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The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, −2, −3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss., The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, −2, −3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss.

A cardinal obstacle to performing quantum-mechanical simulations of strongly correlated matter is that, with the theoretical tools presently available, sufficiently accurate computations are often too expensive to be ever feasible. Here we design a computational framework combining quantum-embedding (QE) methods with machine learning. This allows us to bypass altogether the most computationally expensive components of QE algorithms, making their overall cost comparable to bare density functional theory. We perform benchmark calculations of a series of actinide systems, where our method accurately describes the correlation effects, reducing by orders of magnitude the computational cost. We argue that, by producing a larger-scale set of training data, it will be possible to apply our method to systems with arbitrary stoichiometries and crystal structures, paving the way to virtually infinite applications in condensed matter physics, chemistry, and materials science., Nordita SUQC 20220330

Many cases of recurrent pregnancy loss (RPL) defined as ≥3 consecutive pregnancy losses are suggested to be caused by an aberrant maternal immune response against the fetus or trophoblast. Human leukocyte antigen (HLA)–DRB1 and -DQB1 polymorphisms are associated with most autoimmune disorders and studies of HLA-DBB1 polymorphism in RPL patients are thus relevant. In previous studies, the HLA-DRB1*03 allele was found with increased prevalence in RPL patients. We wanted to clarify whether HLA-DRB1 alleles indeed were associated with RPL among women of Caucasian descent. A total of 1078 women with unexplained RPL and 2066 bone marrow donors were HLA-DRB1-typed and subsets were also HLA-DQB1 typed. All patients were initially HLA-DRB1-typed by DNA-based low-resolution techniques and subsets of patients and all controls were typed by high-resolution techniques. Among patients, the HLA-DRB1*07 allele frequency was significantly increased compared with controls; OR 1.29 (95 % CI 1.09−1.52), p < 0.0025; after correction for multiple comparisons pc = 0.031. The HLA-DRB1*07/*07 genotype was highly increased in patients with RPL compared with controls: OR 2.27 (1.31−3.93), p = 0.0027. The frequency of the HLA-DRB1*07 phenotype in RPL patients had increased significantly (p = 0.002) in three studies from our group published 1994–2021. The allele frequency of HLA-DRB1*03 was not increased in RPL patients compared with controls; OR 0.96 (0.83−1.12). In conclusion, the previous association between HLA-DRB1*03 and RPL could not be confirmed in our study whereas an association to HLA-DRB1*07 was detected for the first time. Since the latter association is a new finding, it should be confirmed in future studies.

Purpose: Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses and affects 1–3% of couples trying to conceive. Pregnancy loss is more common among RPL patients’ siblings than in the general population. Our objective was to investigate whether first-degree relatives with pregnancy losses influenced the chance of live birth in the first pregnancy after referral among women with RPL. Materials and methods: This is a cohort study of 2138 women with RPL seen at the Danish RPL Unit at Copenhagen University Hospital, Rigshospitalet between January 1st 2000 and December 31st 2017 with follow-up until December 2018. Pregnancies among first-degree relatives were reported by patients at their first consultation. Chance of live birth after referral was compared by logistic regression analysis. Results: Overall, 76% of the referred women achieved a pregnancy after referral and of these, 58% delivered a live born child. Women whose mother had experienced pregnancy loss were referred at a younger age than women with no pregnancy losses among first-degree relatives (mean age 33.6 (SD 4.6) versus 34.3 (SD 4.5), p = 0.002). Pregnancy losses among first-degree relatives did not influence chance of live birth. Conclusions: Our results indicate that pregnancy losses among first-degree family members is not an important risk factor for outcome of the first pregnancy after referral among women with RPL.

STUDY QUESTION: Is there a different prognostic impact for consecutive and non-consecutive early pregnancy losses in women with secondary recurrent pregnancy loss (RPL)?SUMMARY ANSWER: Only consecutive early pregnancy losses after the last birth have a statistically significant negative prognostic impact in women with secondary RPL.WHAT IS KNOWN ALREADY: The risk of a new pregnancy loss increases with the number of previous pregnancy losses in patients with RPL. Second trimester losses seem to exhibit a stronger negative impact than early losses. It is unknown whether the sequence of pregnancy losses plays a role for the prognosis in patients with a prior birth.STUDY DESIGN, SIZE, DURATION: This retrospective cohort study of pregnancy outcome in patients with unexplained secondary RPL included in three previously published, Danish double-blinded placebo-controlled trials of intravenous immunoglobulin (IvIg) conducted from 1991 to 2014. No other treatments were given. Patients with documented explained pregnancy losses (ectopic pregnancies and aneuploid miscarriages) were excluded.PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 168 patients included in the trials, 127 had secondary RPL and experienced a subsequent live birth or unexplained pregnancy loss in the first pregnancy after giving informed consent to participate in the trials (the index pregnancy). Data analyzed by multivariate analysis included the independent variables age, the number of early pregnancy losses before and after the last birth, respectively and a second trimester pregnancy loss before or after the last birth, respectively. The outcome variable was unexplained loss in the index pregnancy.MAIN RESULTS AND THE ROLE OF CHANCE: In patients with secondary RPL, both a late and each early loss before the last birth did not significantly influence the risk of a new pregnancy loss in the index pregnancy: incidence rate ratio (IRR) 1.31 (95% CI 0.62-2.77) and IRR

