Economic Evaluation of Elective Cesarean Section on Maternal Request Compared With Planned Vaginal Birth-Application to Swedish Setting Using National Registry Data.

OBJECTIVES: There is a lack of consensus around the definition of delivery by cesarean section (CS) on maternal request, and clinical practice varies across and within countries. Previous economic evaluations have focused on specific populations and selected complications. Our aim was to evaluate the cost-effectiveness of CS on maternal request compared with planned vaginal birth in a Swedish context, based on a systematic review of benefits and drawbacks and national registry data on costs. METHODS: We used the results from a systematic literature review of somatic risks for long- and short-term complications for mother and child, in which certainty was rated low, moderate, or high using the Grading of Recommendations Assessment, Development and Evaluation. Swedish national registry data were used for healthcare costs of delivery and complications. Utilities for long-term complications were based on a focused literature review. We constructed a decision tree and conducted separate analyses for primi- and multiparous women. Costs and effects were discounted by 3% and the time horizon was varied between 1 and 20 years. RESULTS: Planned vaginal birth leads to lower healthcare costs and somatic health gains compared with elective CS without medical indication over up to 20 years. Although there is uncertainty around, for example, quality-of-life effects, results remain stable across sensitivity analyses. CONCLUSIONS: CS on maternal request leads to increased hospitalization costs in a Swedish setting, taking into account short- and long-term consequences for both mother and child. Future research needs to study the psychological consequences related to different delivery methods, costs in outpatient care, and productivity losses.

Antibodies against Phosphorylcholine and Malondialdehyde during the First Two Years of Life.

Abs against phosphorylcholine (anti-PC) and Abs against malondialdehyde (anti-MDA) may be protective in chronic inflammation, like atherosclerosis and cardiovascular disease. It is not known how they develop early in life. Ab titers were measured using ELISA in healthy women (n = 105; born into life study) and their children. Plasma samples were collected from the mothers before conception and from the children at birth as well as at 1 and 2 y after birth. Extracted Abs were compared using a proteomics de novo sequencing approach. It was observed that children were born with very low levels of IgM anti-PC, whereas IgM anti-MDA was present at birth. Both IgM anti-PC and anti-MDA increased during the first 2 y of life, but IgM anti-PC in contrast to IgM anti-MDA was still significantly lower than in the mothers. IgG anti-PC decreased after 1 y but reached similar levels as mothers' after 2 y, whereas IgG anti-MDA reached similar levels as mothers' already after 1 y. Proteomics peptide sequencing analysis indicated large peptide sequence variation without specific clone expression during the early stage of life compared with the adult stage for which specific peptide sequences dominated. IgM anti-PC levels develop much slower than anti-MDA and are still relatively low at 2 y. We hypothesize that anti-PC is developed by a combination of preprogramming and exposure to the external world, in which infectious agents may play a role. For anti-MDA, preprogramming is likely to play a major role and at an earlier stage than for anti-PC.

Ambient air pollution and inflammation-related proteins during early childhood.

BACKGROUND AND AIM: Experimental studies show that short-term exposure to air pollution may alter cytokine concentrations. There is, however, a lack of epidemiological studies evaluating the association between long-term air pollution exposure and inflammation-related proteins in young children. Our objective was to examine whether air pollution exposure is associated with inflammation-related proteins during the first 2 years of life. METHODS: In a pooled analysis of two birth cohorts from Stockholm County (n = 158), plasma levels of 92 systemic inflammation-related proteins were measured by Olink Proseek Multiplex Inflammation panel at 6 months, 1 year and 2 years of age. Time-weighted average exposure to particles with an aerodynamic diameter of <10 µm (PM10), <2.5 µm (PM2.5), and nitrogen dioxide (NO2) at residential addresses from birth and onwards was estimated via validated dispersion models. Stratified by sex, longitudinal cross-referenced mixed effect models were applied to estimate the overall effect of preceding air pollution exposure on combined protein levels, "inflammatory proteome", over the first 2 years of life, followed by cross-sectional protein-specific bootstrapped quantile regression analysis. RESULTS: We identified significant longitudinal associations of inflammatory proteome during the first 2 years of life with preceding PM2.5 exposure, while consistent associations with PM10 and NO2 across ages were only observed among girls. Subsequent protein-specific analyses revealed significant associations of PM10 exposure with an increase in IFN-gamma and IL-12B in boys, and a decrease in IL-8 in girls at different percentiles of proteins levels, at age 6 months. Several inflammation-related proteins were also significantly associated with preceding PM10, PM2.5 and NO2 exposures, at ages 1 and 2 years, in a sex-specific manner. CONCLUSIONS: Ambient air pollution exposure influences inflammation-related protein levels already during early childhood. Our results also suggest age- and sex-specific differences in the impact of air pollution on children's inflammatory profiles.

