Angiogenic factors and the lectin pathway of complement in women with secondary recurrent pregnancy 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.

'You're never pregnant in the same way again': prior early pregnancy loss influences need for health care and support in subsequent pregnancy.

STUDY QUESTION: What are couples' needs for health care and support in a subsequent pregnancy after prior early pregnancy loss (PL) and how do needs change across the pregnancy? SUMMARY ANSWER: Couples described unmet needs for pregnancy care in the first 20 weeks of pregnancy and were more satisfied with the care provided during the remainder of the pregnancy. WHAT IS KNOWN ALREADY: Despite early PL being common (∼25% of pregnancies), there is a paucity of research to guide practice to optimize treatment and support future pregnancies. There has been low priority for the issue in research and a pervasive acceptance that couples should 'just try again' after experiencing PL. Women with prior PL report increased anxiety during the first trimester of pregnancy compared to those without previous PL. No longitudinal studies explore what couples' needs are throughout the pregnancy and how these needs shift across time. STUDY DESIGN SIZE DURATION: This was a qualitative longitudinal dyadic (joint) interview study. In total, 15 couples who were pregnant after a prior PL were interviewed four times over their pregnancy. Couples were recruited from the Copenhagen Pregnancy Loss Cohort Research Programme. Interviews were held in person at the hospital or university, or online. Interviews ranged from 20 to 91 min (mean = 54 min). PARTICIPANTS/MATERIALS SETTING METHODS: Inclusion criteria included couples with one to two prior early PL(s) who self-reported a new pregnancy and were willing to be interviewed together and in English. Couples were interviewed four times: after a positive pregnancy test and once in each trimester. Interviews were transcribed and data were analysed using thematic analysis to compare and contrast needs of the couples at each of the four time periods in the pregnancy and across the entire pregnancy. One same-sex couple and 14 heterosexual couples participated. MAIN RESULTS AND THE ROLE OF CHANCE: Couples' needs were categorized into two main longitudinal themes across the pregnancy, divided by the 20-week scan. Within each longitudinal theme, there were two themes to represent each time period. In the longitudinal theme 'The first 20 weeks: a 'scary' gap in care' there were two themes: Positive pregnancy test: 'Tell them it's not the same pregnancy' and First trimester: 'We craved that someone was taking care of us'. The standard pregnancy care offered in the public healthcare system in Denmark includes a scan at 12 and 20 weeks. While all couples wished for additional access to scans and monitoring of the foetus in early pregnancy to provide reassurance and detect problems early, they described considerable variation in the referrals and care they were offered. Both partners expressed a high degree of worry and anxiety about the pregnancy, with pregnant women in particular describing 'surviv[ing] from scan to scan' in the early weeks. Couples took scans wherever offered or paid for comfort scans, but this resulted in fragmented care. Instead, they wished for continuity in care, and acknowledgement and sensitivity that a pregnancy after PL is not the same as a first pregnancy. In the longitudinal theme 'The second 20 weeks: Safety in the care system' there were two themes: Second trimester: 'I think we are in good hands' and Third trimester: 'It's more of a 'nice to know' everything is OK than a 'need to know'. Couples reported their distress was lower and overall needs for care were met during this time. They expressed general satisfaction with regular or extended antenatal support although, as in the first 20 weeks, additional acknowledgement and sensitivity regarding their history of PL was desired. Couples said they felt more secure given that they had access to a 24-hour telephone support by midwife/nurse if they had any concerns or questions. LIMITATIONS REASONS FOR CAUTION: Participants were self-selected from an ongoing cohort study of patients presenting at hospital with PL. Single women were not included in the study. This study was limited to data collection in Denmark; however, other countries with public healthcare systems may have similar offerings with regard to their provision of antenatal care, care provided in recurrent pregnancy loss (RPL) clinics and the availability of private scans. WIDER IMPLICATIONS OF THE FINDINGS: The findings underscore that an early PL creates an increased need for monitoring and care in a subsequent pregnancy. This study highlights a gap in pregnancy care for those with a history of PL given that their need for monitoring and support is high in the early weeks of a new pregnancy before they have access to antenatal care, and before they have had multiple PLs and can be referred to the RPL unit. STUDY FUNDING/COMPETING INTERESTS: This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 101028172 for E.K. The Copenhagen Pregnancy Loss Cohort is funded by a grant from the BioInnovation Institute Foundation. H.S.N. has received scientific grants from Freya Biosciences, Ferring Pharmaceuticals, BioInnovation Institute, Ministry of Education, Novo Nordisk Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Ole Kirks Fond, and Independent Research Fund Denmark. H.S.N. received personal payment or honoraria for lectures and presentations from Ferring Pharmaceuticals, Merck, Astra Zeneca, Cook Medical, Gedeon Richter, and Ibsa Nordic. All other authors declare no competing interests.

