Introduction

Molar pregnancies, also known as hydatidiform moles, are a class of tumours known as gestational trophoblastic disease (GTD) that form as a result of abnormal fertilisation of the egg by sperm. A molar pregnancy will not survive, with many individuals finding out about their molar pregnancy through excessive bleeding and miscarriage. While the overall risk of molar pregnancy is extremely small for most individuals, they can cause problems in terms of their high recurrence rates, potential for forming various cancers, as well as the overall psychological/emotional impact of losing a pregnancy. 

There has been much talk of the use of in-vitro fertilisation (IVF) and other assisted reproductive technology (ART) to alleviate the risks of molar pregnancy in individuals. IVF is a laboratory procedure where an egg is removed from an individual’s uterus and fertilised with sperm in a lab to produce an embryo that is subsequently implanted into the uterus. This article aims to provide an overview of the different types of molar pregnancy and their risks, as well as outline how IVF is useful in inhibiting molar pregnancy risks.

Types of molar pregnancy

Complete molar pregnancy

A complete molar pregnancy is a molar pregnancy resulting from a sperm fertilising an egg that is free from the female’s genes. Complete molar pregnancies normally contain no evidence of foetus tissue and the overall development of an embryo, and consist only of molar tissue that form a mass of multiple vesicles. 

The risk of persistent gestational trophoblastic disease (GTD), which is a tumour that develops from trophoblast cells surrounding the developing embryo cell that has the potential to be cancerous. This is much more common with complete molar pregnancies than with partial molar pregnancies. 

The molar tissue resulting from a complete molar pregnancy can be treated through surgery or drug treatment since most GTD tumours are benign (noncancerous). However, invasive moles can occur in approximately 15% of complete molar pregnancy cases; molar tissue continues to remain within the womb and is usually treated through chemotherapy treatments.¹ 

Partial molar pregnancy

A partial molar pregnancy occurs when 2 sperm cells fertilise an egg instead of 1 sperm cell. This results in the embryo having more chromosomes, with such embryos containing 3 sets of chromosomes (69) instead of the normal 2 sets (46), ultimately resulting in too much genetic material.¹ 

As a result, the embryo develops minimally and irregularly due to the development of fluid-filled sacs, leading to the resulting foetus usually dying within a few weeks after conception. Partial molar pregnancies are rarer than complete molar pregnancies, with surgery and drug treatments being the most commonly used methods of treatment. 

Incidence of molar pregnancy in IVF

While IVF does not eliminate the occurrence of molar pregnancy, it does significantly lower the risks of molar pregnancy and formation of GTD tumours compared to natural conception. According to a 2019 data evaluation collected and conducted by the Human Fertility and Embryology Authority (HFEA), between 1991 and 2018, fresh IVF was associated with a relatively low incidence of molar pregnancy, at 0.02%, in contrast to a risk rate of 0.08% in naturally conceived pregnancies. 

This can be attributed to the fact that during the IVF procedure, fertilisation and the early development of the embryo can be observed and altered to prevent any abnormalities in the developmental processes, a process known as preimplantation genetic diagnosis (PGD). Overall, a combination of IVF and PGD can be used to avoid the risks of molar pregnancies.³   

Causes and risk factors

Genetic factors

Overall, genetic factors play a huge role in the development of molar pregnancies. In particular, deleterious mutations of maternally-inherited genes such as NLRP7 and KHDC3L have been associated with a sharp recurrence of molar pregnancies.⁴ 

In addition, as outlined previously, fertilisation of an empty egg and the fertilisation of an egg by two sperm cells results in complete and partial molar pregnancies, respectively, through the formation of moles with irregular sets of chromosomes.^1,4 

Thus, abnormalities with regard to fertilisation and chromosomal expression can greatly accelerate the chances of a molar pregnancy.   

Age-related risks

Studies have found sharp increases in the prevalence of molar pregnancy in individuals aged 45 and older; for complete molar pregnancies, a 2013 study assessing approx. 5,700 patients in England and Wales found that risk rates varied from a 1 in 1000 chance for individuals aged between 18-40 to an extremely high 1 in 8 chance for individuals aged 50 and above.⁵ 

This increased risk of molar pregnancy could be due to a decrease in the quality of eggs in older age and the higher risk of chronic conditions such as high blood pressure and cholesterol. Consequently, older individuals who wish to become pregnant should be cautious about potentially developing complete or partial molar pregnancies and may benefit from interventions such as IVF. 

