Recurrent Molar Pregnancies Research Articles

From Challenges to Discovery: A Case Report on Recurrent Molar Pregnancy in a 30-Year-Old Woman with Multiple Pregnancy Losses

This case report presents the unique case of a 30-year-old woman with a recurrent molar pregnancy, a condition characterized by abnormal growth of placental trophoblasts. The patient, with a gravidity of 3 and parity of 0+2, experienced difficulties in conceiving a viable fetus despite ovulation induction drug treatment. Molar pregnancy is rare, and cases with recurrent miscarriages are even more uncommon. Common symptoms of molar pregnancy include vaginal bleeding, abdominal pain, and pelvic pressure during the first trimester. Diagnosis typically involves assessing HCG serum levels, performing an ultrasound of the uterus, and conducting a biopsy of the aborted specimen. Miscarriage is a common outcome, and in cases of diagnosis, dilation, and curettage are often performed. This report highlights the rarity of recurrent molar pregnancy and emphasizes its potential occurrence.

From Challenges to Discovery: A Case Report on Recurrent Molar Pregnancy in A 31-Year-Old Woman with Multiple Pregnancy Losses

From Challenges to Discovery: A Case Report on Recurrent Molar Pregnancy in A 31-Year-Old Woman with Multiple Pregnancy Losses

COVID-19-related multiple inflammatory syndrome-C and pulmonary embolism in Aicardi-Goutries syndrome.

COVID-19-related multiple inflammatory syndrome-C and pulmonary embolism in Aicardi-Goutries syndrome.

High Risk of Gestational Trophoblastic Neoplasia Development in Recurrent Hydatidiform Moles with NLRP7 Pathogenic Variations.

Pathogenic variations of the NLRP7 and KHDC3L genes are responsible for familial recurrent hydatidiform moles, a rare autosomal recessive phenomenon that can lead to severe comorbidities. Little is known about the diversity of genetic defects or the natural course of disease progression among recurrent hydatidiform mole cases from distinct ethnicities. In this study, we aimed to investigate the mutation profile and pregnancy outcomes in patients with multiple molar pregnancies. Three unrelated cases with recurrent molar pregnancies are included in this study. None of the patients had a known family history of molar pregnancy. Clinical findings and follow-up results are documented. Sanger sequencing is used to reveal genetic defects in exons and exon-intron boundaries of NLRP7 and KHDC3L genes. NLRP7 pathogenic variants were found in all three cases. In two cases, homozygous, c.2471+1G>A canonical splice cite variant was identified and in one case a homozygous, c.2571dupC (p.Ile858HisfsTer11) frameshift variant was identified. No variant in the KHDC3L gene was found in any case. In all cases, the development of gestational trophoblastic neoplasia complicated the clinical course and the treatment plans. We found that defects of the NLRP7 gene are principally responsible for etiology in our region, and the mutation profile suggests a founder effect in the Turkish population. We suggest early genetic diagnosis and counseling in molar pregnancies and recommend close follow-up in terms of conversion to gestational trophoblastic neoplasia.

Understanding of already known fact: Evaluating frequency and determinants of Hydatidiform Molar Pregnancy

Introduction: Sporadic presentation of hydatidiform has been reported previously as 1 in 1000 pregnancies. In rare cases asymptomatic molar pregnancies can cause problems if not identified in early radiological investigations. The aim of this study is to evaluate the frequency of hydatidiform (molar pregnancy) presenting with associated symptoms, analysis of determinants and management in Sindh, Pakistan. Methodology: This is a cross sectional study, patients were divided into categories according to maternal age, gravida while Beta HCG values were reported along with radiological investigation reporting to confirm hydatidiform molar pregnancy. Statistical package of social science version 21 was used to analyze the data. Results: Total 51 patients were identified with hydatidiform molar pregnancy during study period of 12 months from more than 1000 full term reported pregnancies, indicating 5.1% prevalence of disorder. The diagnosis has been confirmed only 1 (1.9%) case of partial molar pregnancy while 50 (99.1%) were complete molar pregnancy cases, managed by suction evacuation method, risks factors of hydatidiform molar pregnancy with advanced maternal age, recurrent molar pregnancy and positive family history the odds ratio has indicated positive association between first two determinants with OR of 1.71 and 1.21 respectively. Conclusion: Overall recorded frequency of hydatidiform in our institute is 5.1% within 1 year. Advanced maternal age and previous history of molar pregnancies are risk factors of hydatidiform.

