Five frequently asked questions about genetics of Recurrent Pregnancy Loss
Over last ten years, I have consulted and counselled hundreds of couple who have suffered pregnancy loss, either in form of miscarriages or stillbirths. Miscarriage (also known as pregnancy loss) is a relatively common problem encountered in up to 15 to 25 % of all clinically recognized pregnancies, and in many of these cases the actual cause of pregnancy loss remains unidentified.
Most of the miscarriages are sporadic in nature and can be attributed to defects within the fetus. However, some woman may lose their pregnancy repeatedly. Recurrent pregnancy loss (RPL) is defined as loss of three or more consecutive clinically recognized pregnancies and affects around 1% of couples actively trying to conceive. RPL causes significant anxiety for the suffering patients, especially for the pregnancies resulting from fertility treatment. In addition, RPL in patients undergoing fertility treatment also causes significant financial stress for the couple.
Both Maternal age and number of previous miscarriages independently increase the risk of miscarriage in the subsequent pregnancy. However patients with RPL still have a remarkably good prognosis for live births. Also, the overall incidence of pregnancy loss with IVF pregnancy is almost same as in wider population.
The real cause of RPL remains unknown in up to 50% of the women, despite of all the advancements in diagnostics. The known causes of RPL include –
Environmental and occupational causes
While genetic abnormalities in the fetus are known to cause up to 50% of sporadic early pregnancy losses, only about 2 to 5% cases of RPL can actually be attributed to genetic abnormalities in the fetus. In this article, I will focus only on understanding of genetics of reproduction and genetic causes of RPL. I will discuss other causes and management of RPL in my upcoming posts.
Here are five things you need to know about the genetic causes of RPL
What is a chromosome?
The basic genetic unit of human body is “DNA”, which is packed together to form “Gene”. Genes are the working sub-units of DNA and carry the information that determines the features or characteristics passed on from one generation to another. Human beings are estimated to have between 20,000 to 25,000 genes. Genes are located inside the nucleus of cells and are found on thread like structures, known as which are the “Chromosomes”.
Chromosomes are arranged in pairs inside nucleus of the cells. Each human cell normally contains 23 pairs of chromosomes, with one chromosome of each pair inherited from one of the parents. The first twenty two pairs of chromosomes are same in both men and women, and are known as “Autosomes”. The 23rd pair is known as the “Sex chromosomes” and is identified as either “X” or “Y” chromosome. The type of sex chromosome determines the gender of the person, with females having two X chromosomes and males having one X and one Y chromosome.
Every person has got 2 copies of each gene, one inherited from each parent. While most of the genes are same in all individuals, a small number of genes (< 1%) are unique for each individual and these genes eventually make all human beings individual.
What is cell division?
In order to grow and reproduce the cells have to continuously divide to produce “daughter cells”. This cell division can be of two types- mitosis or meiosis. Without getting into technicalities, it would suffice here to know that the sex cells (both male and female) divide by meiosis and one cell produces four cells (known as gametes – eggs in women and sperms in men) at the end of the division.
How is the fetus formed?
An embryo is formed when the egg and sperm meet each other and the sperm penetrates the wall of the egg, thus bringing its own genetic material into the genetic material of the egg. This process, known as fertilization of the egg, produces a cell with full set of genetic material (23 pairs of chromosomes) for the offspring. The embryo thus formed multiplies repeatedly and very quickly to create a mass of cells, which then differentiate to form different organs of the future baby.
What are common genetic anomalies which can cause RPL?
A variety of genetic factors can cause pregnancy loss. The commonly known causes include-
Aneuploidy- an extra number of chromosome
Translocation and inversion of chromosomes- fault in structure of chromosome
Deletion or duplication of chromosome- fault in amount of DNA in a chromosomes
Single gene mutations- chromosomal abnormality at the level of genes
Aneuploidy – Aneuploidy is an error of cell division, which results in the “daughter” cells having wrong number of chromosomes. In some cases there is a missing chromosome, while in other cases, there is an extra chromosome inside the cell. Thus, such individuals with aneuploidy may have cell with 45, 47, or 48 chromosomes. Such individuals will have cells with improper genetic information, which can result in miscarriages. In some cases with aneuploidy (as in cases of Down’s syndrome), the fetus may survive but the child is likely to be born with various abnormalities. The most common aneuploidies are extra chromosome number 16, 18, 21.
Translocation – In translocation, a segment from one chromosome is transferred to another chromosome or to a new site on the same chromosome. Translocation could either be non-reciprocal, in which there is a one way migration of chromosomal segment or reciprocal, which involve exchange of segments from two different chromosomes. Translocation leads to alteration in the alignment of the genetic structure of the fetus and could, in some cases, result in miscarriage.
Inversion – An inversion is a chromosomal rearrangement in which the affected segment of a chromosome is reversed end to end, and typically occurs when a single chromosome undergoes breakage and rearrangement within itself.
Inversions and translocations may not cause any genetic abnormalities in carriers (parents), as long as the rearrangement is balanced with no extra or missing DNA. However, the gametes (eggs and sperms) in affected people carry unbalanced (excess or insufficient) amount of genetic material. The resultant pregnancy is, therefore, genetically abnormal and can lead to infertility, recurrent miscarriages and sometimes increased risk of cancer.
Deletion and Duplication of Chromosomes – In deletion, a portion of the chromosome is missing or deleted, whereas in duplication, a portion of the chromosome is duplicated, resulting in extra genetic material. Both these genetic abnormalities can lead to various kinds of syndromes in the offspring.
Single gene mutation – Single gene mutations are caused by DNA alterations within one particular gene. These mutations can affect the mother or the fetus.
Mutations in the mother can interfere with implantation of the fetus, thus causing infertility or recurrent miscarriage. Some examples of maternal single gene disorders include maternal myotonic dystrophy, connective tissue disorders like Marfan Syndrome and Ehler Danlos Syndrome and sickle cell disease.
Single gene mutations in fetus, which could lead to RPL include autosomal dominant lethal skeletal dysplasia, Type 2 osteogenesis imperfecta, autosomal recessive disorders like Alpha Thalassemia and X chromosome linked disorders which typically are lethal in male fetus.
What are chance of live birth after RPL
The chances of having a live birth after recurrent miscarriages are not as grim as they appear. The overall probability of live birth after RPL for women aged between 30 and 34 years of age is approximately 66- 70%. The probability, however, goes down with each extra pregnancy loss beyond 3 and increasing maternal age. Newer technologies like “Preimplantation Genetic Diagnosis” (PGD) can help in improving the chances of live birth in couples with known genetic disorders, as it helps in selecting the embryos with the correct genetic composition before transferring into the uterus.
Thorough evaluation of couples who have already encountered miscarriages in two consecutive pregnancies is recommended, because the risk of another miscarriage after 2 lost pregnancies is already almost 30% compared with a risk of miscarriage of 33% after 3 lost pregnancies.
Please write to me at firstname.lastname@example.org if you have any questions related to RPL or if you need more information on this subject.