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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. [ABSTRACT FROM AUTHOR]

Summary: Most relevant studies in animals and humans indicate that some degree of systemic or uterine inflammation is necessary both for normal implantation and pregnancy. However, if inflammation becomes too excessive it might cause pregnancy complications such as fetal resorption/miscarriage. The main regulator of the correct level of inflammation at the feto–maternal interface seems to be the uterine CD16− CD56bright natural killer (NK) cells. Trophoblast debris, apoptotic cells and progesterone probably stimulate/regulate the production of inflammatory cytokines from these cells. Miscarriage of karyotypically normal embryos may occur when the level of inflammation at the feto–maternal interface falls outside the optimal range. This may be caused by an insufficient influx of CD56bright NK cells into the decidua, too little soluble histocompatibility leukocyte antigen (HLA)-G secretion from the trophoblast, hypersecretion of inflammatory cytokines due to the presence of high-production polymorphisms, presence of maternal HLA-DR alleles associated with high tumor necrosis factor (TNF)-α production, or maternal mannose-binding lectin deficiency. [Copyright &y& Elsevier]

Controversy exists as to whether active immunotherapy with allogeneic lymphocyte transfusions (ALT) or passive immunotherapy with intravenous immunoglobulin (IvIg) improve the chance of live birth in women with unexplained recurrent miscarriages (RM). Meta-analyses of the placebo-controlled trials carried out as Cochrane reviews have concluded than none of the different forms of immunotherapy has proved effective in the total RM population. However, the included trials have generally been small and very heterogenous with respect to the clinical histories of patients and the immunization protocols. Thus, other meta-analyses which have looked at the efficacy in subgroups of RM patients have reported that ALT and IvIg may be effective in women with primary RM and secondary RM, respectively. In RM clinics in Denmark, ALT with donor lymphocytes or IvIg immunotherapy have been tested in several placebo-controlled trials since 1986 in which greater doses than used in other trials have been administered, and both treatments are now used for routine therapy. Our results have convinced us that using the correct immunization protocols on the right subsets of RM patients is effective, but we admit that new placebo-controlled trials focusing on subsets of RM patients are now urgently needed. Furthermore, treated patients should be extensively monitored for changes in a series of immune parameters that may predict pregnancy success and be of importance for our understanding of the mechanisms of action of immunotherapy in RM. [Copyright &y& Elsevier]