Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of recurrent pregnancy loss. Evidence on whether levothyroxine treatment improves pregnancy outcomes in women who are TPO-Ab positive women with recurrent pregnancy loss is scarce. The aim of this study was to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. METHODS: The T4LIFE trial was an international, double-blind, placebo-controlled, phase 3 study done in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium, and one tertiary hospital in Denmark. Women (18-42 years) who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range were eligible for inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibodies, or ß2-glycoprotein-I IgG or IgM antibodies), other autoimmune diseases, thyroid disease, previous enrolment in this trial, or contraindications for levothyroxine use. Before conception, women were randomly assigned (1:1) to receive either levothyroxine or placebo orally once daily. The daily dose of levothyroxine was based on preconception TSH concentration and ranged from 0·5-1·0 µg/kg bodyweight. Levothyroxine or placebo was continued until the end of pregnancy. The primary outcome was live birth, defined as the birth of a living child beyond 24 weeks of gestation measured in the intention-to-treat population. The trial was registered within the Netherlands Trial Register, NTR3364 and with EudraCT, 2011-001820-39. RESULTS: Between Jan 1, 2013, and Sept 19, 2019, 187 women were included in the study: 94 (50%) were assigned to the levothyroxine group and 93 (50%) were assigned to the placebo group. The trial was prematurely stopped when 187 (78%) of the 240 predefined patients had been included because of slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (risk ratio 1·03 [95% CI 0·77 to 1·38]; absolute risk difference 1·6% [95% CI -12·7 to 15·9]). Seven (7%) women in the levothyroxine group and seven (8%) in the placebo group reported adverse events, none of them were directly related to the study procedure. INTERPRETATION: Compared with placebo, levothyroxine treatment did not result in higher live birth rates in euthyroid women with recurrent pregnancy loss who were positive for TPO-Ab. On the basis of our findings, we do not advise routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. FUNDING: Dutch Organization for Health Research and Development, Fonds NutsOhra, Dutch Patient Organization of Thyroid Disorders, the Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Dutch Patient Organization of Thyroid Disorders.

T2*-weighted placental magnetic resonance imaging: a biomarker of placental dysfunction in small-for-gestational-age pregnancies.

BACKGROUND: The antenatal identification of placental dysfunction in small-for-gestational-age fetuses with normal fetal Doppler flows remains an obstetrical challenge. In a significant fraction of such pregnancies, placental dysfunction is revealed by clinical manifestations such as preeclampsia, preterm delivery, or severe small-for-gestational-age at birth or by abnormal findings in the postnatal placental histologic examination. Therefore, new methods to identify placental function directly in pregnancy at the time of small-for-gestational-age diagnosis is highly needed. T2*-weighted placental magnetic resonance imaging is sensitive to changes in placental morphology and oxygenation and is thereby related to placental function. Previous studies have demonstrated that pregnancies complicated by low birthweight and preeclampsia are characterized by low placental T2* values. However, the specific performance of placental T2* in the prediction of placenta-related outcomes in small-for-gestational-age pregnancies with normal fetal Doppler flows remains to be explored. OBJECTIVE: In small-for-gestational-age pregnancies with normal fetal Doppler flows, we aimed to evaluate T2*-weighted placental magnetic resonance imaging as an antenatal biomarker of placental dysfunction. In addition, we aimed to investigate the correlation between placental T2* and Doppler flow measurements of fetal and uterine arteries at the time of magnetic resonance imaging. STUDY DESIGN: In this prospective cohort study, the inclusion criterion was suspected small-for-gestational-age (ultrasound estimated fetal weight Z-score ≤-2.0 [2.3rd centile]) with normal fetal Doppler flows (middle cerebral artery pulsatility index Z-score > -2.0 and umbilical artery pulsatility index Z-score <2.0). The T2*-weighted placental magnetic resonance imaging scan was performed at inclusion in a 1.5 T system. The outcomes was placental dysfunction at birth defined by low birthweight (Z-score ≤-2.0), preeclampsia, preterm delivery (gestational age<37 weeks), or abnormal placental histologic examination such as placental vascular malperfusion according to the Amsterdam Consensus Statement. RESULTS: We included 92 pregnancies at 26+5 to 39+6 weeks gestation. The median time interval between the magnetic resonance imaging scan and birth was 4.6 weeks (interquartile range, 2.7-7.8 weeks). At birth, 55% (51/92) of pregnancies revealed at least 1 sign of placental dysfunction; 49% (40/81) had abnormal placental histologic examination, 29% (27/92) were born with low birthweight, 13% (12/92) were delivered preterm, and 7% (6/92) had preeclampsia. When adjusted for gestational age at magnetic resonance imaging, the placental T2* Z-score was a significant predictor of abnormal placental histologic examination (area under the curve, 0.73; P=.001), small-for-gestational-age at birth (area under the curve, 0.63; P=.030), preeclampsia (area under the curve, 0.88; P=.005), and preterm delivery (area under the curve, 0.81; P=.001). The placental T2* was reduced in pregnancies with a combination of clinical manifestations and abnormal placental histologic examination (T2* Z-score=-1.52±1.35 [mean±standard deviation]; P=.0001) and in clinically uneventful pregnancies with abnormal placental histologic examination (T2* Z-score=-0.79±0.97; P=.045). At the time of magnetic resonance imaging, the placental T2* Z-score showed a significant linear correlation with the uterine artery pulsatility index Z-scores (r=-0.24; P=.016) and the middle cerebral artery pulsatility index Z-scores (r=0.29; P=.017) but not with the umbilical artery pulsatility index Z-scores (r=0.18; P=.17) and the cerebroplacental ratio (r=0.03; P=.77). CONCLUSION: This study indicates that placental dysfunction is frequent in small-for-gestational-age fetuses with normal fetal Doppler flows. In this cohort, T2*-weighted placental magnetic resonance imaging is a sensitive biomarker of placental dysfunction regardless of the clinical manifestations. This finding supports a paradigm shift in the conception of placental dysfunction that may cover a wide spectrum of clinical and subclinical manifestations.

