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The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal–fetal relationship between gestational duration and birth weight.

Objectives: The aim of the study was to create a simple assay for microchimerism detection independent of sex and without HLA genotyping. Methods: The method is based on detection of insertion or deletions utilizing a multiplex PCR followed by fragment analysis by capillary electrophoresis, and probe-based qPCR assays. A total of 192 samples, taken either before pregnancy, during 1st trimester, or either during 2nd trimester or at miscarriage, obtained from a cohort of 97 female patients with either primary or secondary recurrent pregnancy loss, were screened for fetal microchimerism by the indel panel as well as an existing assay based on detection of the Y-chromosome marker; DYS14. Results: The overall prevalence of DYS14 positive samples was 29% (55/192) whereas 32% (61/192) tested positive by the indel method. There was an overall agreement of 64% (122/192) between the results obtained by the two methods. A Fisher's Exact test showed no statistic significant difference in the prevalence of microchimerism detected by the two methods at any of the three times of sampling. The distribution of the number of positive wells detected by both methods were compared by a Mann-Whitney U test, which showed no statistically significant difference at any of the three times of sampling. Conclusion: The data indicates that microchimerism can be detected efficiently by the indel method. This makes it possible to detect both female and male cells without the need of HLA-genotyping. Furthermore, the indel method has potential to be implemented as a routine analysis. This will remove the sex bias in future explorations of the role microchimerism plays in health and disease.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic and the associated regulations issued to minimize risk of disease transmission seem to have had an impact on general mental health in most populations, but it may have affected pregnant women even more because of pregnancy-related uncertainties, limited access to healthcare resources, and lack of social support. We aimed to compare the mental health response among pregnant women with that in similarly aged women from the general population during the first wave of the COVID-19 pandemic. Material and methods: From April 14 to July 3, 2020, 647 pregnant women in their second trimester were enrolled in this study. For comparison, 858 women from the general Danish population (20–46 years) were sampled from an ongoing observational study. Participants responded to a questionnaire including six mental health indicators (concern level, perceived social isolation, quality of life, anxiety, mental health, and loneliness). Loneliness was measured using the UCLA Three-item Loneliness Scale and anxiety by the Common Mental Health Disorder Questionnaire 4-item Anxiety Subscale. Results: The pregnant women had better scores during the entire study period for all mental health indicators, and except for concerns, social isolation, and mental health, the differences were also statistically significant. Pregnant women were more concerned about becoming seriously ill (40.2% vs. 29.5%, p < 0.001), whereas the general population was more concerned about economic consequences and prospects. Many pregnant women reported negative feelings associated with being pregnant during the COVID-19 pandemic and concerns regarding social isolation and regulation-imposed partner absence during hospital appointments and childbirth. All mental health indicators improved as Denmark began to reopen after the first wave of the pandemic. Conclusions: Pregnant women exhibited lower rates of poor mental health compared with the general popu

Introduction: The impact of early pregnancy complications on completed family size is unknown. Here, we hypothesize that early pregnancy complications and adverse outcomes may influence family size. Material and methods: In this nationwide, registry-based study we included all 458 475 women born 1957–1972 who lived in Denmark from age 20–45 years with at least one registered pregnancy. The main outcome of the study was number of children per woman by age 45, estimated using a Generalized Linear Mixed Model. Exposures were: (a) total number of pregnancy losses experienced (0, 1, 2, ≥3); (b) highest number of consecutive pregnancy losses (0, 1, 2, ≥3); (c) sex of firstborn child; (d) outcome of first pregnancy (live birth, stillbirth, pregnancy loss, ectopic pregnancy, or molar pregnancy). Results: Number of live births was negatively influenced by maternal age and adverse first pregnancy outcomes, especially ectopic pregnancies. A 30-year-old woman with a first ectopic pregnancy was expected to have 1.16 children (95% CI 1.11–1.22) compared with 1.95 children (95% CI 1.86–2.03) with a first live birth. Three or more consecutive losses also decreased number of live births significantly: 1.57 (95% CI 1.50–1.65) compared with 1.92 (95% CI 1.84–2.0) with only live births. The total number of pregnancy losses had no effect before the age of 35 years. Sex of firstborn had no effect. Conclusions: Previous pregnancy history has a significant effect on number of children per woman, which is important at both individual and societal levels. Pathophysiological research of adverse pregnancy outcomes should be an urgent priority as the causes remain poorly understood.

Introduction: Pregnancy loss is frequent. We aimed to assess the frequency and trends in pregnancy losses according to female age and mode of conception over a 40-year follow-up period. Material and methods: In a national historical prospective cohort study, we followed all Danish women 10-49 years over the 40-year study period 1978-2017. Data on pregnancies and their outcomes were obtained from the National Health Registry, the Medical Birth Registry and the National Fertility Registry. Incidence rates per 100 pregnancies and per 1,000 women-years as well as lifetime risks per 100 women were calculated. Women included in the lifetime analysis were followed from age 12 to age 49. Pregnancy loss included spontaneous abortion, missed abortion and anembryonic pregnancy. Results: In 3 519 455 recorded pregnancies, 337 008, or 9.6%, were diagnosed with a pregnancy loss. The proportion increased from 7.5% in 1978-1979, peaked at 10.7% in 2000 and thereafter decreased to 9.1% in 2015-2017. Pregnancy loss rate in women 10-14 years was 3.9%, increasing gradually with age to 26.9% in pregnant women 45-49 years, a 6.9-fold increase. Loss rates were slightly lower in naturally conceived pregnancies than in assisted pregnancies except for women above 45 years, where the risk of loss was higher in the spontaneously conceived group. Lifetime risk of specific numbers of losses were: 0: 76.9%, 1: 17.9%, 2: 3.9%, 3: 0.87%, and 4+: 0.35%. Conclusions: The proportion of women experiencing pregnancy loss has changed little throughout four decades and is still primarily influenced by female age. More than 75% of pregnant women are never recorded with a pregnancy loss, and <1.5% will experience three or more losses.