HLA-DRB1 polymorphism in recurrent pregnancy loss: New evidence for an association to HLA-DRB1*07.

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.

SARS-CoV-2 in first trimester pregnancy: a cohort study.

STUDY QUESTION: Does maternal infection with severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) in first trimester pregnancy have an impact on the fetal development as measured by nuchal translucency thickness and pregnancy loss? SUMMARY ANSWER: Nuchal translucency thickness at the first trimester scan was not significantly different in pregnant women with versus without SARS-CoV-2 infection in early pregnancy and there was no significantly increased risk of pregnancy loss in women with SARS-CoV-2 infection in the first trimester. WHAT IS KNOWN ALREADY: Pregnant women are more vulnerable to viral infections. Previous coronavirus epidemics have been associated with increased maternal morbidity, mortality and adverse obstetric outcomes. Currently, no evidence exists regarding possible effects of SARS-CoV-2 in first trimester pregnancies. STUDY DESIGN, SIZE, DURATION: Cohort study of 1019 women with a double test taken between 17 February and 23 April 2020, as a part of the combined first trimester risk assessment, and 36 women with a first trimester pregnancy loss between 14 April and 21 May 2020, prior to the double test. The study period was during the first SARS-CoV-2 epidemic wave in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohort 1 included pregnant women with a double test taken within the study period. The excess serum from each double test was analyzed for SARS-CoV-2 antibodies. Results were correlated to the nuchal translucency thickness and the number of pregnancy losses before or at the time of the first trimester scan. Cohort 2 included women with a pregnancy loss before the gestational age for double test sample. Serum from a blood test taken the day the pregnancy loss was identified was analyzed for SARS-CoV-2 antibodies. The study was conducted at a public university hospital serving ∼12% of pregnant women and births in Denmark. All participants in the study provided written informed consent. MAIN RESULTS AND THE ROLE OF CHANCE: Eighteen (1.8%) women had SARS-CoV-2 antibodies in the serum from the double test suggestive of SARS-CoV-2 infection in early pregnancy. There was no significant difference in nuchal translucency thickness for women testing positive for previous SARS-CoV-2 infection (n = 16) versus negative (n = 966) (P = 0.62). There was no significantly increased risk of pregnancy loss for women with antibodies (n = 1) (OR 3.4, 0.08-24.3 95% CI, P = 0.27). None of the women had been hospitalized due to SARS-CoV-2 infection. None of the women with pregnancy loss prior to the double test (Cohort 2) had SARS-CoV-2 antibodies. LIMITATIONS, REASONS FOR CAUTION: These results may only apply to similar populations and to patients who do not require hospitalization due to SARS-CoV-2 infection. A limitation of the study is that only 1.8% of the study population had SARS-CoV-2 antibodies suggestive of previous infection. WIDER IMPLICATION OF THE FINDINGS: Maternal SARS-CoV-2 infection had no effect on the nuchal translucency thickness and there was no significantly increased risk of pregnancy loss for women with SARS-CoV-2 infection in first trimester pregnancy. Evidence concerning COVID-19 in pregnancy is still limited. These data indicate that infection with SARS-CoV-2 in not hospitalized women does not pose a significant threat in first trimester pregnancies. Follow-up studies are needed to establish any risk to a fetus exposed to maternal SARS-CoV-2 infection. STUDY FUNDING/COMPETING INTEREST(S): Prof. H.S.N. and colleagues received a grant from the Danish Ministry of Research and Education for research of COVID-19 among pregnant women. The Danish government was not involved in the study design, data collection, analysis, interpretation of data, writing of the report or decision to submit the paper for publication. A.I., J.O.-L., J.B.-R., D.M.S., J.E.-F. and E.R.H. received funding from a Novo Nordisk Foundation (NNF) Young Investigator Grant (NNF15OC0016662) and a Danish National Science Foundation Center Grant (6110-00344B). A.I. received a Novo Scholarship. J.O.-L. is funded by an NNF Pregraduate Fellowship (NNF19OC0058982). D.W. is funded by the NNF (NNF18SA0034956, NNF14CC0001, NNF17OC0027594). A.M.K. is funded by a grant from the Rigshospitalet's research fund. H.S.N. has received speaker's fees from Ferring Pharmaceuticals, Merck Denmark A/S and Ibsa Nordic (outside the submitted work). N.l.C.F. has received a grant from Gedeon Richter (outside the submitted work). A.M.K. has received speaker's fee from Merck (outside the submitted work). The other authors did not report any potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Chance of live birth in the first pregnancy after referral among patients with recurrent pregnancy loss is not influenced by their relatives' reproductive history.