Genetic Screening of Susceptible Women to Recurrent Molar Pregnancy for Prevention of Gestational Choriocarcinomas

Hydatidiform mole is an abnormal pregnancy characterized by hyper-proliferation of trophoblastic cells (both cytotrophoblast and syncytiotrophoblast). If the proliferation phenomenon not well controlled, e.g. due to poor medical health care system, mole can become invasive and lead to gestational choriocarcinomas. Gestational choriocarcinoma by strong metastatic potentiality, as one of the most aggressive, malignant form of gestational trophoblastic disease, could be spread through directly vascular and the middle layer of the uterine wall (Myometrium‎) and would involve distant sites such as the lungs, spleen, intestines, kidney, and liver. When a hydatidiform mole occurs once, it is known as sporadic hydatidiform mole; if it happens again, the condition is known as recurrent hydatidiform mole. In recurrent form, the gestational choriocarcinoma occurrence risk increased up to a 100-fold. Therefore, early onset identify of susceptible women to recurrent molar pregnancy is clinical importance because of the increased risk of developing neoplasia. Due to the role of maternal homozygous and compound heterozygous recessive gene, mutations have been reported in hydatidiform mole occurrence, women screening can be improved by molecular genotyping methods.

NLRP7 interacts with EBP1 providing evidence for its role in molar pregnancies and development.

Abstract Recurrent hydatidiform molar pregnancies are characterized by uncontrolled proliferation of trophoblasts resulting in the failure of the embryo and placenta to develop properly. Previous studies genetically mapped a mutation in NLRP7 as a cause for recurrent molar pregnancies with abnormal methylation patterns. The goal of this study is to identify human proteins that interact with NLRP7, especially those that are involved in DNA acetylation and methylation, which could lead to the development of molar pregnancies. A yeast two-hybrid system using a human cDNA library was used to screen for interacting proteins and protein interactions were verified by co-immunoprecipitation in HEK 239T cells. Additional experiments are being performed to determine the change in global methylation when NLRP7 and EBP1 interact. Yeast screening results indicated several proteins that interact with NLRP7, however further testing will be focused on the interaction with EBP1, a human protein involved in growth regulation. Having potentially identified a protein involved in development through acetylation/deacetylation that interacts with NLRP7, we hope to shed more light on the molecular pathways that lead to the formation of recurrent molar pregnancies.

A Case Report of Pregnancy Outcome Following Four Consecutive Complete Molar Pregnancies: Review of Genetic Basis of Recurrent Molar Pregnancies and Pillars of Management

A Case Report of Pregnancy Outcome Following Four Consecutive Complete Molar Pregnancies: Review of Genetic Basis of Recurrent Molar Pregnancies and Pillars of Management

The growth regulator human proliferation-associated 2G4 (PA2G4) protein interacts with NLRP7 which is involved in recurrent hydatidiform molar pregnancy

Abstract Recurrent hydatidiform molar pregnancies are characterized by uncontrolled proliferation of trophoblasts resulting in the failure of the embryo and placenta to develop properly. Previous studies genetically mapped a mutation in NLRP7 as a cause for recurrent molar pregnancies. The goal of this study is to identify human proteins that interact with NLRP7, especially those that are involved in DNA acetylation and methylation, which could lead to the development of molar pregnancies. A yeast two-hybrid system using a human cDNA library was used to screen for interacting proteins, and protein interactions were verified by co-immunoprecipitation in HEK 239T cells. Additional experiments are planned to determine the functional significance of such interactions. Yeast screening results indicated several proteins that interact with NLRP7, however further testing will be focused on the interaction with Human proliferation-associated 2G4 (PA2G4), a human protein involved in growth regulation. Having potentially identified a protein involved in development through acetylation/deacetylation that interacts with NLRP7, we hope to shed more light on the molecular pathways that lead to the formation of recurrent molar pregnancies.

Potential genetic causes of miscarriage in euploid pregnancies: a systematic review.

