Recent Advances in Genomic Studies of Gestational Duration and Preterm Birth.

Preterm birth (PTB) is the leading cause of infant mortality and morbidity. For several decades, extensive epidemiologic and genetic studies have highlighted the significant contribution of maternal and offspring genetic factors to PTB. This review discusses the challenges inherent in conventional genomic analyses of PTB and underscores the importance of adopting nonconventional approaches, such as analyzing the mother-child pair as a single analytical unit, to disentangle the intertwined maternal and fetal genetic influences. We elaborate on studies investigating PTB phenotypes through 3 levels of genetic analyses: single-variant, multi-variant, and genome-wide variants.

Smoking during pregnancy and its effect on placental weight: a Mendelian randomization study.

BACKGROUND: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. METHODS: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 690 to 804) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (N = 4267 to 4606). The sample size depends on the smoking definition used for different analyses. The analysis was performed in pre-pregnancy smokers only, due to the specific role of the single-nucleotide polymorphism (SNP) rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation. RESULTS: Fixed effect meta-analysis showed a 182 g [95%CI: 29,335] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal effect on placental weight was 11 g [95%CI: 1,21] per cigarette per day. Similarly, smoking at the end of pregnancy was causally associated with higher placental weight. Using the residuals of birth weight regressed on placental weight as the outcome, we showed evidence of lower offspring birth weight relative to the placental weight, both for continuing smoking at the start of pregnancy as well as continuing smoking throughout pregnancy (change in z-score birth weight adjusted for z-score placental weight: -0.8 [95%CI: -1.6,-0.1]). CONCLUSION: Our results suggest that continued smoking during pregnancy causes higher placental weights.

Global health systems strengthening: FIGO's strategic view on reducing maternal and newborn mortality worldwide.

OBJECTIVE: To demonstrate that successful health systems strengthening (HSS) projects have addressed disparities and inequities in maternal and perinatal care in low-income countries. METHODS: A comprehensive literature review covered the period between 1980 and 2022, focusing on successful HSS interventions within health systems' seven core components that improved maternal and perinatal care. RESULTS: The findings highlight the importance of integrating quality interventions into robust health systems, as this has been shown to reduce maternal and newborn mortality. However, several challenges, including service delivery gaps, poor data use, and funding deficits, continue to hinder the delivery of quality care. To improve maternal and newborn health outcomes, a comprehensive HSS strategy is essential, which should include infrastructure enhancement, workforce skill development, access to essential medicines, and active community engagement. CONCLUSION: Effective health systems, leadership, and community engagement are crucial for a comprehensive HSS approach to catalyze progress toward universal health coverage and global improvements in maternal and newborn health.

European Association of Perinatal Medicine (EAPM), European Board and College of Obstetricians and Gynaecologists (EBCOG), European Midwives Association (EMA). Joint position statement: Substandard and disrespectful care in labour - because words matter.

Substandard or disrespectful care during labour should be of serious concern for healthcare professionals, as it can affect one of the most important events in a woman's life. Substandard care refers to the use of interventions that are not considered best-practice, to the inadequate execution of interventions, to situations where best-practice interventions are withheld from patients, or there is lack of adequate informed consent. Disrespectful care refers to forms of verbal and non-verbal communication that affect patients' dignity, individuality, privacy, intimacy, or personal beliefs. There are many possible underlying causes for substandard and disrespectful care in labour, including difficulties in modifying behaviours, judgmental or paternalistic attitudes, personal interests and individualism, and a human tendency to make less arduous, less difficult, or less stressful clinical decisions. The term "obstetric violence" is used in some parts of the world to describe various forms of substandard and disrespectful care in labour, but suggests that it is mainly carried out by obstetricians and is a serious form of aggression, carried out with the intent to cause harm. We believe that this term should not be used, as it does not help to identify the underlying problem, its causes, or its correction. In addition, it is generally seen by obstetricians and other healthcare professionals as an unjust and offensive term, generating a defensive and less collaborative mindset. We reach out to all individuals and institutions sharing the common goal of improving women's experience during labour, to work together to address the underlying causes of substandard and disrespectful care, and to develop common strategies to deal with this problem, based on mutual comprehension, trust and respect.