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.

Pregnancy outcomes after recurrent pregnancy loss: a longitudinal cohort study on stress and depression.

RESEARCH QUESTION: Are self-reported symptoms of stress and depression associated with pregnancy outcomes within the first year after referral to a tertiary recurrent pregnancy loss unit? DESIGN: Prospective cohort study with online questionnaires using the Major Depression Inventory (MDI) and Cohen's Stress Scale (PSS) at referral and after 1 year. The study was conducted between 2010 and 2014. A total of 301 women who had experienced recurrent pregnancy loss completed the first questionnaire. One year after referral, 185 women (61%) completed a follow-up questionnaire. RESULTS: A score above the threshold for major depression on the MDI at referral was not a predictor for outcome in the first pregnancy after referral; OR (95% CI) for live birth 1.71 (0.66 to 4.44), neither was increasing scores on the PSS: OR 0.98 (95% CI 0.94 to 1.02). At follow-up, women who had achieved a pregnancy resulting in a live birth had significantly lower scores on both the MDI: 13.45 (11.05) versus 11.04 (11.07); difference -2.41 (95% CI -4.60 to -0.23); and the PSS: mean 17.69 (7.59) versus 13.03 (6.83); difference -4.66 (95% CI -6.04 to -3.28), respectively. This was not the case for women who did not have a successful pregnancy. Women who experienced recurrent pregnancy loss after a successful birth were less likely to report symptoms corresponding to major depression than women who had only experienced losses (n = 7 [5%] versus 19 [12%]; P = 0.04). CONCLUSIONS: Self-reported emotional distress did not affect future chance of live birth. A live born child decreased emotional distress.

Recurrent pregnancy loss: couples' perspectives on their need for treatment, support and follow up.

