Vascular Health of Females with History of Assisted Reproductive Technology.

The use of assisted reproductive technologies (ART) for the treatment of infertility is gaining popularity. Limited data on the overall vascular health of females with history of ART are available. This pilot study aimed to investigate the overall vascular health of females with history of ART compared to individuals who conceived spontaneously. The assessment of overall vascular health included the measurement of brachial blood pressure, central blood pressure, and pulse wave velocity, as well as the evaluation of the arterial stiffness and carotid intima-media thickness (cIMT) of the common carotid arteries. Conventional blood lipids including lipoprotein a (Lp(a)) were also determined. In total, 45 females with history of ART and 52 females who conceived spontaneously were included (mean age: 47.72 ± 5.96 years vs. 46.84 ± 7.43 years, p = 0.525). An initial comparison revealed a significantly higher prevalence of elevated Lp(a) in ART females (p = 0.011). However, after multiple comparison correction, the significant result disappeared (p = 0.132). Within the cohort of ART females, no significantly higher cardiovascular risk was detected regarding vascular function. The potentially higher prevalence of elevated Lp(a) in ART females must be further investigated in future studies, as it might contribute to the impaired reproductive process in this cohort.

Vascular function in a cohort of children, adolescents and young adults conceived through assisted reproductive technologies-results from the Munich heARTerY-study.

Background: Over 8 million individuals worldwide have been conceived through assisted reproductive technologies (ART). There is conflicting evidence on the cardiovascular health of ART offspring. This study aimed to investigate vascular function in a cohort of children, adolescents and young adults conceived through ART compared to spontaneously conceived peers. Methods: Anthropometric variables, diet quality, level of physical activity and sedentary behavior were assessed. An extensive evaluation of vascular function was conducted. Blood pressure as well as endothelial function were evaluated. Carotid intima-media thickness was recorded sonographically. Blood draws were taken to determine blood lipids as well as HbA1c. Results: In total, 66 ART subjects conceived through in vitro fertilization (IVF) or intracytoplasmic sperm injection and 86 spontaneously conceived peers were included in this observational cohort study. Both groups were similar in age [11.31 (8.10-18.00) vs. 11.85 (8.72-18.27) years, P=0.373]. ART subjects displayed a significantly higher body fat percentage [19.30% (15.80-26.02%) vs. 15.91% (13.21-21.00%), P=0.007]. Both groups did not differ significantly in diet quality, physical activity, sedentary behavior, and vascular function. Blood lipids and HbA1c were comparable between both groups. ART subjects showed significantly lower levels of triglycerides compared to spontaneously conceived peers. The prevalence of lipoprotein (a) [Lp(a)] ≥50 mg/dL tended to be higher within the ART cohort. Vascular function did not deteriorate more profoundly with age in ART subjects than in spontaneously conceived peers. Conclusions: The results of the current study do not indicate a significantly lower vascular function in a cohort of children, adolescents and young adults conceived through ART compared to spontaneously conceived peers. Future studies should address the prevalence of elevated Lp(a) levels in infertile individuals who sought ART treatment. In addition, more studies evaluating body fat percentage as well as cardiovascular morbidity in adult ART subjects are required. For a more precise cardiovascular risk stratification, multi-center studies with larger ART sample sizes, preferably at adult age, are required in the future.

Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/050, May 2022).

Purpose The aim of this guideline is to standardize the diagnosis and therapy of recurrent miscarriage (RM) using evidence from the recent literature. This is done by using consistent definitions, objective evaluations and standardized treatment protocols. Methods When this guideline was compiled, special consideration was given to previous recommendations in prior versions of this guideline and the recommendations of the European Society of Human Reproduction and Embryology, the Royal College of Obstetricians and Gynecologists, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine, and a detailed individual search of the literature about the different topics was carried out. Recommendations Recommendations about the diagnostic and therapeutic procedures offered to couples with RM were developed based on the international literature. Special attention was paid to known risk factors such as chromosomal, anatomical, endocrinological, physiological coagulation, psychological, infectious and immune disorders. Recommendations were also developed for those cases where investigations are unable to find any abnormality (idiopathic RM).