Extracellular Vesicles: An Important Biomarker in Recurrent Pregnancy Loss?

Recurrent pregnancy loss (RPL) has an estimated incidence of 1-3% of all couples. The etiology is considered to be multifactorial. Extracellular vesicles (EVs) take part in numerous different physiological processes and their contents show the originating cell and pathophysiological states in different diseases. In pregnancy disorders, changes can be seen in the composition, bioactivity and concentration of placental and non-placental EVs. RPL patients have an increased risk of pregnancy complications. The aim of this prospective study was to examine whether measuring different specific EV markers in plasma before and during pregnancy could be used as predictors of pregnancy loss (PL) in women with RPL. Thirty-one RPL patients were included in this study; 25 had a live birth (LB group) and six had a new PL (PL group). Five blood samples were obtained, one before achieved pregnancy and the others in gestational week 6, 8, 10 and 16. Moreover, some of the patients received intravenous immunoglobulin (IVIG) infusions as part of treatment, and it was also examined whether this treatment influenced the EV levels. Seventeen EV markers specific for the immune system, coagulation, placenta and hypoxia were analyzed in the samples with EV Array, a method able to capture small EVs by using an antibody panel targeting membrane proteins. Comparing the LB and PL groups, one EV marker, CD9, showed a significant increase from before pregnancy to gestational week 6 in the PL group. The changes in the other 16 markers were nonsignificant. One case of late-onset PL showed steeply increasing levels, with sudden decrease after gestational week 10 in nine of 17 markers. Moreover, there was an overall increase of all 17 markers after IVIG treatment in the LB group, which was significant in 15 of the markers. Whether increases in EVs positive for CD9 characterize RPL patients who subsequently miscarry should be investigated in future larger studies.

Women with Recurrent Pregnancy Loss More Often Have an Older Brother and a Previous Birth of a Boy: Is Male Microchimerism a Risk Factor?

Known etiologic factors can only be found in about 50% of patients with recurrent pregnancy loss (RPL). We hypothesized that male microchimerism is a risk factor for RPL and aimed to explore whether information on family tree and reproductive history, obtained from 383 patients with unexplained RPL, was supportive of this hypothesis. The male:female sex ratio of older siblings was 1.49 (97:65) in all RPL patients and 1.79 (52:29) in secondary RPL (sRPL) patients, which differed significantly from the expected 1.04 ratio (p = 0.027 and p = 0.019, respectively). In contrast, the sex ratio of younger siblings was close to the expected ratio. Sex ratio of the firstborn child before sRPL was 1.51 (p = 0.026). When combined, 79.1% of sRPL patients had at least one older brother, a firstborn boy, or both. This differed significantly from what we expected based on the distribution of younger siblings and a general 1.04 sex ratio of newborns (p = 0.040). We speculate whether (s)RPL patients possibly acquired male microchimerism from older brother(s) and/or previous birth of boy(s) by transplacental cell trafficking. This could potentially have a detrimental impact on their immune system, causing a harmful response against the fetus or trophoblast, resulting in RPL.

Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss.