STUDY QUESTION: What do couples referred to or attending a recurrent pregnancy loss (RPL) clinic believe they need in terms of treatment, support and follow up? SUMMARY ANSWER: Men and women wish for more information, earlier access to treatment, support and follow up that is sensitive to their history of pregnancy loss (PL), includes both members of the couple, and acknowledges the psychological impact of RPL. WHAT IS KNOWN ALREADY: Previous research has highlighted women's dissatisfaction with medical care provided post-PL and their desire for medical professionals to have increased awareness about PL and recognition of the psychological impact of PL. Less is known about the needs of the male partner, the needs of those experiencing RPL and whether the needs differ during different reproductive stages. STUDY DESIGN, SIZE, DURATION: Over a 2-month period in 2017-2018, 13 couples who were referred to the national RPL program in Copenhagen, Denmark were qualitatively interviewed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were heterosexual couples with at least three consecutive PLs before 12 weeks' gestation with no children or one child prior to the PLs, not currently pregnant, and willing to be interviewed in English. Couples were interviewed together in a semi-structured format. Data were analyzed using thematic analysis. Invitations (n = 30) were sent to couples recently referred to the RPL program who indicated an interest in participating and 17 couples contacted the interviewer to schedule an interview. Due to cancellations, 15 interviews were held. Data from 13 interviews that met the study criteria were used for the current analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The participants had experienced a median of three PLs (range 3-6). Both men and women described the cumulative effect of RPL with an increase in pressure and exhaustion by the third and subsequent losses. Inclusion of the male partner in consultations and treatment was seen as important. Men felt pressured to remain positive and support their partners despite their own feelings of loss. The findings showed that couples desired reliable and accurate information about RPL. They wished for recognition from the medical community that RPL has a significant psychological impact, and stressed that effective treatment should include both members of the couple, with attention to both physical and psychological aspects of the RPL and should be tailored to their current reproductive stage, in order to help them cope with the negative impact of RPL and the anxiety associated with conception and another pregnancy. LIMITATIONS, REASONS FOR CAUTION: Participants were self-selected thus findings cannot be generalized to all couples with RPL. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study addressing the needs of the female and male partners in couples suffering from RPL. The findings highlight a disconnect between couples' perceived needs and their experience of medical care after RPL. This may be partly due to a discrepancy in couples' and medical professionals' perceptions of the PLs. The findings highlight that medical professionals need to take a holistic and couple-focused approach in their treatment of RPL and include attention to the psychological impact and cumulative effect of the multiple PLs on the couple. The results underscore the need for informational resources and psychological support for couples experiencing RPL, tailored to their reproductive stage. STUDY FUNDING/COMPETING INTEREST(S): EK was funded by a Travel/Training Fellowship from ReproUnion, co-financed by the European Union, Interreg V ÖKS. No other competing interests were declared. TRIAL REGISTRATION NUMBER: N/A.

Recurrent pregnancy loss: what is the impact of consecutive versus non-consecutive losses?

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 0.88 (95% CI 0.70-1.11), respectively. In contrast, the impact on risk of pregnancy loss conferred by a late and by each early pregnancy loss occurring after the birth was significant: IRR 2.15 (95% CI 1.57-2.94, P < 0.0001) and IRR 1.14 (95% CI 1.04-1.24, P = 0.002), respectively. LIMITATIONS, REASONS FOR CAUTION: Of the patients, 48% were treated with IvIg, which could influence the results. However, allocation to IvIg was random and prognostic variables were equally distributed in IvIg and placebo-treated patients. WIDER IMPLICATIONS OF THE FINDINGS: A birth in women with secondary RPL eradicates the negative prognostic impact of previous pregnancy losses and this finding is important for our understanding of the pathogenesis. It indicates that only consecutive pregnancy losses should count in the definition of RPL. STUDY FUNDING/COMPETING INTERESTS: There was no particular funding for this study. The authors declare that there is no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable for two of the included randomized controlled trials. For the last trial: Clinical.Gov NCT00722475.

Depression and emotional stress is highly prevalent among women with recurrent pregnancy loss.

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 IMPLICATIONS OF THE FINDINGS: This study should entail a heightened awareness of mental distress among care providers for women with RPL. STUDY FUNDING/COMPETING INTERESTS: No specific funding was sought for this study. The Soon Parents Study is funded by National Institute of Child Health and Human Development (R01 HD060680-01A4). No authors have competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Intravenous immunoglobulin treatment for secondary recurrent miscarriage: a randomised, double-blind, placebo-controlled trial.