DNA methylation differences at birth after conception through ART.

STUDY QUESTION: Is there a relation between ART and DNA methylation (DNAm) patterns in cord blood, including any differences between IVF and ICSI? SUMMARY ANSWER: DNAm at 19 CpGs was associated with conception via ART, with no difference found between IVF and ICSI. WHAT IS KNOWN ALREADY: Prior studies on either IVF or ICSI show conflicting outcomes, as both widespread effects on DNAm and highly localized associations have been reported. No study on both IVF and ICSI and genome-wide neonatal DNAm has been performed. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional study comprising 87 infants conceived with IVF or ICSI and 70 conceived following medically unassisted conception. The requirement for inclusion in the study was an understanding of the Swedish language and exclusion was the use of donor gametes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were from the UppstART study, which was recruited from fertility and reproductive health clinics, and the Born into Life cohort, which is recruited from the larger LifeGene study. We measured DNAm from DNA extracted from cord blood collected at birth using a micro-array (450k array). Group differences in DNAm at individual CpG dinucleotides (CpGs) were determined using robust linear models and post-hoc Tukey's tests. MAIN RESULTS AND THE ROLE OF CHANCE: We found no association of ART conception with global methylation levels, imprinted loci and meta-stable epialleles. In contrast, we identify 19 CpGs at which DNAm was associated with being conceived via ART (effect estimates: 0.5-4.9%, PFDR < 0.05), but no difference was found between IVF and ICSI. The associated CpGs map to genes related to brain function/development or genes connected to the plethora of conditions linked to subfertility, but functional annotation did not point to any likely functional consequences. LIMITATIONS, REASONS FOR CAUTION: We measured DNAm in cord blood and not at later ages or in other tissues. Given the number of tests performed, our study power is limited and the findings need to be replicated in an independent study. WIDER IMPLICATIONS OF THE FINDINGS: We find that ART is associated with DNAm differences in cord blood when compared to non-ART samples, but these differences are limited in number and effect size and have unknown functional consequences in adult blood. We did not find indications of differences between IVF and ICSI. STUDY FUNDING/COMPETING INTEREST(S): E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128) and JPI-H2020 Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL) under proposal number 655 (PREcisE Project) through ZonMw (529051023). Financial support was provided from the European Union's Seventh Framework Program IDEAL (259679), the Swedish Research Council (K2011-69X-21871-01-6, 2011-3060, 2015-02434 and 2018-02640) and the Strategic Research Program in Epidemiology Young Scholar Awards, Karolinska Institute (to A.N.I.) and through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Strategic Research Program in Epidemiology at Karolinska Institutet and the Swedish Heart-Lung Foundation and Danderyd University Hospital (Stockholm, Sweden). The funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Reference Intervals for Fecal Calprotectin in Pregnant Women Using a Particle Enhanced Turbidimetric Assay.