Left ventricular systolic function in subjects conceived through assisted reproductive technologies.

Background: Over the past decades, assisted reproductive technologies (ART) have gained remarkable influence in the treatment of infertility and account for more than 2 % of births in European countries nowadays. Accumulating evidence suggests ART to cause cardiovascular alterations, including left ventricular (LV) dysfunctions, within its offspring. The aim of this study was to assess LV systolic function in subjects conceived through ART in comparison to spontaneously conceived peers. Methods: For the assessment of LV morphology and LV function, M-Mode echocardiography, pulsed wave Doppler and two-dimensional speckle tracking echocardiography (2DSTE) were applied. LV ejection fraction (EF) and fractional shortening (FS) were assessed in M-Mode and calculated by Teichholz formula. EF was additionally assessed semiautomatically through 2DSTE. Results: In total, 64 ART subjects and 83 spontaneously conceived controls with no significant differences in age (12.52 ± 5.64 years vs. 13.20 ± 5.95 years, p = 0.486) and sex were included in the analysis. In the ART cohort, significantly lower values were observed for M-Mode assessed EF (63.63 ± 5.17 % vs. 65.35 ± 5.10 %, p = 0.046) and FS (34.26 ± 3.87 % vs. 35.60 ± 3.84 %, p = 0.038). However, after the adjustment for birth weight percentile and gestational age, M-Mode assessed EF and FS displayed no significant differences between both groups. LV morphology and remaining systolic function parameters, such as mitral annular plane systolic excursion, aortic velocity time integral, global peak longitudinal strain and 2DSTE measured EF, were comparable between both groups. Conclusion: This study suggests a lower LV systolic function in ART subjects, visualized by significantly lower values for M-Mode assessed EF and FS, compared to spontaneously conceived peers. The clinical relevance of these findings has to be investigated as the above-mentioned parameters were in normal reference range. In addition, LV systolic function parameters evaluated by other echocardiographic imaging modalities were comparable between both groups. Therefore, further studies will be required to evaluate the influence of ART on LV systolic function and cardiovascular morbidity in the future.

Left Ventricular Diastolic Function in Subjects Conceived through Assisted Reproductive Technologies.

Subjects conceived through assisted reproductive technologies (ART) potentially suffer from impaired left ventricular (LV) function due to premature vascular aging. This study aimed to evaluate whether subtle differences in LV diastolic function can be observed echocardiographically between young ART subjects and their spontaneously conceived peers. The echocardiographic assessment included the measurement of LV dimensions, mitral inflow velocities, and myocardial velocity at early diastole (E', cm/s) at the LV wall and the interventricular septum (IVS). An average from E/E'LV and E/E'IVS (E/E'AVG) was derived. In total, 66 ART subjects and 83 controls (12.85 ± 5.80 years vs. 13.25 ± 5.89 years, p = 0.677) were included. The ART subjects demonstrated a significantly lower E'LV (19.29 ± 3.29 cm/s vs. 20.67 ± 3.78 cm/s, p = 0.020) compared to their spontaneously conceived peers. Study participants of ≥ 10 years of age displayed a significantly higher E/E'AVG (6.50 ± 0.97 vs. 6.05 ± 0.99, p = 0.035) within the ART cohort. The results of this study demonstrate a significantly lower LV diastolic function in the ART subjects. However, no significant changes in LV diastolic function were observed between the two groups when the results were adjusted for age, birth weight percentile, and gestational age. Those ART subjects born preterm might have an elevated risk of developing LV diastolic alterations and could therefore profit from close echocardiographic monitoring.

Subjects Conceived through Assisted Reproductive Technologies Display Normal Arterial Stiffness.