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.

Fear of childbirth in nulliparous and multiparous women: a population-based analysis of all singleton births in Finland in 1997-2010.

OBJECTIVE: To identify risk factors for fear of childbirth (FOC) according to parity and socioeconomic status, and to evaluate associations between FOC and adverse perinatal outcomes. DESIGN: A cohort study. SETTING: The Finnish Medical Birth Register. POPULATION: All 788 317 singleton births during 1997-2010 in Finland. METHODS: Fear of childbirth was defined according to the International Classification of Diseases code O99.80, and its associations with several risk factors and perinatal outcomes were analysed by multivariable logistic regression. MAIN OUTCOME MEASURES: Prevalence of, risk factors for and outcomes of FOC. RESULTS: Fear of childbirth was experienced by 2.5% of nulliparous women and 4.5% of multiparous women. The strongest risk factors for FOC in nulliparous women were depression [adjusted odds ratio (aOR), 6.35; 95% confidence interval (CI), 5.25-7.68], advanced maternal age (aOR, 3.78; 95% CI, 3.23-4.42) and high or unspecified socioeconomic status. In multiparous women, the strongest risk factors for FOC were depression (aOR, 5.47; 95% CI, 4.67-6.41), previous caesarean section (CS) (aOR, 3.02; 95% CI, 2.93-3.11) and high or unspecified socioeconomic status. Among both nulliparous and multiparous women, FOC was associated with higher rates of CS (3.3-fold and 4.5-fold higher, respectively) and a lower incidence of low birthweight (<2500 g), small for gestational age babies, preterm birth and low Apgar scores at 1 minute. CONCLUSIONS: High and unspecified socioeconomic status, advanced maternal age and depression are predisposing factors for FOC regardless of parity. Among multiparous women, a previous CS increases vulnerability to FOC. FOC is associated with increased rates of CS, but does not adversely affect other pregnancy outcomes.

A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage.

Previously, siblings of patients with idiopathic recurrent miscarriage (IRM) have been shown to have a higher risk of miscarriage. This study comprises two parts: (i) an epidemiological part, in which we introduce data on the frequency of miscarriage among 268 siblings of 244 patients with IRM and (ii) a genetic part presenting data from a genome-wide linkage study of 38 affected sibling pairs with IRM. All IRM patients (probands) had experienced three or more miscarriages and affected siblings two or more miscarriages. The sibling pairs were genotyped by the Affymetrix GeneChip 50K XbaI platform and non-parametric linkage analysis was performed via the software package Merlin. We find that siblings of IRM patients exhibit a higher frequency of miscarriage than population controls regardless of age at the time of pregnancy. We identify chromosomal regions with LOD scores between 2.5 and 3.0 in subgroups of affected sibling pairs. Maximum LOD scores were identified in four occurrences: for rs10514716 (3p14.2) when analyzing sister-pairs only; for rs10511668 (9p22.1) and rs341048 (11q13.4) when only analyzing families where the probands have had four or more miscarriages; and for rs10485275 (6q16.3) when analyzing one sibling pair from each family only. We identify no founder mutations. Concluding, our results imply that IRM patients and their siblings share factors which increase the risk of miscarriage. In this first genome-wide linkage study of affected sibling pairs with IRM, we identify regions on chromosomes 3, 6, 9 and 11 which warrant further investigation in order to elucidate their putative roles in the genesis of IRM.

Hereditary thrombophilia and recurrent pregnancy loss: a retrospective cohort study of pregnancy outcome and obstetric complications.

