to reduce the risk of PTB and ensure the health of the newborn. Additionally, multifetal reduction can lower the risk of spontaneous preterm delivery and neonatal complications by reducing the number of fetuses (5). A study found that mothers with triplets who underwent pregnancy reduction to twins experienced lower rates of PTB and antenatal complications, with a risk of PTB comparable to mothers of spontaneously conceived twin pregnancies (27). Another study found that multifetal reduction from twin to a singleton before 15-week gestation can reduce the risk of PTB (28). Multifetal reduction may decrease the risk of preeclampsia in women with higher-order multifetal gestations (29). Therefore, multifetal reduction may be a potential option to decrease the risk of PTB in MPs women. This study confirms that MPs (twin, triplets, and quadruplets) is one of the risks of PTB, which may give us some implications that mothers with MPs may need more attention and management from family, hospital, and society in life and medical care.

There are several limitations in this study. Firstly, the data on cesarean deliveries were not provided in this database. Therefore, for mothers who delivered by cesarean section, we were unable to obtain information on whether mothers passively chose to PTB or actively chose to PTB, and we were unable to perform subgroup analyses of PTB caused by cesarean and spontaneous PTB, which might have a small impact on the results. Secondly, although we adjusted for many factors, however, some other factors that closely associated with PTB were not provided in NVSS, such as vaginal bleeding, cervical length (30), maternal thyroid function (31), maternal marijuana use (32), and so on. Therefore, we cannot exclude the possibility of potential residual confounding arising from these factors or unknown factors. Thirdly, the data used in this study were all from the US (high-income country), reducing their applicability in other countries, particularly in low- and middle-income countries.

Conclusions

In this national study based on the real-world birth data in the US, MP was associated with an increased risk of PTB. Pregnancies involving three or more fetuses were associated with exceptionally high rates of PTB, exceeding 94% in our cohort. The severity of PTB increased significantly with the number of fetuses. These findings are suggestive of women with MP warranting targeted prevention for PTB.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2024-518/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2024-518/prf

Funding: This study was funded by the Clinical PhD Starting Research Fund of Guangzhou Women and Children’s Medical Center (to T.G.) (No. 2023BS021) and the President Foundation of Zhujiang Hospital, Southern Medical University (to T.W.) (No. yzjj2023qn26).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2024-518/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was carried out in compliance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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