Multiple studies reported signs of vascular dysfunction in subjects conceived through assisted reproductive technologies (ART). The assessment of arterial stiffness in this cohort seems beneficial for risk stratification. Regional arterial stiffness of the abdominal aorta (AAO) and the common carotid arteries (CCA) was evaluated sonographically using two-dimensional speckle tracking in subjects conceived through ART and spontaneously conceived peers. Global arterial stiffness was assessed utilizing an oscillometric blood pressure device. The cohorts of 67 ART subjects and 86 spontaneously conceived peers (11.31 (8.10-18.20) years vs. 11.85 (8.72-18.27) years, p = 0.43) did not differ significantly in parameters of regional and global arterial stiffness. In the sub-analysis of study participants ≥10 years of age, markers of arterial stiffness did not display significant differences between both groups. However, a higher tendency of brachial systolic blood pressure was demonstrated in the ART cohort compared to the control group (120.18 ± 9.57 mmHg vs. 116.55 ± 8.05 mmHg, p = 0.050). The present study displayed no significant differences in arterial stiffness between ART subjects and spontaneously conceived peers. Moreover, this study suggests that arterial stiffness does not elevate more profoundly in ART subjects with increasing age. Further studies are required for a more detailed cardiovascular risk stratification of the ART cohort.

Vascular Health in Adults Born After Using Assisted Reproductive Technologies.

An increasing number of children are conceived by assisted reproductive technologies (ART). Several studies indicated vascular alterations in ART children. However, limited data is available within the adult ART population. Therefore, this study investigated the overall vascular health of young ART adults in comparison to spontaneously conceived peers. In total, 16 ART subjects and 22 spontaneously conceived peers (22.06 ± 2.21 years vs. 22.00 ± 2.14 years, p = 0.194) were enrolled for the assessment of endothelial function, brachial blood pressure, central blood pressure, pulse wave velocity, carotid intima-media thickness, and blood lipids. No significant differences in vascular function were detected between the in vitro fertilization subgroup (n = 9), the intracytoplasmic sperm injection subgroup (n = 7) and spontaneously conceived peers. This pilot study suggests an unimpaired vascular function in young ART adults. In the future, multi-centric studies with a greater sample size are required to confirm the results of the current study and enable precise cardiovascular risk stratification of the adult ART population.

Seasonal dynamic of cholecalciferol (D3) and anti-Muellerian hormone (AMH) with impact on ovarian response and IVF/ICSI.

OBJECTIVE: Recent studies revealed intriguing associations between cholecalciferol (D3) and reproductive functions. Seasonal changes of D3 concentrations are well known; however, they are not always considered in the context of reproductive functions. In this study, we analyzed D3 serum concentration in IVF/ICSI patients with respect to seasonal 3-month quartiles and anti-Muellerian hormone (AMH) referring to the impact on Assisted Reproductive Technologies (ART) outcome. MATERIALS AND RESEARCH METHODS: We studied 469 female patients, presenting between 2012 and 2018 for ART treatment in our fertility center. D3 as well as the AMH serum concentrations were measured at the beginning of the follicle stimulation (days 3-5 of menstrual cycles). Results were evaluated with respect to seasonal quartiles and outcome of the ART cycles. RESULTS: D3 concentrations showed significant fluctuations within annual quartiles with a pronounced peak in August-October and a minimum in February-April (26.0 vs. 20.5 mg/dl; p < 0.0001). Similar seasonal dynamics were found for AMH (2.98 vs. 1.78 ng/ml; p = 0.010) and these were associated with significantly shorter stimulation periods during August-October (11.29 vs. 12.12 days; p = 0.042), higher number of fertilized oocytes between August and October (6.23 vs. 4.97; p = 0.05) along with a trend towards higher numbers of cumulus-oocyte complexes. However, no such differences were found for the numbers of MII oocytes or pregnancy rates. CONCLUSION: Our data indicate seasonal 3-month quartile variations of AMH concentrations and characteristics of ART, such as days of ovarian stimulation and number of fertilized oocytes. Highest AMH concentrations were found between August and October and this quartile was associated with highest D3 concentrations.

Epigenetic changes occur in placentas of spontaneous and recurrent miscarriages.