BACKGROUND: The association among hereditary thrombophilia, recurrent pregnancy loss (RPL) and obstetric complications is yet uncertain. The objective of the study was to assess the prognostic value of the factor V Leiden (FVL) and prothrombin (PT) mutations for the subsequent chance of live birth for women with RPL. METHODS: Pregnancy outcome was recorded in a retrospective cohort of 363 women with a minimum of three consecutive pregnancy losses (early miscarriage, late miscarriage or stillbirth/neonatal death) who were not treated with anticoagulation therapy. RESULTS: Of the 363 women, 29 were FVL-mutation carriers and 6 were PT-mutation carriers. The unadjusted live birth rate was 45.7% in FVL/PT carriers versus 63.4% in FVL/PT non-carriers, P = 0.04. The adjusted odds ratio for live birth in FVL/PT carriers was 0.48 (95% CI = 0.23-1.01), P = 0.05. Among the obstetric complications, only excessive bleeding was found to be associated with FVL/PT mutations. CONCLUSIONS: In the unadjusted analysis, FVL and PT mutations have a negative prognostic impact on the live birth rate in women with RPL; however, when adjusting for significant covariates, the results no longer reach statistical significance. Strong conclusions on the association between obstetric complications and hereditary thrombophilia cannot be drawn from this study. Whether anticoagulation therapy would improve the prognosis in women with RPL and FVL/PT mutations remains to be documented in large randomized controlled trials.

H-Y antibody titers are increased in unexplained secondary recurrent miscarriage patients and associated with low male : female ratio in subsequent live births.

BACKGROUND: The birth of a boy is significantly more common than a girl prior to secondary recurrent miscarriage (SRM) and is associated with a poorer chance of a subsequent live birth. Children born after SRM are more likely to be girls. High-titer antisera specific for male antigens (H-Y) have been shown to arrest development of male bovine embryos efficiently. We consequently questioned the role of H-Y antibodies in women with SRM. METHODS: Serum samples from patients with unexplained SRM (n = 84), unexplained primary recurrent miscarriage (PRM) (n = 12) and healthy women (n = 37) were obtained. The samples were taken during pregnancy (gestational weeks 4-5) for 77 (80%) of the patients. Enzyme-linked immunosorbent assay was used to detect immunoglobulin G antibodies that specifically recognized any of the five recombinant H-Y proteins (EIF1AY, RPS4Y1, ZFY, DDX3Y and UTY) and their H-X homologs. RESULTS: H-Y-specific antibodies were more frequent in SRM patients (46%) compared with female controls (19%, P = 0.004) and PRM patients (8%, P = 0.01). The presence of H-Y antibodies in early pregnancy was associated with a low male: female birth ratio among the subsequent live births, as only 12% of children born to H-Y antibody-positive patients were boys compared with 44% boys born to H-Y antibody negative patients (P = 0.03). CONCLUSIONS: The high frequency of H-Y antibody-positive SRM patients and the association between the presence of these antibodies in early pregnancy and the low number of male offspring, suggest that maternal immune responses against H-Y antigens can cause pregnancy losses. Further exploring these mechanisms may increase our understanding of unexplained SRM.

Frequency and impact of obstetric complications prior and subsequent to unexplained secondary recurrent miscarriage.

BACKGROUND: The chance of a live birth after a diagnosis of secondary recurrent miscarriage (SRM) is reduced in patients who, prior to the miscarriages, gave birth to a boy and carry HLA class II alleles that efficiently present male-specific (H-Y) antigens to the immune system. Information about obstetric complications in births prior and subsequent to the SRM diagnosis is limited. The relations between maternal carriage of H-Y-restricting HLA, fetal sex, obstetric complications and prognosis are unknown. METHODS: Women with unexplained SRM referred to the Danish Recurrent Miscarriage Clinic between 1986 and 2006 (n = 358) were included; 213 gave birth after the diagnosis. Controls, retrieved from the Danish National Birth Registry, were all women with singleton birth of parity 0, 1982-2005 (n = 608,068) and parity 1, 1986-2008 (n = 510,264). Cross-linkage to the National Discharge Registry identified birth complication diagnoses related to the relevant births among patients and controls. RESULTS: The sex ratio was 1.49 in births prior to SRM and 0.76 in birth after SRM (P < 0.0001). For SRM patients with only late miscarriages (>10 weeks gestation), the corresponding sex ratios were 2.31 and 0.21. Compared with the control groups, obstetric complications were more frequent both before (39% versus 24% P

A community-based long-term follow up of women undergoing obstetric fistula repair in rural Ethiopia.

