Preventing Spontaneous Preterm Birth: Insights from Genomics

Mortality and morbidity due to infants being born preterm remains one of the greatest health burdens facing society. Many factors influence the risk for spontaneous preterm birth, both genetic and environmental. To date, generally effective interventions to prevent preterm birth have not been identified. In this paper, we discuss the impact of preterm birth and the challenges that have limited insights so far. New advances in genomics, systems biology, and population/personalized medicine show promise in overcoming previous barriers and leading to new insights and preventive treatments

FIGO good practice recommendations on delayed umbilical cord clamping

Funding Information: Ana Bianchi reports no conflicts of interest. Ben W. Mol reports an investigator grant from NHMRC; consultancy for ObsEva; and research funding from Guerbet, Ferring, and Merck KGaA. Bo Jacobbson reports research grants from Swedish Research Council, Norwegian Research Council, March of Dimes, Burroughs Wellcome Fund, and the US National Institute of Health; clinical diagnostic trials on NIPT with Ariosa (completed), Natera (ongoing), Vanadis (completed), and Hologic (ongoing) with expenditures reimbursed per patient; clinical probiotic studies with product provided by FukoPharma (ongoing, no funding), and BioGaia (ongoing; also provided a research grant for the specific study); collaboration in IMPACT study where Roche, Perkin Elmer, and Thermo Fisher provided reagents to PLGF analyses; coordination of scientific conferences and meetings with commercial partners such as NNFM 2015, ESPBC 2016, and a Nordic educational meeting about NIPT and pre‐eclampsia screening. Bo Jacobbson is also Chair of the FIGO Working Group for Preterm Birth and the European Association of Perinatal Medicine special interest group on preterm delivery; steering group member of Genomic Medicine Sweden; chairs the Genomic Medicine Sweden complex diseases group; and is Swedish representative in the Nordic Society of Precision Medicine.Peer reviewedPublisher PD

Metabolomic profiles of mid-trimester amniotic fluid are not associated with subsequent spontaneous preterm delivery or gestational duration at delivery

Introduction:Spontaneous preterm delivery (<37 gestational weeks) has a multifactorial etiology with still incompletely identified pathways. Amniotic fluid is a biofluid with great potential for insights into the feto-maternal milieu. It is rich in metabolites, and metabolic consequences of inflammation is yet researched only to a limited extent. Metabolomic profiling provides opportunities to identify potential biomarkers of inflammatory conditioned pregnancy complications such as spontaneous preterm delivery.Objective:The aim of this study was to perform metabolomic profiling of amniotic fluid from uncomplicated singleton pregnancies in the mid-trimester to identify potential biomarkers associated with spontaneous preterm delivery and gestational duration at delivery. A secondary aim was to replicate previously reported mid-trimester amniotic fluid metabolic biomarkers of spontaneous preterm delivery in asymptomatic women.Method:A nested case-control study was performed within a larger cohort study of asymptomatic pregnant women undergoing mid-trimester genetic amniocentesis at 14-19 gestational weeks in Gothenburg, Sweden. Medical records were used to obtain clinical data and delivery outcome variables. Amniotic fluid samples from women with a subsequent spontaneous preterm delivery (n = 37) were matched with amniotic fluid samples from women with a subsequent spontaneous delivery at term (n = 37). Amniotic fluid samples underwent untargeted metabolomic analyses using liquid chromatography-mass spectrometry. Multivariate random forest analyses were used for data processing. A secondary targeted analysis was performed, aiming to replicate previously reported mid-trimester amniotic fluid metabolic biomarkers in women with a subsequent spontaneous preterm delivery.Results:Multivariate analysis did not distinguish the samples from women with a subsequent spontaneous preterm delivery from those with a subsequent term delivery. Neither was the metabolic profile associated with gestational duration at delivery. Potential metabolic biomarker candidates were identified from four publications by two different research groups relating mid-trimester amniotic fluid metabolomes to spontaneous PTD, of which fifteen markers were included in the secondary analysis. None of these were replicated.Conclusions:Metabolomic profiles of early mid-trimester amniotic fluid were not associated with spontaneous preterm delivery or gestational duration at delivery in this cohort

Importance of the environment for gestational duration variability and correlation between relatives - results from the Medical Swedish Birth Registry, 1973-2012

It has been suggested that the intergenerational associations in gestational age at delivery are considerably affected by temporal changes in the environmental conditions. We explored whether changing environment affects familial resemblance of gestational age at delivery. Understanding how correlation changes in different settings allows to design better studies aimed to detect genes and environmental factors involved in the parturition process. The Swedish Medical Birth Register was used to retrieve births during 1973-2012. In total, 454,433 parent-child, 2,247,062 full sibling, 405,116 maternal half-sibling and 469,995 paternal half-sibling pairs were identified. A decreasing trend in correlation, associated with increasing age gaps, was observed among all siblings, with the largest drop for full siblings, from p = 0.32 (95% confidence interval (CI): 0.31, 0.33) for full siblings with one-year gap to p = 0.16 (95% CI: 0.10, 0.22) for full siblings with age gap above 20 years. A variation in association between full siblings born up to two years apart was observed; estimate p = 0.28 (95% CI: 0.26, 0.3) in 1973, and p = 0.36 (95% CI: 0.33, 0.38) in 2012. Observed variability in the association in gestational age at delivery between the relatives with respect to their birth year or age gap suggests the existence of temporally changing environmental factors

