From pregnancy risk to offspring cardiovascular disease : preeclampsia and preterm birth

<p dir="ltr"><b>Background</b></p><p dir="ltr">Preterm birth and hypertensive disorders of pregnancy are major contributors to perinatal morbidity and mortality, with lasting effects on both maternal and offspring health. Early pregnancy is a critical period for identifying women at risk of complications such as preeclampsia and preterm birth, however effective predictive and preventive tools are lacking. While advances in perinatal care have improved survival for preterm infants, long- term cardiovascular outcomes remain uncertain.</p><p dir="ltr"><b>Aims</b></p><p dir="ltr">This thesis investigates:</p><p dir="ltr">(1) the association between preterm birth < 37 gestational weeks and risk of heart failure in childhood and early adulthood;</p><p dir="ltr">(2) the association between preterm birth < 37 gestational weeks and risk of pulmonary hypertension;</p><p dir="ltr">(3) maternal, interpregnancy, and previous pregnancy factors associated with first-time preeclampsia in second pregnancy; and (4) developing and evaluating a first-trimester prediction model for preterm birth in nulliparous and parous women.</p><p dir="ltr"><b>Methods</b></p><p dir="ltr">This thesis is based on four studies using Swedish nationwide register data and a large Swedish multicentre pregnancy cohort. Studies I-III were register-based cohort studies using the Swedish Medical Birth Register with linkages to Swedish national registers including the National Patient Register, Cause of Death Register, Register of Education, Total Population Register, and Multi-Generation Register. Study IV used data from the prospectively collected IMPACT cohort (Study for Improving Maternal, Pregnancy, and Child Outcomes) linked to the Swedish Pregnancy Register.</p><p dir="ltr">Study I followed over 2.6 million individuals born between 1987 and 2012 from 1 year of age to the end of 2013 for incident heart failure.</p><p dir="ltr">Study II followed over 3.1 million individuals born between 1987 and 2016 from 1 year of age to the end of 2017 for pulmonary hypertension.</p><p dir="ltr">Study III included 808,107 women with first and second consecutive singleton deliveries between 1992 and 2019.</p><p dir="ltr">Study IV included 12,486 women enrolled in the first trimester (10+5 to 14+6 gestational weeks) who subsequently delivered at or after 22 gestational weeks.</p><p dir="ltr">Exposures In Study I and II, the exposures were gestational age at birth and birth weight for gestational age. For Study III the exposures were complications in first pregnancy, interpregnancy changes (weight/BMI, interval, and new onset chronic disease), and maternal characteristics. Study IV evaluated predictors including maternal and obstetric history, biophysical markers (MAP: blood pressure and mean arterial pressure), biochemical (PAPP-A: pregnancy associated plasma protein A and PlGF: placental growth factor) and ultrasound (UtA-PI: uterine pulsatility index) as predictors of preeclampsia.</p><p dir="ltr">Outcomes</p><p dir="ltr">The outcome in Study I was incident heart failure, and in Study II pulmonary hypertension. In Study III, the outcome was first-time preeclampsia in the second pregnancy. In Study IV, the outcomes were preterm birth (<37 weeks) and early preterm birth (<34 weeks), both overall and spontaneous.</p><p dir="ltr">Statistical analyses</p><p dir="ltr">Statistical analyses in this thesis include Poisson regression (Study I), Cox proportional hazards regression (Study II), modified Poisson regression (Study III), and logistic regression and random forest models (Study IV). Prediction model performance in Study IV was assessed through discrimination (area under the curve, AUC), detection rates at predefined screen-positive rates, and calibration assessment. Additional statistical approaches were applied for sensitivity analyses.</p><p dir="ltr"><b>Results</b></p><p dir="ltr">Study I found a higher risk of heart failure among individuals born preterm, compared to term, with the strongest associations among those born extremely preterm. Associations remained robust after adjustment for maternal characteristics, birth weight, parental cardiovascular history, and after excluding congenital malformations.</p><p dir="ltr">Study II demonstrated an elevated risk of pulmonary hypertension following preterm birth, particularly among those born before 32 weeks. Associations persisted in sensitivity analyses and after adjusting for maternal and perinatal factors.</p><p dir="ltr">Study III identified interpregnancy weight gain as a risk factor for first-time preeclampsia in the second pregnancy, while weight loss was associated with lower risk. Previous pregnancy complications, along with interpregnancy diagnosis of chronic disease, were also associated with increased risks.</p><p dir="ltr">Study IV found acceptable performance of models for predicting preterm birth in parous women, but poor performance in nulliparous women. Biophysical, biochemical, and ultrasound markers added modest incremental gains. Performance was slightly better for early preterm birth, but overall predictive capacity remained limited.</p><p dir="ltr"><b>Conclusions</b></p><p dir="ltr">This thesis highlights the long-term cardiovascular consequences of preterm birth for the offspring, as well as the importance of prior pregnancy and interpregnancy factors for maternal risk in future pregnancies. Gestational age at birth adds clinically relevant information to cardiovascular risk assessment in childhood and young adulthood. Interpregnancy weight change is a risk factor for preeclampsia, offering potential opportunities for prevention. Early prediction of preterm birth remains challenging, particularly in nulliparous women. Together, these studies illustrate the strength of Swedish register data for life-course research, and emphasize the need for targeted follow-up and prevention strategies for both mothers and their offspring.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Carr H,</b> Cnattingius S, Granath F, Ludvigsson JF, Edstedt Bonamy AK. Preterm Birth and Risk of Heart Failure Up to Early Adulthood. J Am Coll Cardiol. 2017 May 30;69(21):2634-2642. <a href="https://doi.org/10.1016/j.jacc.2017.03.572" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.jacc.2017.03.572</a></p><p dir="ltr">II. <b>Carr H,</b> Gunnerbeck A, Eisenlauer P, Johansson S, Cnattingius S, Ludvigsson JF, Edstedt Bonamy AK. Severity of preterm birth and the risk of pulmonary hypertension in childhood: A population-based cohort study in Sweden. Paediatr Perinat Epidemiol. 2023 Sep;37(7):630-640. <a href="https://doi.org/10.1111/ppe.12997" rel="noreferrer" target="_blank">https://doi.org/10.1111/ppe.12997</a></p><p dir="ltr">III. <b>Carr H,</b> Johansson K, Snowden JM, Newby-Kew A, Cnattingius S, Ludvigsson JF, Stephansson O, Wikström AK, Sandström A. Maternal and Interpregnancy Factors and Risks of First-Time Preeclampsia in Second Pregnancy: A Swedish National Cohort Study. BJOG. 2025 Sep 1. Epub ahead of print. <a href="https://doi.org/10.1111/1471-0528.18348" rel="noreferrer" target="_blank">https://doi.org/10.1111/1471-0528.18348</a></p><p dir="ltr">IV. <b>Carr H*</b>, Kupka E*, Bergman L, Carlsson Y, Hastie R, Edstedt Bonamy AK, Johansson S, Wang C, Hansson S, Conner P, Lindgren P, Kublickas M, Larsson AO5, Wikström AK, Sandström A. Development of an early pregnancy prediction model for preterm birth - using the Swedish Study for Improving Maternal, Pregnancy, and Child outcomes (IMPACT). Unpublished. [Manuscript]</p><p dir="ltr">*Shared first authors</p>