OBJECTIVES: To assess urinary and reproductive health and quality of life following surgical repair of obstetric fistula. DESIGN: Follow-up study. SETTING: A newly established fistula clinic (2004) at Gimbie Adventist Hospital, a 71-bedded district general hospital in West Wollega Zone, in rural Western Ethiopia. POPULATION: Thirty-eight women (86%) of 44 who had undergone fistula repair were identified in their community. METHODS: Community-based structured interviews 14-28 months following fistula repair, using a customised questionnaire addressing urinary health, reproductive health and quality of life. MAIN OUTCOME MEASURES: Urinary health at follow up was assessed as completely dry, stress or urge incontinence, or fistula. King's Health Questionnaire was modified and used for the quality-of-life assessment. RESULTS: At follow up, 21 women (57%) were completely dry, 13 (35%) suffered from stress or urge incontinence and three (8%) had a persistent fistula. Surgery improved quality of life and facilitated social reintegration to a level comparable to that experienced before fistula development for both women who were dry and those with residual incontinence (P = 0.001). For women still suffering from fistula no change was seen (P = 0.1). Four women became pregnant following their surgery, among which there was one maternal death, three stillbirths and one re-occurrence of fistula. CONCLUSION: Community-based, long-term follow up after fistula repair succeeded in Western rural Ethiopia. Despite one-third still suffering stress or urge incontinence, the women reported improved quality of life and social reintegration after fistula closure.

Biomarkers for early effects of carcinogenic dual-acting PPAR agonists in rat urinary bladder urothelium in vivo.

Small-molecule agonists of the peroxisome proliferator-activated receptor (PPAR) alpha and gamma isoforms (dual-acting PPAR agonists) can cause urothelial cancers in rodents. Rats were dosed orally for 16 days with bladder carcinogenic (ragaglitazar) as well as non-bladder carcinogenic (fenofibrate and rosiglitazone) PPAR agonists and protein changes were assayed in the urinary bladder urothelium by Western blotting. Dose levels reflected 10-20 x human exposure, and the ragaglitazar dose was in the carcinogenic range. Ragaglitazar induced expression of the transcription factor Egr-1, phosphorylation of the c-Jun transcription factor and phosphorylation of the ribosomal S6 protein were observed. These changes were also observed in rats dosed with either rosiglitazone or fenofibrate. However, the protein changes were stronger (Egr-1 induction) or of a longer duration (S6 phosphorylation) in ragaglitazar-treated animals. Animals co-administered fenofibrate (a specific PPARalpha agonist) and rosiglitazone (a specific PPARgamma agonist) exhibited Egr-1 and S6 protein changes more similar to those induced by ragaglitazar (a dual-acting PPARalpha/gamma agonist) than either fenofibrate or rosiglitazone alone. The findings suggest that ragaglitazar causes Egr-1, c-Jun and S6 protein changes in the urothelium by a mechanism involving PPARalpha as well as PPARgamma, and that the Egr-1, c-Jun and S6 protein changes might have potential biomarker value.

A phase I study of the safety of honeybee venom extract as a possible treatment for patients with progressive forms of multiple sclerosis.

