Evaluating risk factors in recurrent pregnancy loss: A prospective cohort study and its impact on live birth outcomes.

Recurrent pregnancy loss (RPL) affects 1-2 % of all couples trying to conceive and is a challenging heterogeneous condition. This study aimed to evaluate the prevalence and impact of various risk factors in patients suffering from RPL. We performed a prospective cohort study including patients at the tertiary RPL Unit in the Capital Region of Denmark between 1st January 2000 and 1st January 2023. The main outcome of the study was the first pregnancy after referral and whether the pregnancy was ongoing at least to the 22nd gestational week. A total of 2555 patients were included in the study, out of whom 1892 patients achieved a pregnancy after referral to the RPL Unit. This resulted in 1103 live births (58.3 %) and 718 pregnancy losses (37.9 %). Maternal age, BMI, smoking status and the number of prior pregnancy losses were negatively correlated with the likelihood of achieving pregnancy. Furthermore, maternal age, prior pregnancy losses, antiphospholipid syndrome (APS) and uterine malformations were associated with reduced birth rates. Patients with secondary RPL had a higher birth rate compared to those with primary RPL, and patients with APS treated with low-molecular-weight heparin (LMWH) demonstrated a significantly increased birth rate compared to untreated APS patients. These findings suggest that certain risk factors significantly impact the likelihood of achieving pregnancy and live birth following RPL, which can be used in patient guidance.

Thyroid function monitoring during pregnancy in euthyroid women with thyroid autoimmunity.

Background: Thyroid autoimmunity (TAI) may be present in 1-17% of pregnant women. Monitoring of thyroid function in euthyroid pregnant women positive for anti-thyroperoxidase antibodies (TPOAb+) is recommended. Objective: To determine the prevalence and possible clinical and biological risk factors of biochemical progression (rise in serum thyroid-stimulating hormone (TSH) > 2.5 mU/L) at second blood sampling during pregnancy, in euthyroid women (TSH ≤ 2.5 mU/L) according to their TPOAb status. Methods: This study included demographic and biological data from two previously published cohorts (n = 274 women from August 1996 to May 1997 Copenhagen cohort, and n = 66 women from January 2013 to December 2014 Brussels cohort) having at least two measurements of TSH and free thyroxine (FT4) and at least one of TPOAb during spontaneously achieved singleton pregnancies. Results: The majority of women studied did not show biochemical progression. Only 4.2% progressed, significantly more frequently among TPOAb+ women, as compared to TPOAb- group (9.4 vs 2.7%, P = 0.015). No rise in serum TSH > 4 mU/L at 2nd sampling was observed. Higher baseline TSH levels were associated with biochemical progression in both TPOAb+ (P = 0.05) and TPOAb- women (P < 0.001), whereas maternal age, BMI, multiparity, smoking, FT4, and TPOAb concentrations were not significantly different between women with and without progression. Conclusions: Only a minority of euthyroid women with thyroid autoimmunity presented biochemical progression and none with a TSH > 4 mU/L. Larger studies are needed to better target the subset of women who would benefit most from repeated thyroid function monitoring during pregnancy.

Defining gestational thyroid dysfunction through modified non-pregnancy reference intervals: an individual participant meta-analysis.

BACKGROUND: Establishing local trimester-specific reference intervals for gestational TSH and FT4 is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific non-pregnancy reference intervals as compared to trimester-specific reference intervals. METHODS: We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the non-pregnancy reference intervals included an absolute modification (per 0.1 mU/L TSH or 1 pmol/L FT4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 to 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity and positive predictive value (PPV) of aforementioned methodologies with population-based trimester-specific reference intervals. RESULTS: The final study population comprised 52,496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity 0.70, confidence interval [CI] 0.47-0.86; PPV 0.64, CI 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity 0.91, CI 0.67-0.98; PPV 0.71, CI 0.58-0.80). Absolute and fixed modifications yielded similar results. Confidence intervals were wide, limiting generalizability. CONCLUSION: We could not identify modifications of non-pregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned towards studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.

Prospective reproductive outcomes according to sperm parameters, including DNA fragmentation, in recurrent pregnancy loss.