Maternal selenium intake and selenium status during pregnancy in relation to preeclampsia and pregnancy-induced hypertension in a large Norwegian Pregnancy Cohort Study

Background: Pregnancy-induced hypertensive disorders (PIHD), including preeclampsia, cause maternal and perinatal morbidity and mortality worldwide. Several studies have linked selenium supplementation and selenium status to the risk of preeclampsia, but there are no published prospective population-based studies examining associations between dietary selenium intake and preeclampsia. Aim: To examine associations between selenium intake from diet and supplements and selenium blood status and PIHD incidence, with sub-analyses for pregnancy-induced hypertension (PIH) and preeclampsia, in a large pregnancy cohort. Method: The study is based on 69,972 singleton pregnancies from the Norwegian Mother, Father and Child Cohort Study. Maternal dietary selenium intake was assessed with a validated, semi-quantitative food frequency questionnaire at about gestational week 22. Maternal selenium concentrations were measured in whole blood collected around gestational week 18 in a subset of 2572 women. Preeclampsia and PIH diagnosges were obtained from the Medical Birth Registry of Norway. Results: Participants had a median dietary selenium intake of 53 μg/day (IQR 44–62). Dietary selenium intake was not significantly associated with PIHD (adjusted (a) OR 1.03, 95% CI 0.98, 1.08 per SD of selenium intake), preeclampsia or PIH. Threshold analyses for deciles of dietary selenium intake did not show any significant associations. Neither inorganic (aOR 1.01, 95% CI 0.98, 1.05) or organic selenium supplement intake (aOR 0.98, 95% CI 0.95, 1.02) or selenium blood status was significantly associated with PIHD (aOR 1.03, 95% CI 0.86, 1.22) or PIHD subgroups. Conclusion: No significant associations were found between reported selenium intake from diet, or dietary supplements or whole-blood selenium status and PIHD in general or preeclampsia specifically. Hence, the results of this large population-based study, with selenium intake close to the recommended daily intake, do not support previous findings indicating a possible protective effect of selenium supplementation or selenium status with regard to preeclampsia incidence

Associations between cervical intraepithelial neoplasia during pregnancy, previous excisional treatment, cone-length and preterm delivery: a register-based study from western Sweden

BACKGROUND: Excisional treatment of cervical intraepithelial neoplasia (CIN) has been associated with increased risk of preterm delivery (PTD), although the underlying mechanism is as yet unclear. Studies on formalin-fixed excised tissue indicate that the risk increases with cone-length, but the magnitude of increase is uncertain, especially in case of minor excisions (≤10 mm), as well compared to women with untreated CIN during pregnancy. This study assesses the impact of cone-length at previous treatment for CIN as well as diagnosis of CIN during pregnancy on the risk of PTD. METHODS: A register-based cohort study in western Sweden linking cervical cytology, histology, and treatment data from the Swedish National Cervical Screening Registry to data on obstetric outcomes in singleton pregnancies 2008-2016 from the Swedish Medical Birth Registry. These groups were compared for PTD and other obstetric outcomes: (1) women with one excisional treatment (n=3250, including a subgroup (n=2408) with cone-length measured before fixation; (2) women with untreated CIN diagnosed during pregnancy (n=1380); and (3) women with normal cytology (n=42,398). Logistic regression analyses were adjusted for socioeconomic and health-related confounders. RESULTS: Treated women had increased risk of PTD (adjusted odds ratio (aOR) 1.60, 95% confidence interval (CI) 1.21-2.12), spontaneous PTD (aOR 1.95, 95% CI 1.40-2.72) and preterm prelabor rupture of membranes (pPROM) (aOR 2.74, 95% CI 1.66-4.51) compared to the CIN during pregnancy group. ORs were similar when compared to the normal cytology group. Risks of these outcomes increased with cone-length. Mean cone-length was 9.1 mm. Cone-length ≤10 mm was associated with increased risk of PTD (aOR 1.41, 95% CI 1.02-1.94), spontaneous PTD (aOR 1.73, 95% CI 1.18-2.54), and pPROM (aOR 2.44, 95% CI 1.40-4.28), compared to the CIN during pregnancy group. The PTD risk was similar for cone-lengths 3-10 mm, thereafter increasing by 15% with each additional millimeter. CONCLUSIONS: This study suggests that all excisional treatment, including small cones, are associated with increased risk of PTD and pPROM. Risks increase further with cone-length. In women of reproductive age, clinicians should aim to remove all CIN but minimal healthy cervical tissue. Cone-length should be recorded at treatment, for future prenatal risk estimation