BACKGROUND: In contrast to genetic abnormalities which are well known to be responsible for around 50 % of human miscarriages, there is very few data about epigenetic alterations in spontaneous and recurrent miscarriages (SM, RM). The aim of this study was to analyze the histone modification marks H3K9ac and H3K4me3 in SM and RM. METHODS: The abundance of histone modifications H3K4me3/H3K9ac was analyzed by western blot in frozen abortion material of SM and RM compared to a control group of legal pregnancy terminations. Further, to characterize placental tissue cells expressing H3K4me3/H3K9ac immunohistochemistry (IHC) and immunofluorescence was performed in 20 SM, 19 RM and 26 controls. RESULTS: The western blot data showed a tendency to an overall reduction of H3K4me3/H3K9ac, in the placental tissue of particularly SM. Further we differentiated between syncytiotrophoblast, cytotrophoblast and decidual cells and found a significant decrease of H3K4me3 in SM in cytotrophoblast cells and syncytial stroma. In RM H3K4me3 was downregulated exclusively in the syncytiotrophoblast. H3K9ac was reduced in SM and RM in all evaluated compartments, except from the syncytiotrophoblast. CONCLUSION: Our study showed an overall reduced histone modification of H3K4me3 and H3K9ac in the placental tissue of SM. Concerning RM, particularly the reduction of H3K9ac was detected in the placental tissue, indicating that RM group has distinct profile in epigenetic regulation. Whether these histone modifications are part of a possible pathophysiologic cascade during SM and RM or are merely indicating a defective placentation, cannot be concluded from this study.

Effects of intralipid infusions on anti-trophoblast antibody (ATAb)-activities in patients with recurrent pregnancy loss: An observational report.

PROBLEM: Some studies suggest intravenous intralipid infusions (IVIL) to be effective in the treatment of immune-mediated pregnancy failure. To this date it remains to be established, how IVIL might protect pregnancy and therefore a specific subgroup of RPL patients that might benefit from IVIL has not been defined. Anti-trophoblast antibodies (ATAb) have been associated with RPL and appear to mediate immune pathology. We have shown, that ATAb in vitro decrease HCG- and progesterone production pointing to a mechanism how ATAb interfere with normal pregnancies. We have measured ATAb-activities in patients undergoing off label IVIL-treatment. METHOD OF STUDY: Ten RPL-patients with positive ATAb, determined by using the choriocarcinoma cellline JEG-3 and flow cytometry as described before, and otherwise unexplained RPL, received off-label IVIL during pregnancy. Two ATAb-positive RPL patients preferred expectant management. In addition, ATAb-activity was studied in pregnancies of two healthy ATAb-negative volunteers without miscarriages. RESULTS: In RPL patients receiving IVIL, relative ATAb-activity decreased from an average of 56.8±17.0% to 20.8±11.0% (P < .001). The two RPL-patients without IVIL, aborted at 6+3gw and 7+4gw and embryonic genetic testing revealed euploid karyotypes. During pregnancies of the two healthy ATAb-negative individuals, ATAb-activities remained negative (16±9.8%) without significant changes (P = .22). Nine of the 10 pregnancies receiving IVIL proceeded uneventful with healthy newborns ≥37gw. One patient receiving IVIL aborted at 7+6gw and embryonic genetic-testing revealed a trisomy 16. No specific side effects concerning IVIL were noted. CONCLUSIONS: Intralipid preparations during pregnancies of ATAb-positive RPL-patients significantly reduce ATAb-activities and this may indicate a therapeutic mechanism of IVIL.

Maternal and paternal carriage of the annexin A5 M2 haplotype: a possible risk factor for recurrent implantation failure (RIF).

