The rate of preterm birth (before 37 weeks of gestation) has been increasing steadily over the past decades, reaching 7.7% in 2010 in Canada1 (7.2% in the province of Québec2), 12.0% in the United States,3 and approximately 8.6% overall in developed regions.3 Preterm birth is the leading cause of infant mortality and morbidity in industrialized countries4; nevertheless, the vast majority of these children survive to adulthood.5
A significant proportion of preterm deliveries are not associated with known specific causes but risk factors have been identified, including a woman's own birth weight and preterm birth.5,6 Low-birth-weight women (whether preterm or small for gestational age [SGA]) are at increased risk for hypertensive and diabetic complications of pregnancy.7–10 We have also recently reported that women born preterm, independently of being SGA, show a significantly higher incidence of preeclampsia, gestational hypertension, and gestational diabetes.10 The risk for these pregnancy complications was inversely proportional to the women's gestational age; ie, the higher the degree of prematurity, the higher the risk of pregnancy hypertensive and diabetic complications.10 These pregnancy complications can lead to low birth weight and preterm delivery.11–13 The aim of the present study is to examine 1) the relationship of preterm birth between mothers and their offspring and to examine whether this relationship presents a dose–response relationship—ie, whether the more prematurely born a woman is, the greater her risk of delivering preterm and very preterm, and 2) whether pregnancy hypertensive and diabetic complications can underlie this relationship.
MATERIALS AND METHODS
We studied a cohort comprising all women born preterm in the province of Québec (Canada) between 1976 and 1995 (weight [in grams] and gestational age are registered for all births in Québec since 1976) and who delivered at least one neonate between 1987 and 2008; the methods were previously described in details.10 In brief, this population-based study uses an exposed (born preterm) and unexposed (born term) design and was based on record linkage carried out by the Québec Statistics Institute (“Services d'accès aux données à des fins de recherche Direction des services informationnels et technologiques”—Division for Data Access for Research Purposes, Information and Technology Department) of administrative birth-related data files following the Environment for the Promotion of Health and Welfare protocol (http://www.epsebe.ca/diff/epsebe/web/faces/pages/promotion_sante_bien_etre.jspx). The exposed cohort is the whole population of women born preterm between 1976 and 1995 in Québec. Women born at less than 23 weeks of gestation and those born to multifetal (three or more) pregnancies were excluded. With a frequency matching ratio of 1:2, a cohort of unexposed women (ie, born term: between 37 and 42 weeks of gestation) was constituted according to year of birth and singleton compared with twin status. The women were followed prospectively by linking data from the Government of Québec Demographic Events Registry to data from the Ministry of Health–Health Insured Individuals databases to identify those who have had at least one live birth or stillbirth between 1987 and 2008. This study was approved by the Sainte-Justine University Hospital and Research Center Ethics Board and the Québec Office of the Information and Privacy Commissioner, the Québec Statistics Institute, and the Québec Health Insurance Program.
Medical diagnoses were extracted from the MedÉcho database that includes all hospital-based diagnoses. Diagnoses extracted for study women are the pregnancy complications gestational diabetes, gestational hypertension and preeclampsia and eclampsia, premature rupture of membranes, preterm labor (with or without delivery), chorioamnionitis as well as diabetes type 1 and 2, chronic hypertension, and kidney diseases. In Québec, almost all deliveries occur in hospitals (99.6% in 200814). The following information was collected from the Demographic Events Registry as noted on Declaration of Birth: age, parity, and education level of the mother of study women at the time of birth as well as gestational age and birth weight of the study women and of their newborns. The weight percentile for gestational age was calculated using the Canadian reference charts by Arbuckle et al for the study women15,16 (1972 chart for those born from 1976 to 1979 and 1986 chart for those born 1980–1995) and using the Canadian reference charts by Kramer et al17 for their neonates. A birth weight for gestational age below the 10th percentile or above the 90th percentile was used to categorize SGA or large for gestational age (LGA). The medical diagnoses were categorized according to the International Classification of Diseases, 9th Revision coding system before April 2006 and according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision in the later period.