BACKGROUND: Fecal calprotectin is widely used as a marker for inflammatory bowel diseases (IBD). IBD often affects women during their reproductive years, but there are no established reference intervals during pregnancy. The aim of the present study was to define reference values during pregnancy and in the postpartum period to allow comparisons between patient results and reference values. METHODS: Fecal samples were collected from 84 healthy females during pregnancy week 26 to 28 and a second sample was collected six months after delivery. The samples were weighed, extracted, and centrifugated to remove debris. The extracted samples were then analyzed on a chemistry analyzer using a particle enhanced turbidimetric immunoassay reagent. RESULTS: The calculated reference interval during pregnancy was < 127 µg/g (90% confidence interval, 90 - 164 µg/g) and the corresponding reference interval during the postpartum period was < 143 µg/g (60 - 226 µg/g). There were no significant statistical differences between F-calprotectin values analyzed at the two sampling times. CONCLUSIONS: The reference values are slightly higher than the cutoff values of 50 - 100 µg/g often used as General cutoff for fecal calprotectin.

Normal values for calprotectin in stool samples of infants from the population-based longitudinal born into life study.

Faecal calprotectin is a protein used as a diagnostic marker for inflammatory bowel diseases. We determined upper limits for normal calprotectin values for neonatal, 6, 12 and 24 months old children using a turbidimetric immunoassay in a cohort of Swedish children. The advantage of the method is that opposite to previously used enzyme-linked immunosorbent assay (ELISA) method, it enables measuring single samples, and thus, shortens the analysis time significantly. There were 72 samples (41.7% female) collected neonatally, 63 samples (34.9% female) at 6 months, 60 samples (40.0% female) at 12 months and 51 samples (43.1% female) at 24 months. The upper limits for normal values were 233, 615, 136 and 57 µg mg-1 for infants aged 0, 6, 12 and 24 months, respectively.

Limited association between markers of stress during pregnancy and fetal growth in 'Born into Life', a new prospective birth cohort.

AIMS: We aimed to investigate the associations between perceived maternal stress or salivary cortisol levels during pregnancy and birthweight. METHODS: In 2010-2012, we recruited 92 women living in Stockholm, Sweden, and followed them from before conception and through pregnancy and childbirth. Their Perceived Stress Scale (PSS) scores and salivary cortisol levels were collected at 26-28 gestational weeks. Birthweight was collected from medical records. Linear regression analyses and Pearson correlations were performed between the PSS scores or cortisol levels and birthweight, respectively, adjusted for gestational age. RESULTS: No significant associations were found between PSS scores or cortisol levels and birthweight. There was a trend towards higher salivary cortisol levels among infants with lower birthweights, and this effect was attenuated after adjusting for gestational age. Morning cortisol levels (r = -0.31, p = 0.01), the decline in cortisol levels (r = -0.26, p = 0.03) and evening cortisol levels (r = -0.21, p = 0.09) were negatively correlated with PSS scores. CONCLUSION: Maternal stress during pregnancy was not associated with birthweight. The inverse correlation between PSS scores and cortisol levels may indicate other mechanisms for maternal stress on child outcomes than the previous explanation of hypothalamic-pituitary-adrenal axis activity.

Mental health after first childbirth in women requesting a caesarean section; a retrospective register-based study.

BACKGROUND: Psychiatric illness before delivery increases the risk of giving birth by caesarean section on maternal request (CSMR) but little is known about these women's mental health after childbirth. In this study we aimed to compare the prevalence of psychiatric disorders five years before and after delivery in primiparae giving birth by CS on maternal request to all other primiparae giving birth, indifferent on their mode of delivery. METHODS: The study population comprised all women born in Sweden 1973-1983 giving birth for the first time in 2002-2004. Psychiatric diagnoses, in- and outpatient care were retrieved from the National Patient Register in Sweden. The risk of psychiatric care after childbirth was estimated using CSMR, previous mental health and sociodemographic variables as covariates. RESULTS: Psychiatric disorders after childbirth were more common in women giving birth by CSMR compared to the other women (11.2% vs 5.5%, p < 0.001). CSMR increased the risk of psychiatric disorders after childbirth (aOR 1.5, 95% CI 1.2-1.9). The prevalence of psychiatric disorders had increased after compared to before childbirth (mean difference 0.02 ± 0.25, 95% CI 0.018-0.022, p < 0.001). Women giving birth by CSMR tended to be diagnosed in the inpatient care more often (54.9% vs. 45.8%, p = 0.056) and were more likely to have been diagnosed before childbirth as well (39.8% vs. 24.2%, p < 0.001). CONCLUSIONS: Women giving birth by CSMR more often suffer from psychiatric disorders both before and after delivery. This indicates that these women are a vulnerable group requiring special attention from obstetric- and general health-care providers. This vulnerability should be taken into account when deciding on mode of delivery.