Background: Cancer is the second leading cause of death worldwide. Few studies have investigated if recurrent pregnancy loss is associated with an increased risk of cancer. We aimed to assess whether pregnancy loss is associated with later cancer development.Methods: We identified all invasive cancers after age 40, among all Danish women born between January 1957 and December 1972, ensuring a full reproductive history. Cases were matched by birth year 1:10 to cancer-free controls. Women were followed until the end of 2017. The number of pregnancy losses (miscarriages or still births) was correlated to long-term cancer risk using conditional logistic regression, providing odds ratios for specific cancers with different numbers of pregnancy losses, all adjusted for age, education, and other potential confounders.Findings: The study included 28,785 women with cancer (mean age 48.7 [SD 5.0]) and 283,294 matched controls (mean age 48.6 [SD 5.0]). We found no overall association between pregnancy loss and later development of 11 site-specific types of cancer or cancer overall. Taking the sequence of pregnancy losses into account, primary recurrent pregnancy loss (three consecutive pregnancy losses without prior live birth) was associated with later overall cancer by an odds ratio of 1.27 (1.04-1.56). Secondary recurrent pregnancy loss showed no association to cancer.Interpretation: Pregnancy loss was not associated with later cancer development. Women with primary recurrent pregnancy loss had a borderline significant association to later cancer overall, this may be a chance finding.Funding: Ole Kirk's Foundation and Copenhagen University Hospital Rigshospitalet's Research Grant.

INTRODUCTION: The Fertility Assessment and Counselling (FAC) Clinic was initiated to provide women information about their current fertility status to prevent infertility and smaller families than desired. The aim was to study the predictive value of a risk assessment score based on known fertility risk factors in terms of time to pregnancy.MATERIAL AND METHODS: Prospective cohort study of the first 570 women attending the FAC Clinic from 2011 to 2013 at Rigshospitalet, Denmark. A consultation included: risk assessment score sheet with items on infertility risk factors, anti Müllerian hormone and ultrasound. The risk score was categorized as low, medium or high. After two years an email-based questionnaire was distributed regarding subsequent pregnancies.RESULTS: The follow up questionnaire was answered by 519 women (91.1%). The mean age was 35 years and 38% were single at inclusion. The majority (67.8%, 352/519) tried to conceive within two years after attending the FAC Clinic. At follow up 73.6% (259/352) had achieved a pregnancy, 21% (74/352) were still trying and 5.4% (19/352) had given up. Two thirds (65%) with only low risk scores conceived spontaneously within 12 months, while this figure was only 32% for women with at least one high risk score (n=82). Accordingly, presence of at least one high risk score reduced the odds of achieving a pregnancy within 12 months by 75% (OR 0.25, 95%CI; 0.12-0.52).CONCLUSION: The new FAC Clinic concept seems usable and offers a tool for fertility experts to guide women on how to fulfil their reproductive life-plan. This article is protected by copyright. All rights reserved.

Recurrent pregnancy loss, depending on the definition, affects 1% to 3% of women aiming to have a child. Little is known about the direct causes of recurrent pregnancy loss, and the condition is considered to have a multifactorial and complex pathogenesis. The aim of this review was to summarize the evaluation and the management of the condition with specific emphasis on immunologic biomarkers identified as risk factors as well as current immunologic treatment options. The review also highlights and discusses areas in need of further research.

BACKGROUND AND OBJECTIVES: The 8.1 ancestral haplotype (AH) (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2) is a remarkably long and conserved haplotype in the human major histocompatibility complex. It has been associated with both beneficial and detrimental effects, consistent with antagonistic pleiotropy. It has also been proposed that the survival of long, conserved haplotypes may be due to gestational drive, i.e. selective miscarriage of fetuses who have not inherited the haplotype from a heterozygous mother. Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses. The objective was to test the gestational drive theory for the 8.1AH in women with RPL and their live born children.METHODOLOGY: We investigated the inheritance of the 8.1AH from 82 heterozygous RPL women to 110 live born children. All participants were genotyped for HLA-A, -B and -DRB1 in DNA from EDTA-treated blood or buccal swaps. Inheritance was compared with a Mendelian inheritance of 50% using a two-sided exact binomial test.RESULTS: We found that 55% of the live born children had inherited the 8.1AH, which was not significantly higher than the expected 50% (P = 0.29). Interestingly, we found a non-significant trend toward a higher inheritance of the 8.1AH in girls, 63%, P = 0.11 as opposed to boys, 50%, P = 1.00.CONCLUSIONS AND IMPLICATIONS: We did not find that the 8.1AH was significantly more often inherited by live born children of 8.1AH heterozygous RPL women. However our data suggest that there may be a sex-specific effect which would be interesting to explore further, both in RPL and in a background population.