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5-18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3-11·4%), two miscarriages is 1·9% (1·8-2·1%), and three or more miscarriages is 0·7% (0·5-0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

Sporadic miscarriage: evidence to provide effective care.

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units.

Recurrent miscarriage: evidence to accelerate action.

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.

The timing of venous thromboembolism in ovarian cancer patients: A nationwide Danish cohort study.

BACKGROUND AND AIM: Venous thromboembolism (VTE) is associated with excess mortality and morbidity in cancer, and is influenced by patient-, tumor-, and treatment-related factors. We aimed to investigate the impact of such factors in a national cohort of patients with epithelial ovarian cancer (EOC). METHODS: Patients in the Danish Gynecologic Cancer Database (DGCD) with EOC from 2005 to 2014 were followed from time of diagnosis to VTE, or censoring. Surgery, chemotherapy, and vascular epithelial growth factor (VEGF)-inhibitors were included as time-varying exposures in Cox proportional hazard regression models. RESULTS: A total of 551 VTE events were registered in 4991 EOC patients. Median follow-up time was 2.9 years. The 2-year cumulative incidence of VTE was 7.2%. Patients were at highest risk during the first year after EOC diagnosis. Previous VTE was associated with a hazard ratio (HR) of 3.26 (95% confidence interval [CI] 2.42-4.39). Exposure to major pelvic surgery was associated with a HR of 3.21 (95% CI 2.29-4.50). Exposure to chemotherapy or (VEGF)-inhibitors were associated with HRs of 1.91 (95% CI 1.56-2.33) and 1.05 (95% CI 0.57-1.93), respectively. Hazard ratios for patients with clear cell histopathology was 1.46 (95% CI 0.97-2.20) and 2.42 for International Federation of Gynaecology and Obstetrics stage III--IV (95% CI 1.93-3.03). CONCLUSIONS: EOC is associated with a high risk of VTE, particularly within the first year after diagnosis. Major pelvic surgery and chemotherapy were strongly associated with VTE. Person-related risk factors were increasing age and previous VTE. Advanced stage was an independent tumor-related risk factor. These findings support the indication for thrombosis prophylaxis during chemotherapy.

Distribution of Stromal Cell Subsets in Cultures from Distinct Ocular Surface Compartments.

PURPOSE: To reveal the phenotypic differences between human ocular surface stromal cells (hOSSCs) cultured from the corneal, limbal, and scleral compartments. METHODS: A comparative analysis of cultured hOSSCs derived from four unrelated donors was conducted by multichromatic flow cytometry for six distinct CD antigens, including the CD73, CD90, CD105, CD166, CD146, and CD34. RESULTS: The hOSSCs, as well as the reference cells, displayed phenotypical profiles that were similar in high expression of the hallmark mesenchymal stem cell markers CD73, CD90, and CD105, and also the cancer stem cell marker CD166. Notably, there was considerable variation regarding the expression of CD34, where the highest levels were found in the corneal and scleral compartments. The multi-differentiation potential marker CD146 was also expressed highly variably, ranging from 9% to 89%, but the limbal stromal and endometrial mesenchymal stem cells significantly surpassed their counterparts within the ocular and reference groups, respectively. The use of six markers enabled investigation of 64 possible variants, however, just four variants accounted for almost 90% of all hOSSCs, with the co-expression of CD73, CD90, CD105, and CD166 and a combination of CD146 and CD34. The limbal compartment appeared unique in that it displayed greatest immunophenotype diversity and harbored the highest proportion of the CD146+CD34- pericyte-like forms, but, interestingly, the pericyte-like cells were also found in the avascular cornea. CONCLUSION: Our findings confirm that the hOSSCs exhibit an immunophenotype consistent with that of MSCs, further highlight the phenotypical heterogeneity in stroma from distinct ocular surface compartments, and finally underscore the uniqueness of the limbal region.

Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence.

Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.

Treatment with intravenous immunoglobulin in patients with recurrent pregnancy loss: An update.

Intravenous immunoglobulin (IVIg) has a documented clinical effect in many autoimmune diseases and has so far been tested in >10 randomised controlled trials (RCTs) in women with recurrent pregnancy loss (RPL). The results of the RCTs have, however, been very divergent. In meta-analyses of all trials, no significant impact on live birth rate has been reported. In contrast, in sensitivity analyses, IVIg significantly increased live birth rates when initiated prior to conception and it had a borderline significant therapeutic effect in women with secondary RPL. Higher dosages of IVIg and serological signs of autoimmunity in the treated patients tended to increase the success rate after treatment. A follow-up study of patients from our recent RCT also supports a significant therapeutic effect in patients who had received IVIg before conception. The lessons learned from the published trials and meta-analyses should be incorporated in the design of future RCTs of IVIg in the treatment of RPL.