Hypertensive disorders in pregnancy and later dementia: a Swedish National Register Study.

INTRODUCTION: Our aim was to investigate the rate of vascular dementia and dementia in women with previous hypertensive disorders in pregnancy, since white matter lesions of the brain and cardiovascular disease are linked both to dementia and hypertensive disorders in pregnancy. MATERIAL AND METHODS: Prospective population-based registry study on all women giving birth in Sweden between 1973 and 1975 (284 598). Women with and without hypertensive disorders in pregnancy were identified by means of the Swedish Medical Birth Register and linked to the National Patient Register, where data on somatic disease later in life were obtained. International classification of disease was used. The Cox proportional hazard model was used to calculate hazard ratios for both groups and adjusted for possible confounders. Main outcome measures were in-hospital diagnosis of cardiovascular disease, vascular dementia and dementia. RESULTS: No increased risks were seen for vascular dementia or dementia after any hypertensive disorders in pregnancy. If broken down in specific diagnoses for hypertensive disease in pregnancy, adjusted risks for vascular dementia after hypertension and proteinuria during pregnancy the hazard ratio was 6.27 (95% CI 1.65-27.44). Higher risks for cardiovascular disease were confirmed. CONCLUSIONS: Because of the very low absolute risk, the wide confidence interval and risk of misclassification, our results on vascular dementia could be questioned. Considering the pathophysiology of preeclampsia, the findings of brain lesions and the increased risk for cardiovascular disease, the possibly increased risk for all kinds of dementia must be investigated in larger and more well-defined cohorts.

A randomized controlled trial on early induction compared to expectant management of nulliparous women with prolonged latent phases.

OBJECTIVE: To compare early induction and expectant management regarding delivery outcomes and the experience of delivery in nulliparous women with prolonged latent phases. DESIGN: Randomized controlled trial. SETTING: One delivery unit in a Swedish hospital. POPULATION: Nulliparous women at term experiencing continuous contractions impeding rest (women's report) and exceeding 18 h, a cervical dilation of less than 4 cm, intact membranes and with a singleton fetus in cephalic presentation. METHODS: The women were randomly allocated to either early induction (n = 65) or expectant management (n = 64). All participants received medication for therapeutic rest. The early induction group was induced five hours after medication, and the expectant group awaited spontaneous onset of labor. The Wijma Delivery Experience Questionnaire (W-DEQ version B) was filled in after delivery. MAIN OUTCOME MEASURES: The primary outcome was mode of delivery. Secondary outcomes included birth experience, duration of labor, postpartum hemorrhage, and neonatal outcomes. RESULTS: The cesarean section rate was 15 of 65 (23.1%) in the early induction group and 24 of 64 (37.5%) in the expectant group (p = 0.076, OR 2.00, 95% CI 0.93-4.31). No significant differences were shown regarding delivery, neonatal outcomes or birth experience. CONCLUSIONS: No significant differences were shown between the two groups in the rate of cesarean sections or the experience of delivery. According to the actual results, the power to detect a difference was only 45%. The cesarean section rate was high in both groups, regardless of intervention.

Impact of clinical factors and personality on the decision to have a second child. Longitudinal cohort-study of first-time mothers.