Although several reports suggest that bee venom may be an effective treatment for patients with multiple sclerosis (MS), patients may be subjected to real risks of serious allergic reactions as well as emotional and economic costs. This study was conducted to evaluate the safety of bee venom extract as a possible treatment for patients with progressive forms of MS. A total of nine bee venom nonallergic patients with progressive forms of MS, who were 21-55 years of age with no other illnesses, were entered into four groups (A, B, C, and D) on a structured 1-year immunization schedule. Hyperreactivity to bee venom was evaluated by questionnaire, physical examination, and a battery of hematologic, metabolic, and immunologic tests. Responses to therapy were evaluated by questionnaire, functional neurological tests, and changes in measurement of somatosensory-evoked potentials. Although no serious adverse allergic reactions were observed in any of the nine subjects, four experienced worsening of neurological symptoms, requiring termination in the study; this could not be ascribed to side effects of the therapy. Of the remaining five subjects, three felt that the therapy had subjective amelioration of symptoms and two showed objective improvement. Although this preliminary study suggests safety, because of the small numbers studied, there were no definite conclusions regarding efficacy and therefore there was little evidence to support the use of honeybee venom in the treatment of MS. Larger and more carefully conducted multicenter studies will be required to establish efficacy.

Impact of the sex of first child on the prognosis in secondary recurrent miscarriage.

BACKGROUND: The carriage of a male fetus often initiates maternal immunological reactions against male-specific minor histocompatibility (HY) antigens, which, in theory, could result in subsequent recurrent miscarriage (RM). METHODS: Information about subsequent pregnancy outcome was procured among 182 women with RM after a birth (secondary RM) referred since 1986 using questionnaires, telephone interviews and registers. RESULTS: Significantly more of the women had had a male first-born as compared with a female first-born (110 versus 72; P < 0.02). By January 2002, 58% of those who had a male first-born had given birth to a second live infant compared with 76% of those who previously had had a female first-born (P = 0.01). Women in the former group had a significantly lower chance of having a second child than those in the latter (adjusted hazard ratio 0.59; 95% confidence interval 0.41-0.86). The number of miscarriages after admission and the risk of secondary infertility were significantly greater in women with a male first-born than among those with a female first-born (P < 0.001 and P = 0.02; respectively). CONCLUSIONS: A male first-born seems to be associated with a less favourable reproductive potential among women with secondary RM. Maternal immunization against HY antigens may be responsible for these findings.

Generation of an infectious clone of VR-2332, a highly virulent North American-type isolate of porcine reproductive and respiratory syndrome virus.

A full-length cDNA clone of the prototypical North American porcine reproductive and respiratory syndrome virus (PRRSV) isolate VR-2332 was assembled in the plasmid vector pOK(12). To rescue infectious virus, capped RNA was transcribed in vitro from the pOK(12) clone and transfected into BHK-21C cells. The supernatant from transfected monolayers were serially passaged on Marc-145 cells and porcine pulmonary alveolar macrophages. Infectious PRRSV was recovered on Marc-145 cells as well as porcine pulmonary macrophages; thus, the cloned virus exhibited the same cell tropism as the parental VR-2332 strain. However, the cloned virus was clearly distinguishable from the parental VR-2332 strain by an engineered marker, a BstZ17I restriction site. The full-length cDNA clone had 11 nucleotide changes, 2 of which affected coding, compared to the parental VR-2332 strain. Additionally, the transcribed RNA had an extra G at the 5' end. To examine whether these changes influenced viral replication, we examined the growth kinetics of the cloned virus in vitro. In Marc-145 cells, the growth kinetics of the cloned virus reflected those of the parental isolate, even though the titers of the cloned virus were consistently slightly lower. In experimentally infected 5.5-week-old pigs, the cloned virus produced blue discoloration of the ears, a classical clinical symptom of PRRSV. Also, the seroconversion kinetics of pigs infected with the cloned virus and VR-2332 were very similar. Hence, virus derived from the full-length cDNA clone appeared to recapitulate the biological properties of the highly virulent parental VR-2332 strain. This is the first report of an infectious cDNA clone based on American-type PRRSV. The availability of this cDNA clone will allow examination of the molecular mechanisms behind PRRSV virulence and attenuation, which might in turn allow the production of second-generation, genetically engineered PRRSV vaccines.