Placental baseline conditions modulate the hyperoxic BOLD-MRI response.

OBJECTIVES: Human pregnancies complicated by placental dysfunction may be characterized by a high hyperoxic Blood oxygen level-dependent (BOLD) MRI response. The pathophysiology behind this phenomenon remains to be established. The aim of this study was to evaluate whether it is associated with altered placental baseline conditions, including a lower oxygenation and altered tissue morphology, as estimated by the placental transverse relaxation time (T2*). METHOD: We included 49 normal pregnancies (controls) and 13 pregnancies complicated by placental dysfunction (cases), defined by a birth weight < 10th percentile in combination with placental pathological signs of vascular malperfusion. During maternal oxygen inhalation, we measured the relative ΔBOLD response ((hyperoxic BOLD - baseline BOLD)/baseline BOLD) from a dynamic single-echo gradient-recalled echo (GRE) MRI sequence and the absolute ΔT2* (hyperoxic T2*- baseline T2*) from breath-hold multi-echo GRE sequences. RESULTS: In the control group, the relative ΔBOLD response increased during gestation from 5% in gestational week 20 to 20% in week 40. In the case group, the relative ΔBOLD response was significantly higher (mean Z-score 4.94; 95% CI 2.41, 7.47). The absolute ΔT2*, however, did not differ between controls and cases (p = 0.37), whereas the baseline T2* was lower among cases (mean Z-score -3.13; 95% CI -3.94, -2.32). Furthermore, we demonstrated a strong negative linear correlation between the Log10 ΔBOLD response and the baseline T2* (r = -0.88, p < 0.0001). CONCLUSION: The high hyperoxic ΔBOLD response demonstrated in pregnancies complicated by placental dysfunction may simply reflect altered baseline conditions, as the absolute increase in placental oxygenation (ΔT2*) does not differ between groups.

Associations between fetal HLA-G genotype and birth weight and placental weight in a large cohort of pregnant women - Possible implications for HLA diversity.

Birth weight and placental weight are crucial parameters for the survival of fetuses and newborns in mammals. High variation in the MHC is important for an effective adaptive immune response. The maternal immune system must be controlled in relation to the semi-allogenic fetus. The immunoregulatory HLA/MHC class Ib gene, HLA-G, is strongly expressed on extravillous trophoblast cells. We investigated birth weight and placental weight of the newborns in mothers heterozygous for an HLA-G 14bp insertion (Ins)/deletion (Del) gene polymorphism. Separate analyses for pregnancies without preeclampsia (n=185), pregnancies complicated by preeclampsia (n=101), and both groups combined, were performed. Interestingly, we observed the highest mean birth weight and placental weight in homozygous 14bp Del/Del newborns, and the lowest in 14bp Ins/Ins newborns (P=0.008 and P=0.009). The 14bp Del/Del genotype is also associated with high expression of HLA-G on the trophoblast membrane. In theory, fetuses and newborns with intermediate weights and sizes would be an optimal compromise for both the fetus/father and the mother compared with very high and low weights. If such fetuses/newborns more often are heterozygous at the HLA-G gene locus, then newborns with two distinct HLA haplotypes are favored, leading to a higher degree of HLA diversity. The results of the study may indicate that a compromise between an intermediate birth weight and placental weight, induction of maternal tolerance by a fetal-derived non-polymorphic HLA class Ib molecule, and favoring of HLA heterozygous offspring, have evolved in humans.

Prediction of low birth weight: Comparison of placental T2* estimated by MRI and uterine artery pulsatility index.

OBJECTIVE: Neonates at low birth weight due to placental dysfunction are at high risk of adverse outcomes. These outcomes can be substantially improved by prenatal identification. The Magnetic Resonance Imaging (MRI) constant, placental T2* reflects placental structure and oxygenation and thereby placental function. Therefore, we aimed to evaluate the performance of placental T2* in the prediction of low birth weight using the uterine artery (UtA) pulsatility index (PI) as gold standard. METHODS: This was a prospective observational study of 100 singleton pregnancies included at 20-40 weeks' gestation. Placental T2* was obtained using a gradient recalled multi-echo MRI sequence and UtA PI was measured using Doppler ultrasound. Placental pathological examination was performed in 57 of the pregnancies. Low birth weight was defined by a Z-score ≤ -2.0. RESULTS: The incidence of low birth weight was 15%. The median time interval between measurements and birth was 7.3 weeks (interquartile range 3.0, 13.7 weeks). Linear regression revealed significant associations between birth weight Z-score and both placental T2* Z-score (r = 0.68, p < 0.0001) and UtA PI Z-score (r = -0.43, p < 0.0001). Receiver operating characteristic curves demonstrated a significantly higher performance of T2* (AUC of 0.92; 95% CI, 0.85-0.98) than UtA PI (AUC of 0.74; 95% CI, 0.60-0.89) in the prediction of low birth weight (p = 0.010). Placental pathological findings were closely related to the T2* values. CONCLUSIONS: In this population, placental T2* was a strong predictor of low birth weight and it performed significantly better than the UtA PI. Thus, placental T2* is a promising marker of placental dysfunction which deserves further investigation.