All analyses were performed using SPSS 19.0. All reported P values are two-sided. Gestational ages were divided a priori into three categories: before 32 weeks of gestation, 32–36 weeks of gestation, and term (37–42 weeks of gestation). Group comparisons were performed on discrete variables using the χ2 test and on continuous variables using analysis of variance. Preterm birth is before 37 weeks of gestation and very preterm birth is before 32 weeks of gestation.
To establish whether a trend exists between gestational age at birth and preterm and very preterm deliveries, logistic regressions were performed using gestational age as a continuous variable and controlling for singleton compared with twin status and year of birth of the participants. Thereafter, logistic regressions were applied using the three groups of gestational age of the study women to obtain the adjusted odds ratio (OR) with 95% confidence intervals (CIs) for distinguishing the effect of own preterm birth from the effect of confounding variables shown to be associated with delivering preterm (see subsequently). The analyses were realized for 1) the risk of delivering preterm (before 37 weeks of gestation) or very preterm (before 32 weeks of gestation) at least once during the study period (with the number of women affected as a unit of measurement and not the number of episodes, eg, a woman with three preterm deliveries was included as n=1 participant, similar to a woman with only one preterm delivery), and 2) the risk of delivering preterm or very preterm at the first live delivery. The former analysis allows a study of all pregnancies of the study participants over the whole study period. The latter analysis allows controlling for confounding factors (such as pregnancy complications) because the database does not date the diagnosis of the associated condition compared with a specific pregnancy unless present at the first live delivery and for the possibility of overestimating the risk of preterm birth when considering in the analysis women with multiple deliveries. All ORs were adjusted for SGA or LGA, multiple birth, and year of birth of the study women for analysis. For analysis of first live deliveries, additional confounding variables were for study women: type 1 or 2 diabetes,18 chronic hypertension,18 kidney disease,18 age younger than 18 years,19 age older than 30 years,18 pregnancy complications,11–13 and for their newborns: gender,20–22 multiple birth23 and SGA.24 Analyses on their neonate SGA or LGA characteristic were adjusted for the neonate's preterm birth.
The initial population was constituted of all women born from 1976 to 1995 in the province of Québec, Canada (Fig. 1): 51,148 women were born preterm and 823,991 women were born term. Because of missing data, being born before 23 weeks of gestation or to multifetal (three or more) pregnancies, 563 women were excluded. The preterm (exposed) cohort comprises 50,585 women and the term (unexposed) cohort comprises 101,170 women. Five thousand twenty-three women born term could not be matched because of insufficient numbers of term-born twins matching for year of birth and singleton (compared with twin) status. Women who had a live-born delivery or a stillbirth between 1987 and 2008 were identified. Overall, 7,405 women born preterm (554 born at before 32 weeks of gestation and 6,851 born between 32 and 36 weeks of gestation) who delivered 12,248 newborns and 16,714 women born term who delivered 27,879 newborns constituted the final sample for analysis. Table 1 presents characteristics of study women at their own birth and their parity during the study period. Table 2 presents characteristics of study women at the time of their first live delivery along with birth characteristics of their newborns.
For the whole study cohort, gestational age of study women was slightly but significantly correlated with gestational age of their first live delivery (r=0.09, P<.001).
Overall, 14.2% of women were born before 32 weeks of gestation, 13.0% of 32–36 weeks of gestation, and 9.8% of those born term delivered prematurely at least once during the study period, including 2.4%, 1.8%, and 1.2%, respectively, delivered very preterm (both P<.001 for trend; Fig. 2). A similar correlation was observed when data at first live delivery only were analyzed (Table 2): the percentage of women with a preterm delivery was 10.3% (n=53) for those born at before 32 weeks of gestation, 9.3% (n=592) for those born at 32–36 weeks of gestation, and 6.8% (n=1,084) for those born term (P<.001 for trend), including, respectively, 1.7% (n=9), 1.2% (n=74), and 0.7% (n=111) very preterm delivery.