RESEARCH QUESTION: Are the prospective reproductive outcomes in couples experiencing recurrent pregnancy loss (RPL) related to the sperm DNA fragmentation index (DFI), as measured by sperm chromatin structure assay, sperm morphology and sperm concentration at referral? DESIGN: This prospective cohort study included 95 couples seen between 1 April 2018 and 1 December 2019 at the tertiary Copenhagen RPL Unit, Copenhagen University Hospital, Rigshospitalet and Hvidovre Hospital, Denmark. The couples had experienced three or more unexplained consecutive pregnancy losses or two late pregnancy losses (>12 weeks gestation). Follow-up was 12-31 months. RESULTS: Eighty-one of 95 (85.3%) couples achieved pregnancy after referral. In the first pregnancy after referral, 46 (56.8%) couples achieved a live birth, and 35 (43.2%) couples experienced another pregnancy loss. There was no significant difference in baseline DFI between couples that experienced pregnancy loss [median 11.7, interquartile range (IQR) 9.1-17.3] and couples that achieved a live birth (median 12.5, IQR 9.3-16.5; P = 0.971). Improving sperm morphology increased the odds of a live birth after referral (adjusted OR 1.26, 95% CI 1.05-1.52; P = 0.014). DFI and sperm concentration were not associated with the outcome of the first pregnancy after referral. Overall, 35.9% of the men had DFI ≥15 at inclusion. Couples that failed to achieve pregnancy had a higher median DFI of 17.7 (IQR 7.7-27.2) compared with the rest of the cohort (median 12.0, IQR 9.3-16.5; P = 0.041). CONCLUSIONS: At referral, sperm DFI, morphology and concentration cannot be used to identify RPL couples at risk of another pregnancy loss. Increased baseline DFI was associated with difficulty achieving another pregnancy, and improving sperm morphology was associated with increased odds of a live birth.

Smoking and recurrent pregnancy loss: A cohort study of 2829 women.

Smoking during pregnancy is associated with negative reproductive outcome. Less is known about the impact of smoking or previous smoking in women with recurrent pregnancy loss (RPL) which this study aimed to investigate. We included all women <42 years (n=2829) referred to a RPL unit at Copenhagen University Hospital between January 2000 and December 2021 in the cohort with follow-up until June 2022. Patients were categorized as 'smokers at time of referral', 'never-smokers' or 'former smokers'. The main outcomes were pregnancy history prior to referral, prospective pregnancy rate, live birth rate, rates of ectopic pregnancy, and stillbirth. At referral, smokers (n=373) were on average 2.0 years younger (P<0.001) and had experienced significantly more pregnancy losses (P<0.001), and stillbirths (P=0.01) compared to never-smokers (n=2100). Former smokers had a higher risk of stillbirth prior to referral compared to never-smokers but no differences in pregnancy rate or other outcomes. Prospective pregnancy rates were lower for smokers compared with never-smokers (71.8% vs. 77.5%, P=0.02). Live birth rate was 58.0% for the 243 women who smoked at referral compared to 61.4% for the 1488 never-smokers (P=0.32). Stillbirth and ectopic pregnancies were significantly more common for smokers (2.8% vs. 0.4%, P=0.01; 6.0% vs. 2.0%, P<0.008). Women with RPL who smoked at referral were referred younger with a higher number of previous pregnancy losses and stillbirths compared with never-smokers. Fewer smokers achieved a pregnancy after referral but those who did had a similar live birth rate compared to never-smokers, although stillbirths and ectopic pregnancies were more common.

Polyautoimmunity in Patients With Anticyclic Citrullinated Peptide Antibody-Positive and -Negative Rheumatoid Arthritis: a Nationwide Cohort Study From Denmark.

OBJECTIVE: This study aimed to compare the prevalence and incidence of polyautoimmunity between anticyclic citrullinated peptide antibody (anti-CCP)-positive and anti-CCP-negative patients with rheumatoid arthritis (RA). METHODS: In a nationwide register-based cohort study, patients with RA (disease duration ≤ 2 yrs) in the DANBIO rheumatology register with an available anti-CCP test in the Register of Laboratory Results for Research were identified. The polyautoimmunity outcome included 21 nonrheumatic autoimmune diseases identified by linkage between the Danish Patient Registry and Prescription Registry. The age- and sex-adjusted prevalence ratio (PR) was calculated by modified Poisson regression to estimate the prevalence at diagnosis in anti-CCP-positive vs anti-CCP-negative patients. The hazard ratio (HR) of polyautoimmunity within 5 years of entry into DANBIO was estimated in cause-specific Cox regression models. RESULTS: The study included 5839 anti-CCP-positive and 3799 anti-CCP-negative patients with RA. At first visit, the prevalence of prespecified polyautoimmune diseases in the Danish registers was 11.1% and 11.9% in anti-CCP-positive and anti-CCP-negative patients, respectively (PR 0.93, 95% CI 0.84-1.05). The most frequent autoimmune diseases were autoimmune thyroid disease, inflammatory bowel disease, and type 1 diabetes mellitus. During a mean follow-up of 3.5 years, only a few (n = 210) patients developed polyautoimmunity (HR 0.6, 95% CI 0.46-0.79). CONCLUSION: Polyautoimmunity as captured through the Danish National Patient Registry occurred in approximately 1 in 10 patients with RA at time of diagnosis regardless of anti-CCP status. In the years subsequent to the RA diagnosis, only a few and mainly anti-CCP-negative patients developed autoimmune disease.