Characterizing of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta marked by elevated amniotic fluid interferon gamma-induced protein 10 (IP-10) in pregnancies complicated by preterm prelabor rupture of membranes.

OBJECTIVES: This study aimed to determine the occurrence of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta, marked by elevated levels of interferon gamma-induced protein 10 (IP-10) (≥2200 pg/mL) in the amniotic fluid of women with preterm prelabor rupture of membranes (PPROM). Specifically, the study investigated whether these intra-amniotic inflammatory changes were more common in women with microbial invasion of amniotic cavity (MIAC) and intra-amniotic inflammation (IAI), as indicated by increased amniotic fluid interleukin (IL)-6 concentration (≥3000 pg/mL). STUDY DESIGN: A cohort of 114 women with singleton pregnancies complicated by PPROM between 24+0 and 36+6 weeks of gestation were included. Amniotic fluid samples were obtained via amniocentesis upon admission. MIAC diagnosis involved aerobic and anaerobic cultures, as well as polymerase chain reaction (PCR) analysis of the amniotic fluid. Immunoassay tests and enzyme-linked immunosorbent assay (ELISA) were used to determine IL-6 and IP-10 concentrations, respectively. RESULTS: Among the participants, 19.3 % and 15.8 % had MIAC and IAI, respectively. The occurrence of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta was similar between women with and without MIAC (25 % vs. 40.9 %, p = 0.136, adjusted p = 0.213). The rate of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta was significantly higher in women with IAI compared to those without, after adjusting for gestational age at sampling (55.6 % vs. 22.9 %, p = 0.005, adjusted p = 0.011). CONCLUSION: This study revealed comparable rates of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta in women with and without MIAC, but a higher prevalence of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta in women with IAI. These findings suggest involvement of chronic inflammation even in women with PPROM with acute intra-amniotic inflammation.

Angiogenic imbalance in pregnancies with preterm prelabor rupture of membranes between 34 and 37 weeks of gestation.

INTRODUCTION: This study aimed to identify whether microbial invasion of the amniotic cavity and/or intra-amniotic inflammation in women with late preterm prelabor rupture of membranes (PPROM) was associated with changes in concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and its ratio in maternal serum, and whether placental features consistent with maternal vascular malperfusion further affect their concentrations. MATERIAL AND METHODS: This historical study included 154 women with singleton pregnancies complicated by PPROM between gestational ages 34+0 and 36+6 weeks. Transabdominal amniocentesis was performed as part of standard clinical management to evaluate the intra-amniotic environment. Women were categorized into two subgroups based on the presence of microorganisms and/or their nucleic acids in amniotic fluid (determined by culturing and molecular biology method) and intra-amniotic inflammation (by amniotic fluid interleukin-6 concentration evaluation): (1) those with the presence of microorganisms and/or inflammation (at least one present) and (2) those with negative amniotic fluid for infection/inflammation (absence of both). Concentrations of sFlt-1 and PlGF were assessed using the Elecsys® sFlt-1 and Elecsys® PlGF immunoassays and converted into multiples of medians. RESULTS: Women with the presence of microorganisms and/or inflammation in amniotic fluid had lower serum concentrations of sFlt-1 and sFlt-1/PlGF ratios and higher concentrations of PlGF compared with those with negative amniotic fluid. (sFlt-1: presence: median 1.0 multiples of the median (MoM), vs negative: median: 1.5 MoM, P = 0.003; PlGF: presence: median 0.7 MoM, vs negative: median 0.4 MoM, P = 0.02; sFlt-1/PlGF: presence: median 8.9 vs negative 25.0, P = 0.001). Higher serum concentrations of sFlt-1 and sFlt-1/PlGF ratios as well as lower concentrations of PlGF were found in the subsets of women with maternal vascular malperfusion than in those without maternal vascular malperfusion. CONCLUSIONS: Among women experiencing late PPROM, angiogenic imbalance in maternal serum is primarily observed in those without both microbial invasion of the amniotic cavity and intra-amniotic inflammation. Additionally, there is an association between angiogenic imbalance and the presence of maternal vascular malperfusion.