The HLA-G molecule is expressed on trophoblast cells at the feto-maternal interface, where it interacts with local immune cells, and upholds tolerance against the semi-allogeneic fetus. Aberrant HLA-G expression in the placenta and reduced soluble HLA-G levels are observed in pregnancy complications, partly explained by HLA-G polymorphisms which are associated with differences in the alternative splicing pattern and of the stability of HLA-G mRNA. Of special importance is a 14 bp insertion/deletion polymorphism located in the 3'-untranslated region of the HLA-G gene. In the current study, we present novel evidence for allelic imbalance of the 14 bp insertion/deletion polymorphism, using a very accurate and sensitive Digital droplet PCR technique. Allelic imbalance in heterozygous samples was observed as differential expression levels of 14 bp insertion/deletion allele-specific mRNA transcripts, which was further associated with low levels of HLA-G surface expression on primary trophoblast cells. Full gene sequencing of HLA-G allowed us to study correlations between HLA-G extended haplotypes and single-nucleotide polymorphisms and HLA-G surface expression. We found that a 1:1 expression (allelic balance) of the 14 bp insertion/deletion mRNA alleles was associated with high surface expression of HLA-G and with a specific HLA-G extended haplotype. The 14 bp del/del genotype was associated with a significantly lower abundance of the G1 mRNA isoform, and a higher abundance of the G3 mRNA isoform. Overall, the present study provides original evidence for allelic imbalance of the 14 bp insertion/deletion polymorphism, which influences HLA-G surface expression on primary trophoblast cells, considered to be important in the pathogenesis of pre-eclampsia and other pregnancy complications.

OBJECTIVE: To determine whether infusions with intravenous immunoglobulin (IVIg) during early pregnancy increase live birth rate in women with secondary recurrent miscarriage compared with placebo.DESIGN: A single-centre, randomised, double-blind, placebo-controlled trial.SETTING: A tertiary centre for recurrent miscarriage in Copenhagen, Denmark.POPULATION: A group of 82 women with unexplained secondary recurrent miscarriage and at least four miscarriages.METHODS: Women were randomly assigned to repeated infusions with IVIg or placebo (albumin) from the time of positive pregnancy test to gestational week 15 or pregnancy loss.MAIN OUTCOME MEASURE: Primary outcome was birth with neonatal survival in all randomised women.RESULTS: In the intention-to-treat analyses, live birth rates were 23/42 (54.8%) in the IVIg and 20/40 (50.0%) in the placebo group, relative risk 1.11 (95% CI 0.70-1.74). In a per protocol analysis, almost identical results were found. The median gestational length at delivery was higher in the IVIg than the placebo group (282 versus 272 days, P = 0.02) but the mean birthweight was not significantly increased.CONCLUSIONS: In this trial, which is the largest so far, IVIg did not increase the live birth rate in patients with secondary recurrent miscarriage and the treatment cannot be recommended in clinical practice.

STUDY QUESTION: Is the prevalence of psychological stress and moderate/severe depression higher for women with recurrent pregnancy loss (RPL) than pregnancy planners trying to conceive naturally?SUMMARY ANSWER: Both psychological stress and major depression are significantly more common among women with RPL than in those trying to conceive naturally.WHAT IS KNOWN ALREADY: RPL has a significant emotional impact on couples, especially the woman. Previous studies have shown inconclusive results.STUDY DESIGN, SIZE, DURATION: In this cross-sectional study, we compared the prevalence of stress and depression among 301 women with RPL and 1813 women attempting to conceive naturally. We defined RPL as three or more pregnancy losses before 12 weeks' gestation. RPL patients were enrolled from 2010 to 2013 and the comparison group from 2011 to 2014.PARTICIPANTS/MATERIALS, SETTING, METHODS: RPL patients completed an online questionnaire before their first consultation at the Danish RPL Unit. In addition, we included data from a comparison group of 1813 women who participated in the Soon Parents Study (www.SnartForældre.dk). The Major Depression Index (MDI) was used to assess symptoms of depression, and Cohen's Perceived Stress Scale (PSS) was used to measure stress. Relevant demographic data were also retrieved.MAIN RESULTS AND THE ROLE OF CHANCE: Of the RPL patients, 26 (8.6%) had a score on the MDI corresponding to moderate/severe depression, as did 40 (2.2%) of the women in Soon Parents Study (adjusted odds ratio (OR) 5.53 (95% confidence interval (CI): 2.09; 14.61)). A high stress level, defined as ≥19 on the PSS scale, was reported by 124 (41.2%) of the patients and 420 (23.2%) in the comparison group (adjusted OR 1.59 (95% CI 1.03; 2.44)).LIMITATIONS, REASONS FOR CAUTION: We used online questionnaires, and have no interview data. We were unaware if any of the women in the comparison group suffer from RPL.WIDER IMPLICATION