Astrid Marie Kolte

New insights into mechanisms behind miscarriage.

Sporadic miscarriage is the most common complication of early pregnancy. Two or three consecutive pregnancy losses is a less common phenomenon, and this is considered a distinct disease entity. Sporadic miscarriages are considered to primarily represent failure of abnormal embryos to progress to viability. Recurrent miscarriage is thought to have multiple etiologies, including parental chromosomal anomalies, maternal thrombophilic disorders, immune dysfunction and various endocrine disturbances. However, none of these conditions is specific to recurrent miscarriage or always associated with repeated early pregnancy loss. In recent years, new theories about the mechanisms behind sporadic and recurrent miscarriage have emerged. Epidemiological and genetic studies suggest a multifactorial background where immunological dysregulation in pregnancy may play a role, as well as lifestyle factors and changes in sperm DNA integrity. Recent experimental evidence has led to the concept that the decidualized endometrium acts as biosensor of embryo quality, which if disrupted, may lead to implantation of embryos destined to miscarry. These new insights into the mechanisms behind miscarriage offer the prospect of novel effective interventions that may prevent this distressing condition.

IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes

Recent genome-wide association (GWA) studies of type 2 diabetes (T2D) have implicated IGF2 mRNA-binding protein 2 (IMP2/IGF2BP2) as one of the several factors in the etiology of late onset diabetes. IMP2 belongs to a family of oncofetal mRNA-binding proteins implicated in RNA localization, stability, and translation that are essential for normal embryonic growth and development. This review provides a background to the IMP protein family with an emphasis on human IMP2, followed by a closer look at the GWA studies to evaluate the significance, if any, of the proposed correlation between IMP2 and T2D.

Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group

Pregnancy loss prior to viability is common and research in the field is extensive. Unfortunately, terminology in the literature is inconsistent. The lack of consensus regarding nomenclature and classification of pregnancy loss prior to viability makes it difficult to compare study results from different centres. In our opinion, terminology and definitions should be based on clinical findings, and when possible, transvaginal ultrasound. With this Early Pregnancy Consensus Statement, it is our goal to provide clear and consistent terminology for pregnancy loss prior to viability.

Future directions of failed implantation and recurrent miscarriage research

Recurrent implantation failure is today the major reason for women completing several IVF/intracytoplasmic sperm injection attempts without having achieved a child, and is probably also the explanation for many cases of unexplained infertility. Most causes of recurrent miscarriage are still poorly elucidated, but from a theoretical point of view recurrent implantation failure and recurrent miscarriage are suggested to have partly overlapping causes. Recent research has indeed documented that both syndromes can be caused by the same embryonic chromosomal abnormalities and the same maternal endocrine, thrombophilic and immunological disturbances. Consequently, many treatments attempting to normalize these abnormalities have been tested or are currently used in women with both recurrent implantation failure and recurrent miscarriage. However, no treatment for the two syndromes is at the moment sufficiently documented to justify its routine use. In this review, an overview is given regarding present knowledge about causes that may be common for recurrent implantation failure and recurrent miscarriage, and suggestions are put forward for future research that may significantly improve understanding and treatment options for the syndromes.

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.

A firstborn boy is suggestive of a strong prognostic factor in secondary recurrent miscarriage: a confirmatory study

OBJECTIVE To test our previously generated hypothesis that women with secondary recurrent miscarriages with a firstborn boy have a poorer pregnancy prognosis than those with a firstborn girl. DESIGN A study of a retrospective and a prospective cohort. SETTING The Danish recurrent miscarriage clinic. PATIENT(S) Two cohorts of 175 and 130 consecutive patients with unexplained secondary recurrent miscarriage referred from 1986 to 1999 (cohort 1) and 2000 to 2005 (cohort 2), respectively. MAIN OUTCOME MEASURE(S) The odds ratio (OR) for a live birth in the first pregnancy after referral in those with a firstborn boy compared with a firstborn girl in each of the two cohorts. The corresponding OR for a live birth adjusted for relevant prognostic variables in the combined group of patients. RESULT(S) The crude ORs for a live birth in those with a firstborn boy compared with a firstborn girl were very similar in cohorts 1 and 2 (OR = 0.35, 0.33). In the adjusted analysis only two of five included variables significantly predicted live birth: a firstborn boy and the number of previous miscarriages. CONCLUSION(S) Male sex of the firstborn child is a strong negative prognostic factor in women with secondary recurrent miscarriage. A possible explanation is an abnormal maternal immune response against male-specific minor histocompatibility (HY) antigens.

Immunomodulatory treatment with intravenous immunoglobulin and prednisone in patients with recurrent miscarriage and implantation failure after in vitro fertilization/intracytoplasmic sperm injection

OBJECTIVE To assess outcome in terms of live-birth rate after fresh or frozen IVF/intracytoplasmic sperm injection assisted reproductive technology (ART) cycles where immunomodulation was given to patients with recurrent pregnancy loss after prior ART treatments. DESIGN Retrospective cohort study. SETTING Tertiary care university hospital. PATIENT(S) Fifty-two patients with a history of at least three consecutive pregnancy losses after ART who underwent at least one further ART cycle with concurrent immunomodulation in 2003-2012. INTERVENTION(S) Immunomodulation with IV immunoglobulin and prednisone starting from before ET and continuing in the first trimester if pregnancy was established. MAIN OUTCOME MEASURE(S) Live-birth rate per ET and cumulative live-birth rate after up to five ETs. RESULT(S) Nineteen patients (36.5%) achieved a live birth after the first ET with immunomodulation, and a total of 32 patients achieved a live birth in the study period, resulting in a cumulative live-birth rate of 61.5%. There was no significant difference in baseline and immunological parameters between the patients achieving a live birth or not. The live-birth rate after the first immunomodulated ART cycle in our patients is higher than that reported in a previous study. CONCLUSION(S) Immunomodulation with a combination of IV immunoglobulin and prednisone is a promising treatment for recurrent pregnancy loss after ART, but randomized placebo-controlled trials are needed.

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.

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.

Maternal HY-restricting HLA class II alleles are associated with poor long-term outcome in recurrent pregnancy loss after a boy

Women with secondary recurrent pregnancy loss (RPL) after a boy have a reduced chance of live birth in the first pregnancy after referral if they carry HY‐restricting HLA class II alleles, but long‐term chance of live birth is unknown.