The Role of cfDNA Biomarkers and Patient Data in the Early Prediction of Preeclampsia: Artificial Intelligence Model.

OBJECTIVE: Accurate individualized assessment of preeclampsia risk enables the identification of patients most likely to benefit from initiation of low-dose aspirin at 12-16 weeks' gestation when there is evidence for its effectiveness, as well as guiding appropriate pregnancy care pathways and surveillance. The primary objective of this study was to evaluate the performance of artificial neural network models for the prediction of preterm preeclampsia (<37 weeks' gestation) using patient characteristics available at the first antenatal visit and data from prenatal cell-free DNA (cfDNA) screening. Secondary outcomes were prediction of early onset preeclampsia (<34 weeks' gestation) and term preeclampsia (≥37 weeks' gestation). METHODS: This secondary analysis of a prospective, multicenter, observational prenatal cfDNA screening study (SMART) included singleton pregnancies with known pregnancy outcomes. Thirteen patient characteristics that are routinely collected at the first prenatal visit and two characteristics of cfDNA, total cfDNA and fetal fraction (FF), were used to develop predictive models for early-onset (<34 weeks), preterm (<37 weeks), and term (≥37 weeks) preeclampsia. For the models, the 'reference' classifier was a shallow logistic regression (LR) model. We also explored several feedforward (non-linear) neural network (NN) architectures with one or more hidden layers and compared their performance with the LR model. We selected a simple NN model built with one hidden layer and made up of 15 units. RESULTS: Of 17,520 participants included in the final analysis, 72 (0.4%) developed early onset, 251 (1.4%) preterm, and 420 (2.4%) term preeclampsia. Median gestational age at cfDNA measurement was 12.6 weeks and 2,155 (12.3%) had their cfDNA measurement at 16 weeks' gestation or greater. Preeclampsia was associated with higher total cfDNA (median 362.3 versus 339.0 copies/ml cfDNA; p<0.001) and lower FF (median 7.5% versus 9.4%; p<0.001). The expected, cross-validated area under the curve (AUC) scores for early onset, preterm, and term preeclampsia were 0.782, 0.801, and 0.712, respectively for the LR model, and 0.797, 0.800, and 0.713, respectively for the NN model. At a screen-positive rate of 15%, sensitivity for preterm preeclampsia was 58.4% (95% CI 0.569, 0.599) for the LR model and 59.3% (95% CI 0.578, 0.608) for the NN model.The contribution of both total cfDNA and FF to the prediction of term and preterm preeclampsia was negligible. For early-onset preeclampsia, removal of the total cfDNA and FF features from the NN model was associated with a 6.9% decrease in sensitivity at a 15% screen positive rate, from 54.9% (95% CI 52.9-56.9) to 48.0% (95% CI 45.0-51.0). CONCLUSION: Routinely available patient characteristics and cfDNA markers can be used to predict preeclampsia with performance comparable to other patient characteristic models for the prediction of preterm preeclampsia. Both LR and NN models showed similar performance.

FIGO Preconception Checklist: Preconception care for mother and baby.

The preconception period is a unique and opportunistic time in a woman's life when she is motivated to adopt healthy behaviors that will benefit her and her child, making this time period a critical "window of opportunity" to improve short- and long-term health. Improving preconception health can ultimately improve both fetal and maternal outcomes. Promoting health before conception has several beneficial effects, including an increase in seeking antenatal care and a reduction in neonatal mortality. Preconception health is a broad concept that encompasses the management of chronic diseases, including optimal nutrition, adequate consumption of folic acid, control of body weight, adoption of healthy lifestyles, and receipt of appropriate vaccinations. Use of the FIGO Preconception Checklist, which includes the key elements of optimal preconception care, will empower women and their healthcare providers to better prepare women and their families for pregnancy.