Previous molar pregnancies

A crucial feature of molar pregnancy is its high recurrence rate. For many people assigned female at birth (AFAB), molar pregnancy has a common tendency to repeat itself with greater risks; the risk of recurrence after one molar pregnancy is approximately 1-2%, but can spiral up to 15-17% after two molar pregnancies according to a 2003 study assessing pregnancy outcomes following complete or partial molar pregnancies.³ 

Therefore, individuals who have previously had molar pregnancies potentially have a higher chance of facing a molar pregnancy outcome in the future. 

Other factors

Certain ethnic and racial groups are genetically more prone to developing molar pregnancies, with Asian AFAB individuals being twice as likely as individuals belonging to other ethnic groups to develop complete molar pregnancies. Moreover, a 2016 study published in Elsevier outlining the effect of race/ethnicity on molar pregnancy risks on 255 pregnancies in the Northeastern United States has found that Hispanic individuals were less likely to develop complete and molar pregnancies compared to non-Hispanic individuals.⁶ 

Other risk factors that greatly accelerate the chances of molar pregnancy include nutritional deficiencies and exposure to high altitudes.

Specific risks during IVF

Risk of recurrence in subsequent IVF cycles

It is important to consider that while IVF and other forms of assisted reproductive technology (ART) can lower overall chances of the development of a molar pregnancy, the risk of molar pregnancy is not completely eliminated. This risk is dependent on the specific type of IVF procedure undertaken. 

During a fresh cycle IVF procedure that does not involve the freezing of eggs, the incidence of molar pregnancy is 1/4333. However, frozen-cycle IVF involving the use of frozen eggs has an incidence rate of between 1/2317 to 1/28967, suggesting that molar pregnancies may be 50-100% more likely to occur in a frozen-cycle IVF procedure compared to a fresh-cycle procedure.⁷ This is an important point to consider for individuals considering freezing their eggs for IVF at a later date, as frozen IVF procedures are increasingly common due to cost-effectiveness and a desire to preserve fertility. 

Complications in embryo implantation

During the IVF procedure, complications during the implantation of embryos should be considered, as they have a risk of causing the formation of hydatidiform moles. According to the HFEA, among data from 276,655 pregnancies in the UK, between 68 and 71 cases of molar pregnancy developed from fresh or frozen embryos as a result of complications relating to implanting embryos made up of immature oocytes (ovary cells) and abnormal sperm cells, with resulting symptoms including bleeding after approx. 8 weeks post-implantation.⁷ Therefore, the genetic quality of sperm and egg cells have to be properly scrutinised to prevent abnormalities in the resulting embryo.^{4, 7}  

Risk of persistent gestational trophoblastic disease (GTD)

Gestational trophoblastic disease (GTD) tumours grow from the tissue that forms the womb during pregnancy and come in different varieties; molar pregnancy is the most common form of GTD. Persistent GTD is a potential risk following molar pregnancies, including those conceived through IVF procedures, and can lead to further complications such as invasive moles. This risk can be alleviated through regular monitoring at each cycle of the IVF procedure.⁶

Preventive measures

Genetic counselling 

For many individuals considering IVF, genetic counselling serves as a mechanism for the identification of genetic conditions and the successful implantation of an embryo through IVF. In the case of molar pregnancy, genetic counselling can be a tool that can be utilised to detect abnormalities in sperm and eggs, such as dispermic fertilisation and chromosomal anomalies. Moreover, during genetic counselling, other forms of ART may be offered, such as intracytoplasmic sperm injection (ICSI), where sperm is individually injected into an egg, and pre-implantation genetic diagnosis (PGID), allowing for increased monitoring of the embryo implantation process to inhibit molar pregnancy risks.⁷  

Preimplantation genetic diagnosis (PGID)

PGID is a laboratory procedure used to identify abnormalities within the genetic material of embryos prior to implantation during the process of IVF. A major advantage of PGID is that it allows for better embryo selection as it allows the screening of embryos before pregnancy. Indeed, IVF in combination with PGID is a highly recommended way to potentially avoid the formation of complete moles, allowing for a successful pregnancy.³ 

Summary

While IVF does not completely eliminate the risks of molar completely, it can greatly reduce potential risks of molar pregnancy as the embryo is able to be observed and changed prior to implantation to remove any deleterious genetic mutations. IVF can be further used in a beneficial manner through the usage of genetic screening techniques such as PGID to ultimately the abnormalities that are the root cause of the development of molar pregnancies.