OBJECTIVE: This study was carried out to determine the potential role of the M2/ANXA5 haplotype as a risk factor for recurrent implantation failure (RIF). Carriage of the M2/ANXA5 haplotype that induces prothrombotic changes has been implicated in failure of early pregnancies and placenta-mediated complications (preeclampsia, IUGR, preterm birth). MATERIAL AND METHODS: In the present case control study, 63 couples (females and males) with RIF presenting for IVF/ICSI to the Fertility Center of [masked] were analyzed. RIF was defined as ≥ 4 consecutive failed ART-transfers of ≥ 4 blastocysts or ≥ 8 cleavage-stage embryos of optimal quality and maternal age ≤ 41. Fertile female controls (n = 90) were recruited from the same center. Population controls (n = 533) were drafted from the PopGen biobank, UKSH Kiel. RESULTS: Couples carrying the M2/ANXA5 haplotype turned out to have a significantly increased relative risk (RR) for RIF. Compared with female fertile controls, RR was 1.81 with p = 0.037 (OR 2.1, 95%CI 1.0-4.3) and RR was 1.70, with p = 0.004 (OR 2.0, 95%CI 1.2-3.1) compared with population controls (15.4% M2 carriers). Male partners were comparable with RIF females for M2/ANXA5 haplotypes (28.6% vs. 23.8%, p = 0.54). RIF females compared with population controls had a RR of 1.55 (p = 0.09) and RIF males compared with population controls had a RR of 1.9 (p = 0.01). Couples with ≥ 7 failed transfers showed a RR of 1.82 (p = 0.02) compared with population controls. CONCLUSION: Our findings suggest that maternal as well as paternal M2/ANXA5 haplotype carriages are risk factors for RIF. These results allow new insights into the pathogenesis of RIF and might help to identify relevant risk groups.

The Prevalence and Impact of Polycystic Ovary Syndrome in Recurrent Miscarriage: A Retrospective Cohort Study and Meta-Analysis.

Background: The use of different definitions and diagnostic approaches of polycystic ovary syndrome (PCOS) and recurrent miscarriage (RM) has led to a wide range of prevalence rates in the literature. Despite the persistent controversy about the factual prevalence of PCOS in RM, a vast number of studies have revealed evidence about their association with each other. The goals of this study were to evaluate the prevalence of polycystic ovarian morphology and PCOS within the RM population, performing meta-analyses with the obtained data from this study, together with previous reports on this topic and evaluating reproductive outcome in women with RM and PCOS. Methods: A retrospective cohort study with 452 women with RM and a meta-analysis were conducted. The main outcome parameter was the prevalence of PCOS in RM patients. Results: In the retrospective study, the prevalence of PCOS in RM was 9.5%. Negative results for the selected risk factors for RM were present in 283 patients (62.6%). From all evaluated possible underlying causes for RM, only the presence of thrombophilic disorders was significantly associated with PCOS (PCOS: 20.9% versus no PCOS: 7.8%, p = 0.010). In the meta-analysis of three studies on PCOS in RM patients, which used the revised Rotterdam criteria for defining PCOS, an estimated pooled prevalence of 14.3% (95% CI: 6.2-24.9) was found. In the retrospective data set, women in the PCOS group revealed significantly higher luteinizing hormone (LH), testosterone, and Anti-Mullerian hormone (AMH) levels than age- and body mass index (BMI)-matched controls with RM negative for the selected risk facotrs (p < 0.05). The rate of further miscarriages was significantly higher in PCOS women than in controls (71.4% versus 53.6%, respectively; p = 0.031). Conclusions: The prevalence of PCOS seems slightly increased in women with RM. Women with PCOS suffering from RM showed a significantly higher risk for further miscarriage and decreased chances of having a life birth of about 18% which did not reach statistical significance. Therefore, we assume that PCOS plays a moderate role in RM.

Diagnosis and Therapy Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019) - Part 1, Basic Assessment of the Woman.