OBJECTIVE: To investigate which factors related to the first birth influence subsequent reproduction within 5 years after the birth. DESIGN: Prospective cohort study. SETTING: University hospital, Stockholm, Sweden. SAMPLE: Cohort of 547 first-time singleton mothers with a normal pregnancy recruited prospectively of whom 451 women consented to follow-up 5 years later. METHODS: Data were collected by several questionnaires on sexual, reproductive and childbirth-related factors as well as on personality, postnatal depression, fear of childbirth and contact between mother/child. Medical records were also used. Associations between these factors and having a second child were analyzed using logistic regression. MAIN OUTCOME MEASURES: Women's subsequent reproduction. RESULTS: Planning a second child at 9 months postpartum was most important in determining to have a second child. Women who had restored their sex life 9 months after birth and women who had a high score in the personality monotony avoidance scale, were less likely to give birth to a second child. No differences were observed regarding mode of delivery, factors related to birth and having a second child, nor was there an association between postnatal depression, fear of childbirth, a negative birth experience and self-estimated contact with the child and subsequent reproduction. CONCLUSIONS: Circumstances in relation to the first birth, such as mode of delivery and a negative birth experience, did not affect subsequent reproduction. Planning another child by 9 months after birth was the strongest factor correlated with having a second child.

A follow-up cohort study on the risk of prediabetes, comparing women with previous preeclamptic or normotensive pregnancies.

Studies have shown that preeclampsia is associated insulin resistance and cardiovascular events later in life. However, knowledge is lacking regarding a possible association between PE and abnormal glucose tolerance/prediabetes. Thus, the current study aimed to compare the prevalence of prediabetes in women with previous severe preeclampsia to women with previous normotensive pregnancies. Women with severe preeclampsia (index women, n = 45) admitted to Danderyds University Hospital in 1999-2004 were compared to women with normotensive pregnancies, matched for age, parity, and year of delivery (control women, n = 53). In 2013-2016 BMI, blood pressure, waist circumference, insulin, C-peptide, hsCRP, Cystatin C, HDL, triglycerides, and HbA1c were measured and an OGTT was performed. Index women had a higher BMI (p < 0.001) and blood pressure (p < 0.001) in early pregnancy. At follow-up, prediabetes was more common among index women (p = 0.001), as were hypertension (p = 0.003), heredity for diabetes/cardiovascular disease (p = 0.020), and a larger waist circumference (p = 0.024). Preeclampsia increased the risk of having a fasting plasma glucose ≥ 5.6 mmol/l (aOR 7.28, 95% CI 2.44-21.76) and of prediabetes 11-16 years after index pregnancy (aOR 4.83, 95% CI 1.80-12.97). In conclusion, preeclampsia increases the risk of prediabetes independent of heredity, hypertension, and waist circumference. These findings may have implications for screening and prevention.

Biological age is increased by stress and restored upon recovery.

Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.

Risk of surgically managed pelvic floor dysfunction in relation to age at first delivery.

OBJECTIVE: The purpose of this study was to compare the risk of surgically treated stress urinary incontinence (SUI) and pelvic organ prolapse (POP) in relation to mode of delivery and age at first childbirth. STUDY DESIGN: This was a cohort study. Data from the Swedish Medical Birth Register on women with only cesarean delivery (n = 30,880 women) or only vaginal delivery (n = 59,585 women) were compared with the Swedish Patient Register to calculate incidence rates and hazard ratios (95% confidence interval [CI]) for SUI and POP surgery. RESULTS: In analyses that were stratified by age, vaginal delivery consistently increased the risks of SUI and POP surgery. Among vaginally delivered women who were ≥ 30 years old, incidence rates of POP surgery were 13.8 (95% CI, 12.7-15.1), and for younger women were 6.4 (95% CI, 6.0-6.8) per 10,000 person-years. Exclusion of instrumental vaginal delivery did not alter the conclusions. CONCLUSION: Increasing age at first delivery increased the risk of subsequent SUI and POP surgery after both vaginal and cesarean delivery.

Development of gut microbiota during the first 2 years of life.

Although development of microbiota in childhood has been linked to chronic immune-related conditions, early childhood determinants of microbiota development have not been fully elucidated. We used 16S rRNA sequencing to analyse faecal and saliva samples from 83 children at four time-points during their first 2 years of life and from their mothers. Our findings confirm that gut microbiota in infants have low diversity and highlight that some properties are shared with the oral microbiota, although inter-individual differences are present. A considerable convergence in gut microbiota composition was noted across the first 2 years of life, towards a more diverse adult-like microbiota. Mode of delivery accounted for some of the inter-individual variation in early childhood, but with a pronounced attenuation over time. Our study extends previous research with further characterization of the major shift in gut microbiota composition during the first 2 years of life.