Approximately 50% of pregnancy losses are caused by chromosomal abnormalities, such as aneuploidy. The remainder has an apparent euploid karyotype, but it is plausible that there are cases of pregnancy loss with other genetic aberrations that are not currently routinely detected. Studies investigating the use of exome sequencing and chromosomal microarrays in structurally abnormal pregnancies and developmental disorders have demonstrated their clinical application and/or potential utility in these groups of patients. Similarly, there have been several studies that have sought to identify genes that are potentially causative of, or associated with, spontaneous pregnancy loss, but the evidence has not yet been synthesized. The objective was to identify studies that have recorded monogenic genetic contributions to pregnancy loss in euploid pregnancies, establish evidence for genetic causes of pregnancy loss, identify the limitations of current evidence, and make recommendations for future studies. This evidence is important in considering additional research into Mendelian causes of pregnancy loss and appropriate genetic investigations for couples experiencing recurrent pregnancy loss. A systematic review was conducted in MEDLINE (1946 to May 2018) and Embase (1974 to May 2018). The search terms 'spontaneous abortion', 'miscarriage', 'pregnancy loss', or 'lethal' were used to identify pregnancy loss terms. These were combined with search terms to identify the genetic contribution including 'exome', 'human genome', 'sequencing analysis', 'sequencing', 'copy number variation', 'single-nucleotide polymorphism', 'microarray analysis', and 'comparative genomic hybridization'. Studies were limited to pregnancy loss up to 20 weeks in humans and excluded if the genetic content included genes that are not lethal in utero, PGD studies, infertility studies, expression studies, aneuploidy with no recurrence risk, methodologies where there is no clinical relevance, and complex genetic studies. The quality of the studies was assessed using a modified version of the Newcastle-Ottawa scale. A total of 50 studies were identified and categorized into three themes: whole-exome sequencing studies; copy number variation studies; and other studies related to pregnancy loss including recurrent molar pregnancies, epigenetics, and mitochondrial DNA aberrations. Putatively causative variants were found in a range of genes, including CHRNA1 (cholinergic receptor, nicotinic, alpha polypeptide 1), DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1), and RYR1 (ryanodine receptor 1), which were identified in multiple studies. Copy number variants were also identified to have a causal or associated link with recurrent miscarriage. Identification of genes that are causative of or predisposing to pregnancy loss will be of significant individual patient impact with respect to counselling and treatment. In addition, knowledge of specific genes that contribute to pregnancy loss could also be of importance in designing a diagnostic sequencing panel for patients with recurrent pregnancy loss and also in understanding the biological pathways that can cause pregnancy loss.

Risk of recurrent molar pregnancies following complete and partial hydatidiform moles.

Risk of recurrent molar pregnancies following complete and partial hydatidiform moles.

Risk of recurrent molar pregnancies following complete and partial hydatidiform moles.

What is the risk of further molar pregnancies for women with one or more hydatidiform moles (HM) in relation to molar subtype. Women with a complete hydatidiform mole (CM) have a 1 in 100 and 1 in 4 risk of further CM after one or two consecutive CM, respectively, while women with a partial hydatidiform mole (PM) have only a small increase in risk for further molar pregnancies. Women with a molar pregnancy have an increased risk of further HM. A small subgroup of women with recurrent HM has an autosomal recessive condition, familial recurrent hydatidiform moles (FRHM), that predisposes them to molar pregnancies. A retrospective study of subsequent pregnancies in 16 000 women registered at a centralized referral centre, with a CM or PM, between 1990 and 2009. One hundred and sixty-six women with two or more molar pregnancies were identified from electronic records and patient notes. Histopathological features of all molar tissue were reviewed in these cases and genotyping performed where diagnosis was not possible on the basis of histopathological features alone. In addition, genotyping of molar tissue was performed in all cases of women with three or more CM to establish whether the tissue was diploid and biparental or androgenetic. This study confirms an increased recurrence risk of ∼1% for a second molar pregnancy and in addition that this risk is associated with CM rather than PM. The data further indicate that the risk of a third HM is associated almost exclusively with CM and enabled an estimate that 1 in 640 women registered with a CM has the rare condition FRHM. The study also found that there was no significant difference between the risk of developing gestational trophoblastic neoplasia (GTN) for typical sporadic CM and the diploid biparental CM associated with FRHM (GTN; proportion difference 0.05, Z = 0.87, P = 0.29). While pathology was reviewed for all women with two or more molar pregnancies, not all cases registered underwent central review particularly those women registered in the early 1990s. It is therefore possible that the total number of CM and PM may differ slightly from that stated. While women were followed for a minimum of 5 years, it is possible that some women may subsequently have further molar pregnancies that will not have been included in the present study. This is the largest study to date on recurrence for molar pregnancies, and as such provides the most detailed information so far regarding the risk of further molar pregnancies for women with a PM or CM. Furthermore, the data provide new insights into the incidence of the rare autosomal recessive condition, FRHM, important information for counselling women with molar pregnancies. No competing interests declared. No funding was obtained for this study.

