To our knowledge, this study is the first to evaluate relations between systemic and localized maternal comorbidities with PTB by clinical subtype and gestational age. In a large population-based cohort, we demonstrated that comorbidities overall were associated with higher likelihoods of medically indicated PTB, while only comorbidities localized to the reproductive tract were associated with spontaneous PTB. At the population level, several major localized comorbidities (placental abruption, chorioamnionitis, oliogohydramnios, structural abnormality, cervical incompetence) were key contributors to all three clinical subtypes of PTB, especially at < 32 weeks of gestation. In contrast, major systemic comorbidities (preeclampsia, anemia) were the key contributors to medically indicated PTBs, but not spontaneous PTBs. This study is the first to identify anemia as the most important maternal systemic comorbidity contributing to PPROM at the population level.
Hypertension is a major pregnancy complication . We found that preeclampsia/eclampsia was strongly associated with medically indicated PTB, confirming the findings from other studies [1, 4, 27–30]. Data are conflicting as to whether hypertension may be a stronger determinant of early than of late PTB, but previous studies are limited as they often do not differentiate clinical subtypes of PTB [6, 31]. We observed that preeclampsia/eclampsia and pre-existing hypertension were strongly associated with medically indicated PTB at all gestational ages. This was not the case for gestational and unspecified hypertension that were only associated with medically indicated PTB at ≥ 28 weeks, albeit much more weakly. Few studies have evaluated the link between hypertension and spontaneous PTB. Two studies found that pre-existing and gestational hypertension in the US were associated with more than 60% greater odds of spontaneous PTB, but PPROM was not evaluated [29, 32]. In contrast, we found that hypertension was not associated with elevated odds of either PPROM or spontaneous PTB. In fact, ORs were protective for some hypertensive disorders. Close monitoring of hypertensive pregnancies may partly explain the protective associations with PPROM and spontaneous PTB, via shifting of potential PTBs to the medically indicated subtype (through early detection and labour induction).
The influence of diabetes, another common pregnancy complication, also depended on clinical subtype of PTB and gestational age. We confirmed that compared to gestational diabetes, pre-existing diabetes was more strongly associated with medically indicated PTB [18, 33]. Diabetes was associated with greater odds of PPROM after 28 weeks, but the magnitude was also greater for pre-existing than for gestational diabetes. A strong association with spontaneous PTB at 28-31 weeks was only observed for pre-existing diabetes. Other research also suggests strong associations between pre-existing diabetes and spontaneous PTB [18, 29, 33]. One study evaluating the odds of very PTB (< 32 weeks) found strong associations with pre-existing type 1 diabetes, but the clinical subtype of PTB was not differentiated .
Drug dependence and mental disorders are increasingly recognized as drivers of PTB [35–37]. We observed that drug dependence and mental disorders were associated with all clinical subtypes of PTB at most gestational ages. This finding is novel and important because most studies have focused on infections as a cause of PPROM and spontaneous PTB, while other comorbidities have been less studied [1, 8, 38]. Psychological or social stress, psychiatric disorders, and substance abuse have been associated with overall PTB [1, 5, 37, 39], while other research has demonstrated associations between depression and medically indicated PTB at < 35 weeks , and between anxiety/alcohol use and spontaneous PTB . Our findings confirm an association between infections and all PTB clinical subtypes at all gestational ages [1, 8, 10, 11, 32, 42]. Prevention of PTB would likely benefit from greater attention to drug dependence and mental disorders given the probable underreporting of these causes in pregnancy (with consequently underestimated attributable fractions) [35, 36], since the benefits of treatment for infection are uncertain [7, 43, 44].
Remaining causes of systemic comorbidity including cardiovascular disease, edema/renal disease, thyroid disease, and anemia were mainly associated with medically indicated PTB at all gestational ages, as observed elsewhere [4, 18, 30]. Thyroid disease and anemia, however, were mainly associated with PPROM at earlier gestational ages (< 32 weeks). For spontaneous PTB, associations were strong with cardiovascular disease at 28-31 weeks, and weak with thyroid disease at 28-31 weeks and anemia at < 28 weeks. Anemia has been associated with greater odds of spontaneous PTB but not PPROM and medically indicated PTB . Other researchers have observed that thyroid disorders were only associated with PPROM , whereas we found that thyroid disorders were also associated with medically indicated and spontaneous PTBs at 28-31 weeks. More research is needed to better understand the relation between these maternal comorbidities and PTB, especially anemia which was associated with large attributable fractions for PPROM and medically indicated PTB.
Localized comorbidities in general were associated with PTB, especially medically indicated PTB and PPROM at most gestational ages. Several studies have found that overall PTB was associated with cervical incompetence, fetal anomalies, placenta previa, placental abruption, and oligohydramnios [1, 4, 5, 17], and fewer have, like ours, demonstrated stronger associations at lower gestational ages for placental abruption, chorioamnionitis, oligohydramnios, cervical incompetence, and fetal factors [5, 6, 15, 46]. Spontaneous PTB has been linked with placenta previa and abruption, while polyhydramnios/oligohydramnios were associated with both PPROM and spontaneous PTB [1, 14, 42]. Interestingly, we found that previous cesarean delivery was associated with lower odds of PPROM and spontaneous PTB.
This study was subject to limitations. Some comorbidities could not be examined in finer categories due to limited ICD code availability or sample size (e.g., cardiovascular and thyroid disease), and underreporting of certain comorbidities (e.g., drug dependence and mental disorders) is probable. Though hospital data are routinely used for surveillance in Québec , validation of diagnostic (or procedure) codes has not been undertaken, and results should be interpreted in light of probable non-differential misclassification which may have attenuated associations. Though spontaneous PTBs that resulted in cesarean deliveries could not be identified and were classified as medically indicated, our results are consistent with other studies indicating greater frequencies of spontaneous PTB compared with other clinical subtypes [1, 9, 17], which suggests that misclassifications are relatively infrequent. We did not have detailed data on parity or other individual maternal characteristics such as income, race, smoking, genetics, or infertility treatment that are known to be associated with PTB. These characteristics have complex relationships with PTB [1, 13, 47–53], and may be upstream risk factors influencing PTB at least partly through maternal comorbidities. Generalizability of findings to settings without public health insurance is unclear.