Introduction Supporting and counselling couples with fertility issues prior to starting ART is a multidisciplinary diagnostic and therapeutic challenge. The first German/Austrian/Swiss interdisciplinary S2k guideline on "Diagnosis and Therapy Before Assisted Reproductive Treatments (ART)" was published in February 2019. This guideline was developed in the context of the guidelines program of the German Society of Gynecology and Obstetrics (DGGG) in cooperation with the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Aims One third of the causes of involuntary childlessness are still unclear, even if the woman or man have numerous possible risk factors. Because the topic is still very much taboo, couples may be socially isolated and often only present quite late to a fertility center. At present, there is no standard treatment concept, as currently no standard multidisciplinary procedures exist for the diagnostic workup and treatment of infertility. The aim of this guideline is to provide physicians with evidence-based recommendations for counselling, diagnostic workup and treatment. Methods This S2k guideline was developed on behalf of the Guidelines Commission of the DGGG by representative members from different professional medical organizations and societies using a structured consensus process. Recommendations The first part of this guideline focuses on the basic assessment of affected women, including standard anatomical and endocrinological diagnostic procedures and examinations into any potential infections. Other areas addressed in this guideline are the immunological workup with an evaluation of the patient's vaccination status, an evaluation of psychological factors, and the collection of data relating to other relevant factors affecting infertility. The second part will focus on explanations of diagnostic procedures compiled in collaboration with specialists from other medical specialties such as andrologists, human geneticists and oncologists.

Diagnosis and Treatment Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019) - Part 2, Hemostaseology, Andrology, Genetics and History of Malignant Disease.

Introduction Supporting and counselling couples with fertility issues prior to starting ART is a multidisciplinary diagnostic and therapeutic challenge. The first German-language interdisciplinary S2k guideline on "Diagnosis and Therapy Before Assisted Reproductive Treatments (ART)" was published in February 2019. The guideline was developed in the context of the guidelines program of the German Society of Gynecology and Obstetrics (DGGG) in cooperation with the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Aim In one third of cases, the cause of involuntary childlessness remains unclear, even if the woman or man have numerous possible risk factors. Because the topic is still very much taboo, couples may be socially isolated and often only present quite late to a fertility center. There is no standard treatment concept for these patients at present, as there are currently no standard multidisciplinary procedures for the diagnostic workup and treatment of infertility. The aim of this guideline is to provide physicians with evidence-based recommendations for counselling, diagnosis and treatment. Methods This S2k guideline was developed on behalf of the Guidelines Commission of the DGGG by representative members from different professional medical organizations and societies using a structured consensus process. Recommendations This second part of the guideline describes the hematological workup for women as well as additional diagnostic procedures which can be used to investigate couples and which are carried out in cooperation with physicians working in other medical fields such as andrologists, geneticists and oncologists.

Anti α-enolase antibody is a novel autoimmune biomarker for unexplained recurrent miscarriages.

BACKGROUND: We recently demonstrated the increased abundance of anti-trophoblast antibodies (ATAB) in sera of patients with unexplained recurrent miscarriages (uRM). Further, the ATAB-positive sera bound to JEG-3 human choriocarcinoma cells in vitro, resulting in decreased productions of ß-human chorionic gonadotropin (ß-hCG) and progesterone in these cells. However, the specific antigenic epitopes of ATAB have remained unknown. Therefore, it was the aim of this study to determine specific targets of ATAB in uRM patients. METHODS: Potential targets of ATAB were analyzed by 2-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry, and thereby identifying α-Enolase (ENO1). ATAB targeting of ENO1 was further confirmed in a competitive binding assay. Levels of anti-ENO1 antibodies as well as ß-hCG and progesterone were quantified with enzyme-linked immunosorbent assay (ELISA). Additionally, expression of ENO1 was analyzed in first trimester placentas by immunohistochemistry and immunofluorescence analysis. FINDINGS: We here identified ENO1 as a prominent target of ATAB. Serum levels of anti-ENO1 antibodies were increased in ATAB-positive compared to ATAB-negative patients. Further, increased expression of ENO1 and its co-expression with ß-arrestin was found in the extra villous trophoblasts of uRM patients in first trimester placentas. In vitro, anti-ENO1 antibodies decreased the secretion of ß-hCG and progesterone in JEG-3 and primary human villous trophoblast cells. INTERPRETATION: Serum anti-ENO1 antibodies might be an autoimmune biomarker for uRM. Targeting the formation of anti-ENO1 antibodies or inhibition of ENO1 expression could potentially represent therapeutic strategies for these patients. FUND: All authors declare no conflict of interest. Yao Ye was supported by the China Scholarship Council. Hellen Ishikawa-Ankerhold and Christian Schulz were supported by the SFB914, projects Z01 and A10. None of the rest authors has any conflict of interest to declare.

