Which are the causes of Gestational trophoblastic disease?

TL;DR: Gestational trophoblastic disease (GTD) is caused by abnormal fertilization events that lead to the uncontrolled growth of placental tissue. While the exact trigger for these errors is often unknown, the condition primarily arises from chromosomal imbalances during conception, rather than environmental toxins or maternal lifestyle choices.

What causes Gestational trophoblastic disease at a cellular level?

At its core, Gestational trophoblastic disease is a group of conditions originating from the cells that would normally develop into the placenta after fertilization. In a healthy pregnancy, the sperm and egg each contribute half of the genetic material. In many forms of Gestational trophoblastic disease, specifically hydatidiform moles, this process goes awry. For example, in a complete hydatidiform mole, an "empty" egg is fertilized by one or two sperm, resulting in a pregnancy where all genetic material is paternal. This creates a cellular environment that promotes rapid, disorganized growth of trophoblastic cells instead of a developing fetus.

What is the difference between causes and risk factors?

It is crucial to distinguish between the biological cause of Gestational trophoblastic disease and the risk factors that might increase its likelihood. The cause is the specific genetic or cellular error—the "what" that triggers the disease. A risk factor is a circumstance that makes the occurrence statistically more probable. While the primary cause is a fertilization error, research has identified several established risk factors for Gestational trophoblastic disease:

• Maternal Age: Women under age 20 or over age 40 have a statistically higher risk of developing a molar pregnancy.


• Reproductive History: A personal history of a previous molar pregnancy increases the risk of recurrence to approximately 1-2%.


• Ethnicity: Some studies suggest higher incidence rates in certain Southeast Asian populations, though this remains an area of ongoing investigation.


• Dietary Factors: Research has explored links between low levels of carotene and folic acid and a higher incidence of Gestational trophoblastic disease.

Are there genetic factors involved in Gestational trophoblastic disease?

Yes, genetic factors are central to the etiology of Gestational trophoblastic disease. While most cases are sporadic (random) events during fertilization, there is a rare, familial form of recurrent hydatidiform moles. In these specific cases, researchers have identified mutations in the NLRP7 and KHDC3L genes. These genes are responsible for the proper development of the embryo and the regulation of maternal-effect proteins. When these genes are mutated, the body’s ability to correctly manage the genetic imprinting required for a healthy pregnancy is compromised, leading to recurring Gestational trophoblastic disease.

Is the cause of Gestational trophoblastic disease fully understood?

While we have a clear understanding of the chromosomal accidents that lead to molar pregnancies, the exact molecular pathways that cause some cases to progress into more aggressive forms—such as choriocarcinoma—are still being mapped. Medical researchers are currently investigating the role of epigenetic markers and the tumor microenvironment to determine why some trophoblastic cells become malignant while others do not. With 406 members in our DiseaseMaps.org community, we recognize that patients often feel "blamed" for their diagnosis; however, clinical evidence consistently shows that this disease is not caused by anything the mother did or did not do during pregnancy.

Next steps

• Consult with a reproductive endocrinologist or a gynecologic oncologist if you have a history of recurrent pregnancy loss or molar pregnancies.


• Request genetic counseling if you have experienced more than one molar pregnancy to discuss testing for NLRP7 and KHDC3L mutations.


• Join our supportive community at DiseaseMaps.org to connect with others who have navigated the diagnosis and treatment of Gestational trophoblastic disease.


• Keep a detailed record of your reproductive history, including pathology reports, to share with your specialist.

Medical disclaimer: This information is for educational purposes only and does not constitute medical advice, diagnosis, or treatment; always seek the advice of your physician or other qualified health provider with any questions regarding a medical condition.

References

• NIH Genetic and Rare Diseases Information Center (GARD): Gestational Trophoblastic Disease.


• Orphanet: Rare diseases database, entry for Hydatidiform Mole.


• OMIM (Online Mendelian Inheritance in Man): Familial Recurrent Hydatidiform Mole (MIM #231090).


• American College of Obstetricians and Gynecologists (ACOG): Practice Bulletin on Gestational Trophoblastic Disease.