Recurrent Hydatidiform Mole

INTRODUCTION: Hydatidiform mole is an abnormal pregnancy characterized by proliferation of trophoblastic tissue and hydropic placental villi. The incidence is approximately 0.1% of pregnancies. We present a case involving a patient with four molar pregnancies and address management strategies to improve future pregnancy outcomes. CASE REPORT: A 23-year-old woman, gravida 5 para 0040, presented for obstetric care at 9 weeks of gestation. Her obstetric history included three histologically proven complete molar pregnancies and one spontaneous abortion. Initial ultrasonography demonstrated a snowstorm appearance and no fetal pole. The patient underwent suction dilation and curettage. Pathology confirmed complete hydatidiform mole. Serial quantitative human chorionic gonadotropin levels were followed to resolution. The patient and her partner had normal karyotypes. DISCUSSION: The cytogenetics of molar pregnancy may shed light on management options. In complete hydatidiform mole, the genetic material is paternal in origin resulting from fertilization of an oocyte without maternal genetic information. Recurrent complete molar pregnancy may indicate abnormal maternal oocyte formation. In vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) and preimplantation genetic diagnosis is reasonable under such circumstances. If maternal oocytes consistently do not contain a haploid chromosome complement, oocyte or embryo donation may be required for a successful pregnancy. CONCLUSION: In the setting of recurrent molar pregnancy, IVF with ICSI and preimplantation genetic diagnosis may be offered. Other management options would include oocyte or embryo donation.

Recurrent Hydatidiform Molar Pregnancy: A Case Report of 5 Consecutive Molar Pregnancies Complicated by HELLP and DIC, and Review of Literature

Hydatidiform mole is the most common form of gestational trophoblastic disease. Recurrent molar pregnancies are extremely rare. Herein, we reported the case of a patient with five consecutive molars; four of them were complete mole, and one was partial mole complicated by HELLP syndrome and DIC.

Familial Recurrent Hydatidiform Moles: A rare case report

Recurrent hydatidiform moles (RHM) are described as the being of at least two molar pregnancies in the same patient. It is very rare. NLPR7 mutations are found high rate in patients with RHM. KHDC3L is the second responsible gene for RHM. In this paper, we present an interesting case of a familial RHM. Here, we have discussed the genetic counseling to be given to a patient who had been diagnosed as hydatidiform mole in her two previous pregnancies and whose sister had a history of four consecutive molar pregnancies. Because rate of NLPR7 mutation is high in individuals with recurrent molar pregnancy, patients should be recommended to have NLRP7 gene sequence analysis in the first place. If no mutation is detected in this gene, KHDC3l gene sequence analysis should be carried out

Recurrent Pregnancy Loss in a Woman With NLRP7 Mutation

Recurrent hydatidiform moles is an uncommon occurrence. Over the past decade, genetic studies of women with multiple recurrent molar pregnancies have revealed that maternal mutations in two different genes, NLRP7 and C6orf221, result in recurrent moles. We report a 23 year old woman, born of unrelated parents, who has experienced three molar pregnancies in succession. Whilst the first pregnancy was classified as a complete hydatidiform mole, the second and third moles defied classification as complete or partial mole using conventional histology, p57 nuclear staining pattern and ploidy studies. Molecular and cytogenetic studies proved that all three molar pregnancies were diploid and biparental in origin. Gene sequencing analysis showed that the patient is homozygous for a previously described mutation in NLRP7. A SNP microarray ruled out the presence of deletion of the NLRP7 locus. This case draws attention to the fact that recurrent molar pregnancies may be the result of specific, identifiable gene mutations, even in patients from non-consanguineous backgrounds. When pathologists encounter patients with molar pregnancies that are diploid and p57 negative and yet have fetal elements such as nucleated red blood cells or immature fetal tissues, it should heighten their suspicion of a possible genetic basis and appropriate molecular genetic workup performed with counseling offered.