Low CD4 + T cell count is related to specific anti-nuclear antibodies, IFNα protein positivity and disease activity in systemic lupus erythematosus pregnancy.

BACKGROUND: Lymphopenia, autoantibodies and activation of the type I interferon (IFN) system are common features in systemic lupus erythematosus (SLE). We speculate whether lymphocyte subset counts are affected by pregnancy and if they relate to autoantibody profiles and/or IFNα protein in SLE pregnancy. METHODS: Repeated blood samples were collected during pregnancy from 80 women with SLE and 51 healthy controls (HC). Late postpartum samples were obtained from 19 of the women with SLE. Counts of CD4 + and CD8 + T cells, B cells and NK cells were measured by flow cytometry. Positivity for anti-nuclear antibodies (ANA) fine specificities (double-stranded DNA [dsDNA], Smith [Sm], ribonucleoprotein [RNP], chromatin, Sjögren's syndrome antigen A [SSA] and B [SSB]) and anti-phospholipid antibodies (cardiolipin [CL] and ß2 glycoprotein I [ß2GPI]) was assessed with multiplexed bead assay. IFNα protein concentration was quantified with Single molecule array (Simoa) immune assay. Clinical data were retrieved from medical records. RESULTS: Women with SLE had lower counts of all lymphocyte subsets compared to HC throughout pregnancy, but counts did not differ during pregnancy compared to postpartum. Principal component analysis revealed that low lymphocyte subset counts differentially related to autoantibody profiles, cluster one (anti-dsDNA/anti-Sm/anti-RNP/anti-Sm/RNP/anti-chromatin), cluster two (anti-SSA/anti-SSB) and cluster three (anti-CL/anti-ß2GPI), IFNα protein levels and disease activity. CD4 + T cell counts were lower in women positive to all ANA fine specificities in cluster one compared to those who were negative, and B cell numbers were lower in women positive for anti-dsDNA and anti-Sm compared to negative women. Moreover, CD4 + T cell and B cell counts were lower in women with moderate/high compared to no/low disease activity, and CD4 + T cell count was lower in IFNα protein positive relative to negative women. Finally, CD4 + T cell count was unrelated to treatment. CONCLUSION: Lymphocyte subset counts are lower in SLE compared to healthy pregnancies, which seems to be a feature of the disease per se and not affected by pregnancy. Our results also indicate that low lymphocyte subset counts relate differentially to autoantibody profiles, IFNα protein levels and disease activity, which could be due to divergent disease pathways.

Effective and simple interventions to improve outcomes for preterm infants worldwide: The FIGO PremPrep-5 initiative.

Preterm birth remains the leading cause of mortality among under-5's and is a major contributor to the reduction in quality-of-life adjusted years and reduction in human capital. Globally, there are many interventions and care bundles that aim to reduce the impact of preterm birth once preterm labor has ensued and into the neonatal period; not all of these are applicable in all settings. Here, we introduce the FIGO PremPrep-5 initiative, which aims to disseminate key information on the most simple and effective interventions with the aim of increasing implementation globally. Before delivery, we recommend a course of antenatal corticosteroids, and intrapartum magnesium sulfate. At delivery, we recommend delayed cord clamping. Postnatally, we recommend early feeding with breast milk and immediate kangaroo care. While there are many other interventions that may improve outcomes at the time of labor and after preterm birth, these are clinically effective and relatively inexpensive options that can be practiced in most settings and supplemented with more advanced care. We include examples of a training video and infographics that will be used for dissemination.

EUROPEAN ASSOCIATION OF PERINATAL MEDICINE (EAPM) EUROPEAN MIDWIVES ASSOCIATION (EMA) Joint position statement: Caesarean delivery rates at a country level should be in the 15-20 % range.

