Preterm birth (PTB), defined by the World Health Organization (WHO) as delivery before 37 completed weeks of gestation, represents a global clinical and public health challenge (1). It is associated with long-term adverse health effects in children and remains the leading cause of neonatal mortality and infant death (2). About 85% of these births are moderate (32–33 weeks) to late preterm babies (34–36 weeks), 10% are very preterm babies (28–31 weeks), and 5% are extremely preterm babies (<28 weeks) (3). Every year, about one million babies die from prematurity, and many survivors are disabled (4).

Numerous studies have demonstrated a link between obesity and preterm birth (5–7). Obesity can exacerbate the physiological inflammation associated with pregnancy (8). This inflammatory state, which is linked to both advanced maternal age and obesity, is a well-established risk factor for preterm birth (9). Additionally, common metabolic dysregulation, such as dyslipidemia, may be linked to inflammation and infection, and elevated inflammatory proteins may result in hypercholesterolemia, which may be linked to blood clot development and result in pregnancy issues such as placental abruption, which can exacerbate PTB (10, 11). Obesity is known as one of the most important public health concerns with a steadily increasing prevalence around the world, which is a well-known risk factor for many aspects of morbidity and mortality (12, 13), as well as causing a high economic burden to society (14). Current estimates suggest that by 2038 about 38% of the world's population is expected to be obese (15). In parallel with the increase in the general population, the prevalence of overweight and obesity also has increased in pregnant women (16). However, not all obese individuals show an equal health risk (17), some individuals may appear obesity but have normal metabolic conditions. They are defined as metabolically healthy obesity (MHO), a condition in which, despite the significant excess weight, traditional risk factors as insulin resistance, dyslipidemia, and hypertension are not present (18–20). Based on different metabolic conditions and body types, the population can be divided into metabolically unhealthy obesity (MUO), metabolically unhealthy normal weight (MUNW), and seven other types of obesity metabolic phenotypes.

Unfortunately, there are currently few thorough investigations on the relationship between obesity's metabolic abnormalities and pregnancy complications, with the majority of research on the metabolic phenotypes of obesity concentrating on cardiovascular disorders (21–23). In order to enrich this part of the research, we conducted a prospective birth cohort study among Chinese pregnant women. Our main goals are to quantify the separate and combined contributions of obesity and metabolic abnormalities to these pregnancy problems, as well as to clarify the relationship between metabolic obesity phenotypes and the incidence of PTB.

The present study showed that women who were overweight, including obese, were more likely to develop PTB than women who were normal weight, and that people with metabolic abnormalities were more likely to develop PTB even if they had the same weight phenotype. We also found that there was an additive and multiplicative interaction between PTB and metabolic abnormalities and overweight.

Pregnant women who are obese are at greater risk of a variety of pregnancy-related complications compared with women of normal BMI (27). Several studies have shown that the risk of PTB is positively related to obesity. A large prospective cohort study from China showed that compared to women with normal weight, women with overweight or obesity before pregnancy had an increased risk of preterm birth. In addition, the greatest risk of extremely preterm birth was observed in obese women (7). Ju et al. (28) found that overall maternal obesity (BMI ≥ 30.0 kg/m²) and extreme obesity (BMI ≥ 40.0 kg/m²), were both associated with higher rates of prematurity after controlling for other confounders including maternal race, age, socioeconomic status, and smoking during pregnancy. Obesity can enhance the inflammatory status induced by pregnancy (29), which is characterized by a state of chronic inflammation, oxidative stress, and dysregulated adipokine secretion and will promotes the release of damage-associated molecular patterns (DAMPs). These DAMPs amplify uterine and chorioamnionic inflammation via inflammasome activation, potentially leading to intra-amniotic inflammation, which increase the risk of spontaneous extremely preterm birth. In addition, Obesity compromises placental function through multiple interconnected pathways: chronic inflammation and oxidative stress directly damage placental cells and impair nutrient exchange; epigenetic alterations (e.g., DNA methylation) disrupt gene expression patterns critical for placental development; and dysregulation of metabolic mediators (e.g., leptin, apelin) disrupts vascular tone and angiogenesis, while maternal vascular malperfusion is a well-established risk factor for indicated preterm birth (30). Collectively, these mechanisms may lead to PTB (31).