The p.L750V mutation in the NLRP7 gene is frequent in Mexican patients with recurrent molar pregnancies and is not associated with recurrent pregnancy loss

The aim of this study is to analyze NLRP7 mutation frequency in 20 Mexican patients with recurrent hydatidiform moles (RHMs). Twenty patients with RHMs, 50 couples with recurrent pregnancy loss (RPL), and 100 controls were included in the study. Molecular analysis of the NLRP7 coding region was performed in patients with RHMs. Restriction enzyme digestion analysis and direct sequencing of the identified mutations were performed in controls and patients with RPL. Patients displayed between two and six moles, and 10 of them presented other forms of pregnancy loss. Twelve (60%) patients were homozygous for the missense mutation c.2248C > G (p.L750V), five (25%) patients were heterozygous for the p.L750V mutation and the c.1018 G > A (p.E340K) variant, and three (15%) patients were heterozygous for the c.1018 G > A (p.E340K) variant. Five (5%) control women and four women and one man (5%) with RPL were heterozygous for the p.L750V mutation and two (2%) patients with RPL were heterozygous for the p.E340K variant. A total of 60% of our RHM patients presented homozygous p.L750V mutations, 25% were compound heterozygotes for p.L750V mutation and the p.E340K variant, and 15% were heterozygous for p.E340K variant. Heterozygous p.L750V mutations were frequently observed in our population. Homozygous mutations were also present in patients with RHMs. Additional studies are needed to understand the role of the p.E340K variant in RHMs and RPL.

NLRP7 Mutation Analysis in Sporadic Hydatidiform Moles in Tunisian Patients: NLRP7 and Sporadic Mole

Hydatidiform mole, an aberrant human pregnancy, is commonly a nonrecurrent disease. Recently, a rare autosomal recessive form of familial and/or recurrent molar pregnancies was associated with mutations in the NLRP7 gene. To investigate whether NLRP7 mutations exist in Tunisian women with sporadic hydatidiform moles. Genomic DNA from 38 unrelated Tunisian patients with sporadic hydatidiform moles were screened by sequencing all NLRP7 exons. A high-resolution melting curve analysis was performed on 170 DNA controls to analyze new sequence variants. More than 13% of these patients were heterozygous for NLRP7 mutations. We found 2 novel missense mutations in the heterozygous state, c.544G>A (p.Val182Met) in 1 patient and c.1480G>A (p.Ala494Thr) in 2 patients, and 2 already reported mutations, c.1532A>G (p.Lys511Arg) and c.2156C>T (p.Ala719Val), in 2 patients. None of these mutations were identified in 170 controls except for 1 woman who was heterozygous for p.Val182Met. As homozygous NLRP7 mutations are associated with recurrent hydatidiform mole or conception loss, the heterozygous state could represent a risk factor for nonrecurrent mole.

Mutations in NLRP7 are associated with diploid biparental hydatidiform moles, but not androgenetic complete moles

BackgroundNLRP7 (NALP7) has been identified as the major gene involved in the inherited predisposition to recurrent molar pregnancies, a rare recessive condition in which affected individuals have complete hydatidiform moles...

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Genomic imprinting is an epigenetic gene-marking phenomenon that occurs in the germline, whereby genes are expressed from only one of the two parental copies in embryos and adults. Imprinting is essential for normal mammalian development and its disruption can cause various developmental defects and diseases. The process of imprinting in the germline involves DNA methylation of the imprint control regions (ICRs), and resulting parental-specific methylation imprints are maintained in the zygote and act as the marks controlling imprinted gene expression. Recent studies in mice have revealed new factors involved in imprint establishment during gametogenesis and maintenance during early development. Clinical studies have identified cases of imprinting disorders where involvement of factors shared by multiple ICRs for establishment or maintenance is suspected. These include Beckwith-Wiedemann syndrome, transient neonatal diabetes, Silver-Russell syndrome and others. More severe disruptions can lead to recurrent molar pregnancy, miscarriage or infertility. Imprinting defects may also occur during assisted reproductive technology or cell reprogramming. In this review, we summarize our current knowledge on the mechanisms of imprint establishment and maintenance, and discuss the relationship with various human disorders.