Recurrence of second trimester miscarriage and extreme preterm delivery at 16-27 weeks of gestation with a focus on cervical insufficiency and prophylactic cerclage.

INTRODUCTION: The objective of this study was to describe recurrence rates of second trimester miscarriage and extreme preterm delivery by phenotype and use of prophylactic cerclage in a register-based cohort. MATERIAL AND METHODS: We included women with a first second trimester miscarriage or extreme preterm delivery (16+0 to 27+6 gestational weeks) in Denmark in 1997-2012 (n = 9602) by combined use of the Danish Medical Birth Register and the Danish National Patient Register. Eight phenotypes were identified by ICD-10 codes in a hierarchy with the following sequence: major fetal anomaly, multiple gestation, uterine anomaly, placental insufficiency, antepartum bleeding, cervical insufficiency, preterm premature rupture of membranes, and intrauterine fetal death. Recurrence rate after a second trimester miscarriage/spontaneous delivery in the period was calculated based on the register data. In cervical insufficiency outcome was stratified by prophylactic cerclage applied <16 weeks of gestation. RESULTS: Overall recurrence rate was 7.3% (n = 452), a rate that differed by phenotype from <5% (fetal anomaly, multiple gestations, intrauterine fetal death) to 21% (cervical insufficiency). In women with cervical insufficiency the recurrence rate was 28% without cerclage; vaginal cerclage was associated with a significant reduction [adjusted odds ratio (OR) 0.47; 95% CI 0.29-0.76] and abdominal cerclage with an even greater reduction (adjusted OR 0.14; 95% CI 0.03-0.61). CONCLUSIONS: The overall recurrence rate of second trimester miscarriage or extreme preterm delivery was 7%, but it differed significantly by phenotype. The highest rate, 28%, was found in cervical insufficiency, and prophylactic cerclage was associated with a significant reduction in recurrence.

Reproductive Endocrinology in Recurrent Pregnancy Loss.

Endocrine disruptions may be important in patients experiencing recurrent pregnancy loss (RPL). This review focuses on data available on RPL and the endocrine system to investigate relevant, and perhaps modifiable, endocrine factors of importance for the disorder. Evidence indicates that some hormones may be important as immune modulators and a better understanding of this interplay has potential for improving pregnancy outcome in RPL. To date there is a lack of consensus on the effect of endocrine treatment options in RPL and there is a strong need for large randomized-controlled trials.

Immunologic Abnormalities, Treatments, and Recurrent Pregnancy Loss: What Is Real and What Is Not?

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.

Reduced placental oxygenation during subclinical uterine contractions as assessed by BOLD MRI.

OBJECTIVES: During placental Blood Oxygen Level Dependent (BOLD) Magnetic Resonance Imaging (MRI), we have observed spontaneous reductions in placental oxygenation lasting 2-4 min. We hypothesize, that these reductions in placental oxygenation are caused by subclinical uterine contractions. METHODS: We evaluated placental oxygenation during a five-minute placental BOLD MRI in 56 normal pregnancies (gestational week 23-40) and observed a spontaneous reduction in eight cases. The 56 BOLD MRIs were systematically analyzed for signs of uterine contractions, i.e. visual changes in uterus shape and reductions in the number of pixels within Regions of interest (ROI) covering the outline of the entire uterus. RESULTS: The eight reductions in the BOLD signal lasted for 217 ± 51 (mean ± SD) seconds with an average signal loss of 17 ± 5%. They were all associated with a contraction, which started 43 ± 21 s prior to the start of the reduction and ended 71 ± 30 s prior to the end of the reduction. In the remaining 48 MRIs, we observed no contraction. CONCLUSION: We suggest that the observed spontaneous reductions in placental oxygenation are caused by uterine contractions. According to our data, subclinical uterine contractions occur regularly and have a markedly impact on placental oxygenation. Therefore, uterine contractions need to be considered in the interpretation of placental MRI as they may interfere with the MRI results.