Maternal probiotic milk intake during pregnancy and breastfeeding complications in the Norwegian Mother and Child Cohort Study

Purpose: During the time of breastfeeding, a third of all women contract (or: fall ill in) mastitis—the leading cause of precocious weaning. Recent studies indicate that probiotics intake may prevent mastitis by altering the breast’s bacterial flora. The aim of this study was to examine whether probiotic milk intake during pregnancy is associated with less breastfeeding complications and longer breastfeeding duration. Methods: This study included 57,134 women, with live singleton term births, participating in the Norwegian Mother and Child Cohort Study. Probiotic milk intake during the first half of pregnancy was self-reported in a validated food frequency questionnaire at gestational week 22. At 6 month postpartum, women reported complications, including mastitis, and duration and exclusivity of breastfeeding. The association between probiotic milk intake and breastfeeding complications and duration was studied by adjusted logistic regression models. Results: Probiotic milk intake was associated with increased risk for mastitis [adjusted odds ratio (aOR) 1.09, 95% confidence interval (CI) 1.02–1.16] and for any breastfeeding problems during the first month (aOR 1.19, 95% CI 1.10–1.21). However, cessation of predominant (aOR 0.95, 95% CI 0.91–0.96) or any (aOR 0.79, 95%\ua0CI 0.75–0.84) breastfeeding earlier than at 4 months was less frequent in probiotic milk consumers than in non-consumers. Conclusions: Even though probiotic milk intake during the first half of pregnancy was statistically associated with increased risk for breastfeeding complications, including mastitis, the association is probably not causal. Probiotics intake was namely associated with longer breastfeeding duration and there was indication of socioeconomic confounding. Further studies, i.e., large randomized-controlled trials, are needed to understand the association between probiotic intake and breastfeeding complications

A fast wavelet-based functional association analysis replicates several susceptibility loci for birth weight in a Norwegian population

Background Birth weight (BW) is one of the most widely studied anthropometric traits in humans because of its role in various adult-onset diseases. The number of loci associated with BW has increased dramatically since the advent of whole-genome screening approaches such as genome-wide association studies (GWASes) and meta-analyses of GWASes (GWAMAs). To further contribute to elucidating the genetic architecture of BW, we analyzed a genotyped Norwegian dataset with information on child’s BW (N=9,063) using a slightly modified version of a wavelet-based method by Shim and Stephens (2015) called WaveQTL. Results WaveQTL uses wavelet regression for regional testing and offers a more flexible functional modeling framework compared to conventional GWAS methods. To further improve WaveQTL, we added a novel feature termed “zooming strategy” to enhance the detection of associations in typically small regions. The modified WaveQTL replicated five out of the 133 loci previously identified by the largest GWAMA of BW to date by Warrington et al. (2019), even though our sample size was 26 times smaller than that study and 18 times smaller than the second largest GWAMA of BW by Horikoshi et al. (2016). In addition, the modified WaveQTL performed better in regions of high LD between SNPs. Conclusions This study is the first adaptation of the original WaveQTL method to the analysis of genome-wide genotypic data. Our results highlight the utility of the modified WaveQTL as a complementary tool for identifying loci that might escape detection by conventional genome-wide screening methods due to power issues. An attractive application of the modified WaveQTL would be to select traits from various public GWAS repositories to investigate whether they might benefit from a second analysis.publishedVersio

FIGO good practice recommendations on modifiable causes of iatrogenic preterm birth

Funding Information: Catalina M. Valencia reports no conflicts of interest. Ben W. Mol reports an investigator grant from NHMRC; consultancy for ObsEva; and research funding from Guerbet, Ferring, and Merck KGaA. Bo Jacobbson reports research grants from Swedish Research Council, Norwegian Research Council, March of Dimes, Burroughs Wellcome Fund and the US National Institute of Health; clinical diagnostic trials on NIPT with Ariosa (completed), Natera (ongoing), Vanadis (completed) and Hologic (ongoing) with expendidures reimbused per patient; clinical probiotic studies with product provided by FukoPharma (ongoing, no funding) and BioGaia (ongoing; also provided a research grant for the specific study); collaboration in IMPACT study where Roche, Perkin Elmer and Thermo Fisher provided reagents to PLGF analyses; coordination of scientific conferences and meetings with commercial partners as such as NNFM 2015, ESPBC 2016 and a Nordic educational meeting about NIPT and preeclampsia screening. Bo Jacobbson is also Chair of the FIGO Working Group for Preterm Birth and the European Association of Perinatal Medicine's special interest group of preterm delivery; steering group member of Genomic Medicine Sweden; chairs the Genomic Medicine Sweden complex diseases group; and is Swedish representative in the Nordic Society of Precision Medicine.Peer reviewedPublisher PD