Risks of stress urinary incontinence and pelvic organ prolapse surgery in relation to mode of childbirth.

OBJECTIVE: To estimate the risk for stress urinary incontinence and pelvic organ prolapse surgery related to vaginal birth or cesarean delivery. STUDY DESIGN: A cohort study of all women having their first and all subsequent deliveries by cesarean (n = 33,167), and an age-matched sample of women only having vaginal deliveries (n = 63,229) between 1973 and 1983. Hazard ratios were calculated using Cox regression models with 95% confidence intervals. RESULTS: Women only having vaginal deliveries had increased overall risks of incontinence (hazard ratio, 2.9; 95% confidence interval, 2.4-3.6) and prolapse surgery (hazard ratio, 9.2; 95% confidence interval, 7.0-12.1) compared with women only having cesarean deliveries. CONCLUSION: Having only vaginal childbirths was associated with a significantly increased risk of stress urinary incontinence and pelvic organ prolapse surgery later in life compared with only having cesarean deliveries.

Induction of labor and the risk for emergency cesarean section in nulliparous and multiparous women.

OBJECTIVE: To assess the risk for emergency cesarean section among women in whom labor was induced in gestational week ≥41 and to evaluate if parity and mode of induction affected this association. DESIGN: Hospital-based retrospective cohort study. POPULATION: Singleton pregnancies delivered after ≥41 gestational weeks at Danderyd Hospital, Stockholm, Sweden, during 2002-2006. MATERIAL AND METHODS: Of 23 030 singleton pregnancies meeting the entry criteria, 881 were induced with a Bishop score of <7. Obstetric outcome was assessed through linkage with the Swedish Medical Birth Registry and a local obstetrical database containing information from patients' medical files. Results were adjusted for body mass index, age and the use of epidural analgesia. MAIN OUTCOME MEASURE: Risk for emergency cesarean section. RESULTS: Among women who were induced, the proportions delivered by emergency cesarean section were 42% for nulliparous and 14% for multiparous. Compared to spontaneous onset, this corresponded to a more than threefold increase in risk for nulliparous women (OR 3.34, 95%CI 2.77-4.04) and an almost twofold increase in risk for multiparous women (OR 1.94, 95%CI 1.24-3.02). There was no significant difference in risk for emergency cesarean section between the two methods of induction (PGE(2) and transcervical catheter). CONCLUSIONS: Compared to spontaneous onset of delivery, induction of labor is associated with an increased risk for emergency cesarean section both among nulliparous and multiparous women. When labor is induced, the high risk for emergency cesarean must be kept in mind.

Planned vaginal delivery versus planned caesarean section: short-term medical outcome analyzed according to intended mode of delivery.

OBJECTIVE: To compare maternal medical outcome after planned vaginal delivery and planned Caesarean section. METHODS: We conducted a prospective cohort study of healthy primiparous women in Stockholm, Sweden, who were either scheduled for a planned Caesarean section (for breech presentation or at maternal request) or admitted for a vaginal delivery. Data were analyzed according to intended mode of delivery. RESULTS: A total of 541 women were included in the study; of these, 247 had a Caesarean section and 294 a vaginal delivery. There were sociodemographic differences between the groups. No difference in mean estimated blood loss or rate of infection was found. Complications in the planned Caesarean section group were lower than previously reported. The difference in estimated blood loss between women undergoing planned Caesarean section and women who had a vaginal delivery was not more than 7%. Morbidity in the planned vaginal delivery group was mostly due to operative interventions. The Caesarean section group had a longer hospital stay than women who delivered vaginally. CONCLUSION: We found no difference in short-term medical outcomes between primiparous women undergoing planned Caesarean section and those undergoing planned vaginal delivery after analysis according to the intended mode of delivery.