What is multiple miscarriage?

The term “miscarriage” means involuntary pregnancy loss. It occurs in 15% of apparently normal couples, and become “recurrent” in 2% to 3%. Traditionally, miscarriage events are recurrent when it involves loss of 3 or more consecutive pregnancies, usually before 20 weeks of gestation, with or without previous live births. Currently accepted definition of “multiple miscarriage” involves 2 or more failed pregnancies, which would account for up to 5% of all miscarriages and this risk increases significantly after the age of 35.

Known risk factors of multiple miscarriage include endocrine disorder, uterine pathology, nutritional and environmental factors, infections, alloimmune and autoimmune diseases and thrombophilias. Despite years of research, no explanation can be offered to as many as 50% of all cases. Recent medical studies and genetic screening have proposed that certain gene variations in potential mothers are susceptibility factors that increase the risk of idiopathic (or spontaneous) multiple miscarriage.

Blood supply is very important for the developing fetus!

Successful pregnancy is dependent on good blood circulation to deliver sufficient oxygen and nutrients to the placenta and growing fetus. Hence, the development of a functional vascular network is very important in the early stages of pregnancy. Recent studies have shown that inadequate blood vessel network formation may result in gestational complications, including pregnancy loss, intrauterine fetal death, intrauterine growth restriction and pre-eclampsia. Genetic analysis data from multiple miscarriage patients revealed a reduction in expression of genes related to vasculature development.

Genetic variations can increase risk of multiple miscarriage.

Numerous medical literatures point to 3 blood vessels related genes: VEGF, p53 and eNOS as candidate markers in the pathology of spontaneous multiple miscarriage. However, because of the small number of patients participating in each individual study, no significant conclusion can be drawn from these investigations. Recently, a study published in the medical journal Human Reproductive Update performed a systematic data analysis of all published investigations on the involvement of these genes. By combining results from separate studies, it was possible to increase the sample size to allow for a more meaningful statistical examination. In this study, it was shown that genetic variations in these genes (discussed in detail below) were significantly and constantly associated with multiple miscarriage events.


Vascular endothelial growth factor (VEGF) is a strong inducer for the development and maintenance of new blood vessels. It has been shown that VEGF also plays an essential role in the development of placental and fetal blood vessel network. Studies in mice demonstrated that inadequate VEGF caused pregnancy loss due to insufficient blood circulation to the placenta. Several VEGF gene variations have been reported to affect expression and protein activity. One common variation “1154G/A” is reported to be associated with spontaneous multiple miscarriage.


p53 is a well-known tumor suppressor protein which helps prevent cancer. It plays important functions in regulating cell divisions, cell death and protecting the integrity of our genes from DNA damages. In addition to these anti-tumor properties, p53 also plays a critical role during pregnancy as it regulates blood vessels development. Mutant p53 is reported to induce abnormal blood vessels growth and too much or too little p53 can cause embryonic lethality in mouse study models. The p53 genetic variation “72P/R” was reported to alter normal p53 activity in human and affect fertility. The 72R variation is shown to cause blood vessel wall cell death and the 72P variation can lead to abnormal embryo implantation. Both of these detrimental effects significantly increase risk of early pregnancy loss and multiple miscarriage events.


Nitric oxide (NO) is known to mediate blood vessel relaxation, and the lack of NO is associated with blood vessel spasm, which leads to restricted blood flow and reduced oxygen supply. The protein endothelial nitric oxide synthase (eNOS) is required for NO production in blood vessels. During early pregnancy, eNOS is produced in the region of the developing fetus to regulate blood vessel formation in this area. A reduction in eNOS greatly decreases blood flow to the placenta, ultimately compromising oxygen and nutrient delivery to the developing fetus. Two genetic variations: intron-4-VNTR and Q298D were shown to influence blood NO level and were associated with clinical manifestation in pre-eclampsia and cardio-pulmonary problems. These genetic variations are closely associated with spontaneous multiple miscarriage.

What does this mean and what can you do?

The authors of this study concluded that biological functions of these 3 genes are important for the formation and regulation of blood vessels in early pregnancy. Although further investigations which will take into account variations in different ethnic groups and to include larger group of research participants would be needed to validate results from this review, certainly, there is hugh potential in using genetic variations in these genes as clinical markers for evaluating the risk of multiple miscarriage in routing pregnancy care testing.

The advent of genetic sequencing technology allows for a quick test to identify variations in genes like those we just discussed. Here at Geneyouin, we provide competitive genetic testing and consultation services to address your concerns on fertility and pregnancy risk. Please feel free to contact us if you have any questions on this subject.

If you are interested in related topics, please visit the blog Prenatal Diagnostics – Myths of Genetic Testing – Designer Babies by Gouri Mukerjee.

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