While cesarean deliveries performed for health indications can save lives, unnecessary cesareans cause unjustifiable health risks for the mother, newborn, and for future pregnancies. Previous recommendations for cesarean delivery rates at a country level in the 10-15% range are currently unrealistic, and the proposed concept that striving to achieve specific rates is not important has resulted in a confusing message reaching healthcare professionals and the public. It is important to have a clear understanding of when cesarean delivery rates are deviating from internationally acceptable ranges, to trigger the implementation of healthcare policies needed to correct this problem. Based on currently existing scientific evidence, we recommend that cesarean delivery rates at a country level should be in the 15-20% range. This advice is based on the demonstration of decreased maternal and neonatal mortalities when national cesarean delivery rates rise to circa 15%, but values exceeding 20% are not associated with further benefits. It is also based on real-world experiences from northern European countries, where cesarean delivery rates in the 15-20% range are associated with some of the best maternal and perinatal quality indicators in the world. With the increase in cesarean delivery rates projected for the coming years, experience in provision of intrapartum care may come under threat in many hospitals, and recovering from this situation is likely to be a major challenge. Professional and scientific societies, together with healthcare authorities and governments need to prioritize actions to reverse the upward trend in cesarean delivery rates observed in many countries, and to strive to achieve values as close as possible to the recommended range.

Antibiotic treatment reduces the intensity of intraamniotic inflammation in pregnancies with idiopathic vaginal bleeding in the second trimester of pregnancy.

BACKGROUND: Idiopathic bleeding in the second trimester of pregnancy complicates <1% of all pregnancies. This pregnancy complication can be caused by alterations in local hemostasis in the decidua due to infection/inflammation in the choriodecidual niche. This condition is associated with intraamniotic inflammatory complications. Antibiotic therapy effectively reduces the intensity of intraamniotic inflammation in certain pregnancy pathologies. However, whether antibiotic administration can reduce the intensity of the intraamniotic inflammatory response or eradicate microorganisms in patients with idiopathic bleeding during the second trimester of pregnancy remains unclear. OBJECTIVE: This study primarily aimed to determine whether antimicrobial agents can reduce the magnitude of intraamniotic inflammation in patients with idiopathic bleeding in the second trimester of pregnancy by assessing the concentration of interleukin-6 in the amniotic fluid before and after 7 days of antibiotic treatment. The secondary aim was to determine whether treatment with a combination of antibiotics altered the microbial load of Ureaplasma species DNA in amniotic fluid. STUDY DESIGN: This retrospective cohort study included singleton-gestation patients with idiopathic bleeding between 15+0 and 27+6 weeks who underwent transabdominal amniocentesis at the time of admission. Follow-up amniocentesis was performed in a subset of patients unless abortion or delivery occurred earlier. Concentrations of interleukin-6 were measured in the amniotic fluid samples, and the presence of microbial invasion of the amniotic cavity was assessed using culture and molecular microbiological methods. Intraamniotic inflammation was defined as an interleukin-6 concentration ≥3000 pg/mL in the amniotic fluid samples. RESULTS: A total of 36 patients with idiopathic bleeding in the second trimester of pregnancy were included. All the patients underwent initial amniocentesis. Patients with intraamniotic inflammation (n=25) were treated using a combination of antibiotics consisting of intravenous ceftriaxone, intravenous metronidazole, and peroral clarithromycin. The patients without intraamniotic inflammation (n=11) were treated expectantly. In total, 25 patients delivered 7 days after admission. All patients with intraamniotic inflammation at the initial amniocentesis who delivered after 7 days underwent follow-up amniocentesis. Treatment with antibiotics decreased the interleukin-6 concentration in the amniotic fluid at follow-up amniocentesis compared with that at the initial amniocentesis in patients with intraamniotic inflammation (median [interquartile range]: 3457 pg/mL [2493-13,203] vs 19,812 pg/mL [11,973-34,518]; P=.0001). Amniotic fluid samples with Ureaplasma species DNA had a lower microbial load at the time of follow-up amniocentesis compared with the initial amniocentesis (median [interquartile range]: 1.5×105 copies DNA/mL [1.3×105-1.7×105] vs 8.0×107 copies DNA/mL [6.7×106-1.6×108]; P=.02). CONCLUSION: Antibiotic therapy was associated with reduced intraamniotic inflammation in patients with idiopathic bleeding in the second trimester complicated by intraamniotic inflammation. Moreover, antibiotic treatment has been associated with a reduction in the microbial load of Ureaplasma species DNA in the amniotic fluid.