When restricting the analysis to singleton women with a singleton first live delivery, the odds of delivering preterm and very preterm increased with decreasing gestational age categories at the woman's own birth (after adjustment for the following mothers' characteristics: SGA, LGA, year of birth, chronic hypertension, kidney disease, type 1 or 2 diabetes, pregnancy complications, age younger than 18 or 30 years or older; and for newborn characteristics: gender and SGA) (Table 3). Broadening the same analysis to all study women's first live delivery (ie, including those born to or delivering a multiple pregnancy) yielded similar results (for all women born at before 37 weeks of gestation, ORs of delivering preterm [before 37 weeks of gestation] are 1.41 [1.27–1.57] and very preterm [before 32 weeks of gestation] are 1.63 [1.22–2.19]; for those born at before 32 weeks of gestation, ORs of delivering preterm are 1.66 [1.23–2.24] and very preterm are 2.52 [1.26–5.06]). Overall, 10.1% of all first live preterm deliveries in current study can be attributed to a mother's preterm birth. Furthermore, 26.5% of first live preterm deliveries that occurred in the group of women born preterm could be attributed to the mother's preterm birth.
At the first live delivery, the occurrence and odds of delivering preterm were higher among women with pregnancy complications, namely gestational diabetes, gestational hypertension, and preeclampsia or eclampsia, both for the women themselves born preterm or term. For all women without pregnancy complications, the occurrence and odds of delivering preterm were also higher among those born preterm compared with term (after adjustment for women's characteristic's: SGA, LGA, singleton status, year of birth, chronic hypertension, kidney disease, type 1 or 2 diabetes, age younger than 18 or 30 years or older; and for their newborns' characteristic's: multiple birth, gender, and SGA) (Table 4).
Overall, the occurrence and odds of at least one preterm delivery at least once during the study period were increased among women born SGA (whether preterm or term) and for all women born preterm after adjustment for being born from a multiple birth or LGA and for their year of birth (Table 5).
Precise socioeconomic status of participants is not included in the administrative databases except for education level, which was available for 96% of their mothers and for 88% of the study women at the time of first live delivery. When we controlled for education level (for the subgroups for which the data were available), overall results were unchanged: at first live delivery, a woman born preterm shows increased risk of preterm and very preterm delivery with the risk increasing with decreasing own gestational age at birth.
Overall, birth weight of study women is significantly correlated to birth weight of their first live born neonate (r=0.18, P<.001). At first live delivery, 17.6% (596) of women born SGA, 10.1% (n=1,804) of those born appropriate for gestational age, and 4.8% (n=81) of those born LGA delivered a SGA neonate. Women born SGA were 2.03 (95% CI 1.83–2.26) more at risk of delivering a SGA neonate compared with non-SGA women (after adjustment for the following women's characteristics: LGA, singleton status, year of birth, chronic hypertension, kidney disease, type 1 or 2 diabetes, pregnancy complications, age younger than 18 or 30 years or older; and for newborns' characteristics: multiple birth, gender, and preterm birth). Women born preterm were also at increased risk of delivering a SGA neonate (for women born before 32 weeks of gestation: OR 1.33 [95% CI 1.01–1.74] and for those born 32–36 weeks of gestation: OR 1.11 [95% CI 1.01–1.21] compared with women born term after adjustment for the same variables as previously mentioned). At first live delivery, 1.4% (n=7) of women born at before 32 weeks of gestation, 1.0% (n=67) at 32–36 weeks of gestation, and 0.6% (n=95) at term delivered a neonate both preterm and SGA (P<.001 for trend).
At first live delivery, 15.0% (n=252) of women born LGA, 6.5% (n=1,155) of women born appropriate for gestational age, and 3.3% (n=112) of women born SGA delivered an LGA neonate. A LGA-born woman is significantly more at risk (OR 2.58, 95% CI 2.22–2.99) to deliver a LGA neonate compared with an appropriate-for-gestational-age-born woman (adjustments as previously mentioned). Whether the woman was born preterm or term did not modify the risk for her neonate to be born LGA.