Correlation of Vitamin D3 (Calcitriol) Serum Concentrations with Vitamin B12 and Folic Acid in Women Undergoing in vitro Fertilisation/Intracytoplasmatic Sperm Injection.

BACKGROUND: The important role of vitamin D3 in human health is well recognized. In this study, we measured serum concentrations of vitamin D3, vitamin B12 and B9 (folic acid) in 410 women undergoing in vitro fertilisation (IVF)/intracytoplasmatic sperm injection (ICSI) with dedicated focus on 3-month changes in consideration of patients' BMI. METHODS: Patients were of European origin and did not take any supplementation of D3. In preparing for pregnancy, patients took ≥4 weeks 400 µg folic acid combined with 9 µg vitamin B12 and 150 µg iodide as recommended. RESULTS: We found a significant 3-month quartile change of D3 serum concentrations (p < 0.0001) with maximum levels in autumn and lowest in spring. D3 correlated significantly with B12 (p = 0.035, ρ = 0.102) and folic acid (p < 0.0001, ρ = 0.191). BMIs however showed a negative correlation with B12 (p = 0.031, ρ = -0.105) and folic acid (p = 0.012, ρ = -0.125). CONCLUSIONS: Our results suggest a model in which the sun exposure during summer months enables storage of D3 followed by a slow release as a major factor to maintain D3 levels throughout the year. Finally, our data indicate that B12 and folic acid uptake might be influenced by vitamin D receptor and D3, where D3 and the BMI appear to have an indirect relationship - via B12 and folic acid.

Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050).

PURPOSE: Official guideline of the German Society of Gynecology and Obstetrics (DGGG), the Austrian Society of Gynecology and Obstetrics (ÖGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG). The aim of this guideline was to standardize the diagnosis and treatment of couples with recurrent miscarriage (RM). Recommendations were based on the current literature and the views of the involved committee members. METHODS: Based on the current literature, the committee members developed the statements and recommendations of this guideline in a formalized process which included DELPHI rounds and a formal consensus meeting. RECOMMENDATIONS: Recommendations for the diagnosis and treatment of patients with RM were compiled based on the international literature. Specific established risk factors such as chromosomal, anatomical, endocrine, hemostatic, psychological, infectious and immunological disorders were taken into consideration.

Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta-mediated pregnancy complications.

PURPOSE: The aim of this study was to confirm the associated M2/ANXA5 carrier risk in women with placenta-mediated pregnancy complications (PMPC) and to test their male partners for such association. Further analysis evaluated the influence of maternal vs. paternal M2 alleles on miscarriage. METHODS: Two hundred eighty-eight couples with preeclampsia (PE), intrauterine growth restriction (IUGR), or premature birth (PB) were recruited (n = 96 of each phenotype). The prevalence of the M2 haplotype was compared to two control cohorts. They included a group of women with a history of normal pregnancy without gestational pathology (Munich controls, n = 94) and a random population sample (PopGen controls, n = 533). RESULTS: Significant association of M2 haplotype and pregnancy complications was confirmed for women and for couples, where prevalence was elevated from 15.4 to 23.8% (p < 0.001). Post hoc analyses demonstrated an association for IUGR and PB individually. A strong link between previous miscarriages and M2 carrier status was identified which may explain the predisposition to placental pregnancy complication. M2/ANXA5 appears to be a risk factor for adverse pregnancy outcomes related, but not limited to miscarriages, with similar prevalence in women and their male partners. CONCLUSION: These findings support the proposed physiological function of ANXA5 as an embryonic anticoagulant that appears deficient in contiguous specter of thrombophilia-related pregnancy complications culminating more frequently in miscarriage in a maternal M2 carrier background.