FIGO opinion paper: Drivers and solutions to the cesarean delivery epidemic with emphasis on the increasing rates in Africa and Southeastern Europe.

Cesarean delivery rates are rapidly increasing in Southeastern Europe (to more than 60%), North Africa (with a rate as high as 72% in Egypt), and in urban areas in Southern Africa (a rate of over 50% in Lagos, Nigeria). Data on the background to these increases are scarce, but likely to include poor birthing facilities in general hospitals, convenience for the doctor, private medicine, fear of litigation, socioeconomic status, shortage of midwives and nurses, and disappearance of vaginal instrumental deliveries. Options to reverse cesarean delivery trends are discussed. In this context there is a need to be better informed about how women are being counseled regarding vaginal or cesarean delivery. The long-term consequences in subsequent pregnancies for mothers and children may well be largely ignored, while these risks are highest in LMICs where higher birth numbers are desired. FIGO has begun discussions with obstetric and gynecologic societies, healthcare bodies, and governments in several countries discussed in this article, to find ways to lower the cesarean delivery rate. The requests came from the countries themselves, which may prove beneficial in helping advance progress.

Meta-analysis of genome-wide association studies of gestational duration and spontaneous preterm birth identifies new maternal risk loci.

BACKGROUND: Preterm birth (<37 weeks of gestation) is a major cause of neonatal death and morbidity. Up to 40% of the variation in timing of birth results from genetic factors, mostly due to the maternal genome. METHODS: We conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,370 European mothers, respectively. RESULTS: The meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel. The loci mapped to several biologically plausible genes, for example HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC (Vitamin D-binding protein), associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action. CONCLUSION: We report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth.

Smoking during pregnancy and its effect on placental weight: A Mendelian randomization study.

Background: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. Methods: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (up to N = 805) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (up to N = 4475). The analysis was performed in pre-pregnancy smokers only, due to the specific role of the genetic instrument SNP rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation. Results: Fixed effect meta-analysis showed a 175 g [95%CI: 16, 334] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal estimate was a 12 g [95%CI: 2,22] higher placental weight per cigarette per day. Results were similar when the smoking exposures were measured at the end of pregnancy. Using the residuals of birth weight regressed on placental weight as the outcome, we showed weak evidence of lower offspring birth weight relative to the placental weight for continuing smoking. Conclusion: Our results suggest that continued smoking during pregnancy causes higher placental weights.

Exploring the association of parity and its interaction with history of preterm delivery on gestational duration.

PURPOSE: Preterm delivery is a major cause of child mortality. While the relationship between parity and preterm delivery is known, its association with gestational duration and variability remains underexplored. Differences in variance may suggest interaction with other well-established risk factors. METHODS: With 1.1 million spontaneous deliveries (1990-2012) from the Swedish Medical Birth Register, we assessed while accounting for potential confounders the effects of parity on the mean and variance of gestational duration, and its possible interactions with history of preterm delivery. Pedigrees allowed to account for nonobserved, shared confounders using linear mixed models. RESULTS: Parity has a modest association with mean gestational duration, but a large effect on its variance. For example, the first pregnancy had the shortest mean gestational duration, 0.29 days shorter (95% CI: -0.33, -0.25) than the second, and the largest variance (σ2 = 135 days2). Accounting for shared unobserved confounders highlighted a group effect bias, likely linked to the mothers' total number of offspring. Parity interacts with other risk factors, including previous preterm delivery where the magnitude of its effect increases with parity (up to 4.6 days effect difference). CONCLUSIONS: Nonshared factors across a mother's pregnancies highlight parity's importance to gain insight into the mechanisms governing the timing of delivery.