Numerous diseases are directly linked to metabolic issues, which raises the risk of developing a variety of ailments. Despite having a normal BMI, poor metabolic health still raises the risk of many diseases. Numerous studies have linked metabolic abnormalities to both poor pregnancy outcomes and chronic (32–34) and cardiovascular disease (35, 36). Numerous studies have demonstrated that women with a history of hypertension illnesses during pregnancy are more likely to have cardiovascular disease later in life than those with normotensive pregnancies (37). A study including more than 600,000 women in Norway showed that hypertension during pregnancy was associated with an increased risk of subsequent CVD in comparison with normotensive pregnancy and the highest risk was observed when hypertension was combined with small-for-gestational-age infants and/or preterm delivery (38). Inflammation and infection may help explain the association between metabolic abnormalities and PTB. For example, the lipid changes could relate to infammation and infection, and that hypertriglyceridemia may be considered part of the innate immunity and that increased inflammatory proteins may cause hypercholesterolemia. Studies have shown that high cholesterol may contribute to the formation of blood clots, which can lead to complications during pregnancy, such as placental abruption, which can promote PTB (11). It is noteworthy that our results imply that the development of PTB is significantly influenced by the metabolic state prior to pregnancy. PTB is more common in metabolically unhealthy women than in those who are metabolically healthy, and the risk of PTB rises as the number of metabolically unfavorable components rises. This demonstrates the significance of metabolic status as a risk factor for obstetric issues and validates the results of other previous studies (1, 39–41). Meanwhile, among individuals with metabolic abnormalities, the risk of PTB is significantly increased for both normal-weight and overweight women, which illustrates the importance of the metabolic screening in normal-weight women and to reduce the risk of metabolic abnormalities by improving lifestyle habits, such as maintaining a balanced diet and engaging in regular physical activity. For high-risk individuals with metabolic abnormalities, medications like metformin can be used to lower the risk of developing metabolic diseases.

In this sizable population cohort study, we also evaluated the combined impact of obesity and metabolic disorders on PTB. Compared with MHNW women, we discovered that MUNW and MUO women were more likely to have PTB, which was same as the previous study (25). Among overweight women, PTB was much more common in those with metabolic problems. It is worth noting that among individuals with metabolic abnormalities, the risk of PTB is significantly increased for both normal-weight and overweight women. Interaction analysis shows that overweight and metabolic abnormalities have both additive and multiplicative interactions on the occurrence of PTB which demonstrated that the additive interaction accounts for 24% of PTB events in those exposed to both risk factors (metabolically unhealthy and overweight).

The large sample size and the evaluation of interactions between body weight status and metabolic phenotypes on PTB, as well as a quantitative assessment of the association between obesity and metabolic abnormalities, were the primary strengths of our work. However, the present study has several limitations. First, the pre-pregnancy weight used to calculate BMI is provided by the study population, which may affects the accuracy of the BMI calculation. In addition, the BMI cannot show the distribution of body fat or differentiate between lean and fat mass (42). Second, several subgroup analyses were performed with a limited number of studies, making it difficult to achieve a firm conclusion about the findings. Another potential limitation of this study is its hospital-based design. As the sample was recruited from clinical settings rather than the general community, it is susceptible to Berkson's bias. The case mix and risk factor estimates observed in our study may not be directly generalizable to the wider Chinese population. Future studies employing a population-based design are warranted to validate our findings. It is important to note that the study population is from a region with a relatively low mean BMI. This leaner body-habitus distribution resulted in a limited number of individuals with high body mass index in the cohort, creating a “restricted range of exposure.” Methodologically, this most likely led to an attenuation of the effect size of the association between BMI and preterm birth. Therefore, our study might not have fully captured the stronger association that could exist in a population with a broader BMI spectrum. Future research involving multi-center populations with diverse BMI distributions is needed to validate our findings and quantify this association more accurately. We acknowledge that our study may be subject to residual confounding, and its single-center design may affect generalizability. The use of self-reported BMI could lead to non-differential misclassification, likely biasing results toward the null, while the lack of direct visceral adiposity measures is a recognized constraint. Potential misclassification of metabolic status, also likely non-differential, was also noted. Despite these limitations, we have taken care to contextualize our findings and emphasize that they provide valuable hypothesis-generating insights, underscoring the need for future multi-center studies with more precise measurements to confirm our results. Beside, the diagnosis of metabolic abnormalities in early pregnancy carries a risk of over-diagnosis. Physiological adaptations of early pregnancy, such as hemodilution from plasma volume expansion, vasodilation induced by progesterone, and stimulation of thyroid function by human chorionic gonadotropin (hCG), can alter metabolic parameters away from their pre-pregnancy baselines. These adaptations mean that the most diagnostic criteria we employed (such as blood pressure, glucose), which are based on thresholds derived from non-pregnant populations or fixed cut-offs, may have reduced specificity in the context of pregnancy, erroneously categorizing some normal physiological adaptations as pathological states. Future research aimed at establishing pregnancy-specific and gestational-age-adjusted diagnostic criteria for metabolic parameters would greatly enhance the accuracy of such studies.

In conclusion, our study shows that obesity and metabolic disorders have multiplicative and additive interaction effect on PTB and are linked to an increased risk of PTB. Aside from that, metabolic disorders may make normal-weight women more vulnerable to PTB. Therefore, clinical monitoring and treatment of the pregnant woman's metabolism, together with appropriate risk classification and improved prevention, are necessary in addition to focus on overweight or obesity.