The present study indicates that the risk of preterm delivery is significantly higher in women who were preterm themselves. Moreover, this risk presents a dose–response relationship with more preterm women being at greater risk of preterm delivery. Overall, the incidence of at least one preterm delivery increased by more than 30% for the whole group of women born preterm compared with term, and the incidence of very preterm delivery (before 32 weeks of gestation) nearly doubled in women born very preterm compared with term. The risk of preterm delivery is present independently of preeclampsia, gestational hypertension, and gestational diabetes, and of being born SGA.
In a systematic review and meta-analysis (22 studies overall), Shah et al6 reported that maternal low birth weight, preterm birth, or SGA was associated with a neonate's low birth weight (less than 2,500 g), preterm birth, and SGA. The subset of studies examining the effects of maternal preterm birth on preterm delivery (both before 37 weeks of gestation)6 shows an incidence of preterm birth of 5.67% for term compared with 8.43% for preterm women with an OR of 1.49 (CI 1.32–1.67), a risk increase similar to current results for women born before 37 weeks of gestation to deliver at 32–36 weeks of gestation. In a subsequent analysis of a large population-based cohort,25 Swamy et al5 showed that the increased risk of preterm delivery among preterm women presented a dose–response pattern, also similar to what we observed here. This study therefore strengthens previous data reporting increased risk of preterm delivery in women born “low birth weight,” SGA, and preterm. Medical conditions associated with preterm birth and which could affect pregnancy duration, including chronic or pregnancy-related hypertension and diabetes, were not mentioned or not taken into account in the analyses of the published studies.5,6,25 No study examined both preterm birth and SGA on the risk of delivering preterm, SGA, or both; the current results show that both conditions contribute to the risk of preterm delivery, which is further increased for women who were born both preterm and SGA.
Other factors associated with increased risk of preterm birth are not included in the administrative databases and therefore in current analyses such as social stress, smoking, alcohol consumption, and body mass index. Many of these are correlated with socioeconomic status and education; precise evaluation of the former is not recorded in administrative databases; however, taking into account education at the time of first live delivery did not change the results. In the United States, the rate of preterm delivery in black women is twice as high as in white women and remains significantly higher after taking into account socioeconomic factors and social stress26–28; rates of preterm delivery according to mother's race are seldom reported by other countries. In Québec, race is not recorded in the Demographic Events Registry; however, as per census reports, the proportion of black race was 3.5% in the province of Québec in 201129 and thus most probably has few effects on the results of the current study. Medical diagnoses of all the mothers of the study women were not available in the current study, preventing analyses of transmitted or inherited risk factors for preterm delivery such as cervical incompetency.
Beside the conditions that were taken into account in the current study, preterm women could carry undiagnosed or yet unrecognized inherited risk factors for preterm birth or as long-term consequences of prematurity-related conditions. In the current cohorts, spontaneous preterm labor and premature rupture of membranes, hallmarks of inflammation in pregnancy, were significantly more frequent in women born preterm. Whether preterm birth leads to enhanced susceptibility to conditions triggering premature labor such as inflammation and infection, including changes in the microbiota,30,31 is not known. Being born preterm is also now a recognized risk factor for chronic hypertension and diabetes. Despite the fact current analyses controlled for these diagnoses, subclinical conditions such as elevated blood pressure and insulin resistance are most probably prevalent and underrecognized in this young population.
This population study shows an increased risk for preterm delivery in women born preterm. The risk is inversely proportional to the woman's gestational age at birth and appears independent of having been born SGA and of gestational hypertension, preeclampsia, and gestational diabetes. With the high percentage of survival of preterm neonates (currently at least 7% of young adults were born preterm32), the effects on incidence of preterm birth are likely to increase. Although current data do not allow recommendations to differ from standard obstetric care, the increased risk of preterm birth (and of pregnancy complications such as gestational diabetes and preeclampsia) should increase awareness and might justify closer follow-up of women otherwise at borderline risk for these pregnancy complications.
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