Genetic Causes of Recurrent Pregnancy Loss and PGT

The genetic causes of recurrent pregnancy loss fall into three groups: a chromosomally abnormal embryo, which explains about 50% of first-trimester losses; a balanced chromosomal rearrangement in one parent, found in about 2 to 7% of couples with recurrent loss; and, mainly in the second trimester, a single-gene condition. A couple in which one partner carries a balanced translocation has about a 70% chance of a normal child.

Genetics explains a large share of first-trimester pregnancy loss, and it shapes what a couple can do next. For Dr. Kanika Singh, Sr. Consultant - Medical Genetics, Artemis Hospitals, Gurugram, India, the genetic evaluation answers three separate questions. Is the embryo chromosomally abnormal? Does one parent carry a balanced rearrangement that keeps producing abnormal embryos? Or, particularly in the second trimester, is a single-gene condition at work? Each answer leads to a different counselling conversation and a different set of reproductive options, from natural conception with prenatal diagnosis to IVF with pre-implantation genetic testing (PGT). Where these tests sit in the full workup is set out in the complete guide to recurrent pregnancy loss.

Chromosomal abnormalities: the commonest cause of first-trimester miscarriage

The commonest single explanation for an early miscarriage is an embryo with the wrong chromosomal complement. About 50% of first-trimester losses carry a chromosomal abnormality, and the earlier the loss, the higher the proportion. Dr. Singh cited figures of 50 to 90% for losses in the first trimester. In the second trimester the picture changes: only 6 to 12% of stillbirths are associated with a chromosomal abnormality, although testing is still worthwhile.

The abnormality takes several forms:

• Aneuploidy, an abnormal number of chromosomes. Trisomies 16 and 22 are among the most frequent findings in tissue from pregnancy losses, and monosomy X (a single X chromosome) is also seen. Trisomy 13, three copies of chromosome 13, is another example.
• Triploidy, in which every chromosome is present in three copies rather than two.
• More complex structural abnormalities.
• Mosaicism, in which some cells carry the abnormality and others do not.

Does parental age increase the risk?

Age raises the risk. Dr. Singh noted that women above 35 and men above 40 are more likely to produce eggs or sperm with an abnormal number of chromosomes. The contribution is not symmetrical: most aneuploidies in conceptions arise from errors in the egg rather than the sperm, which is why maternal age remains the dominant risk factor for chromosomally abnormal pregnancies.

Most embryonic aneuploidies arise afresh at conception and do not mean that either parent has a chromosomal problem. That distinction matters, because a sporadic aneuploidy carries a very different outlook from an inherited rearrangement.

Balanced translocation and recurrent miscarriage

A balanced translocation is an exchange of segments between two chromosomes in which no genetic material is gained or lost. The carrier is entirely healthy, but can produce eggs or sperm with an unbalanced set of chromosomes, which leads to miscarriage. About one in 600 people in the general population carries a balanced translocation.

The difficulty arises when the carrier makes eggs or sperm (gametes). During meiosis, the cell division that produces gametes, the paired chromosomes must come together and then separate. With a translocation, they can segregate in several ways. Alternate segregation produces gametes that are either completely normal or carry the same balanced arrangement as the parent. Adjacent segregation produces unbalanced gametes, with part of one chromosome missing and part of another duplicated. An embryo formed from an unbalanced gamete will usually miscarry, or, if it survives, may have a birth defect or intellectual disability.

In about 2 to 7% of couples with recurrent loss, one partner carries a balanced rearrangement, and the association is strongest when the losses occur in the first trimester.

Robertsonian translocations

A particular class of translocation involves chromosomes 13, 14, 15, 21 and 22. These are acrocentric chromosomes, whose short (p) arms are very small and carry no essential genes. Two of them can fuse at the centromere, losing the short arms without any clinical effect on the carrier. This is a Robertsonian translocation.

The 13;14 Robertsonian translocation is relatively common in the general population. Carrier couples can have normal children: about 50 to 70% do. But the same rearrangement can also produce recurrent pregnancy loss, and in some families the pattern is not loss at all but repeated pregnancies affected by a birth defect or a recurrent ultrasound abnormality. A family history of either should prompt the question.

Balanced translocation: chances of a healthy baby and the options

As a broad figure, a carrier couple has about a 70% chance of a normal child and about a 30% chance of either further losses or a child with a disability or birth defect. Dr. Singh's counselling message has two halves. The carriers themselves have no illness and never will. But they can produce unbalanced gametes, and the exact risk depends on which chromosomes are involved. She regards genetic counselling as essential, and uses it to motivate couples: the 70% chance of a normal live birth is the figure they need to hear.

The first task is simply to identify these couples, which is why parental karyotyping follows when the pregnancy tissue cannot be tested. The options can then be laid out:

1. Natural conception with prenatal diagnosis. Roughly 70% of pregnancies may continue beyond the first trimester. At that point a prenatal diagnostic test must confirm that the baby's chromosomes are normal, to avoid the birth of a child with a birth defect or intellectual disability. Dr. Singh's reasoning is direct: many of these conditions are manageable but not curable.
2. Donor gametes, sperm or eggs depending on which partner carries the rearrangement.
3. IVF with pre-implantation genetic testing, in which embryos are tested for the chromosomal imbalance before transfer.
4. Adoption.

The 21;21 Robertsonian translocation: no viable own-gamete option

One rearrangement stands apart. In a carrier of a 21;21 Robertsonian translocation, both copies of chromosome 21 are fused into one. Every gamete is unbalanced, so the risk of recurrence is 100%: every pregnancy will carry trisomy 21 or be lost. Prenatal diagnosis and PGT offer nothing here, because there is no normal embryo to select. These couples need donor gametes.

Single-gene causes of second-trimester pregnancy loss

A single-gene (monogenic) condition, caused by a change in one gene, is the genetic cause Dr. Singh looks for in the second trimester, particularly when the same ultrasound abnormality recurs in pregnancy after pregnancy. Chromosomal causes dominate the first trimester. The patterns that should raise the suspicion include:

• Arthrogryposis, with a fetus that moves poorly and develops fixed joint contractures
• Polyhydramnios, an excess of amniotic fluid
• Recurrent hydrops, the accumulation of fluid in the fetus
• Recurrent kidney anomalies
• Short long bones, suggesting a skeletal dysplasia
• Sudden cardiac death or stillbirth, which in some cases has been traced to long QT syndrome in the baby

The recurrence risk, and therefore the counselling, depends on the mode of inheritance.

• Autosomal dominant: a single altered copy of the gene is enough to cause disease. If inherited, the affected parent usually has the condition too. But many dominant conditions arise from a new mutation in the child, so a genetic cause does not always mean that a parent is affected.
• Autosomal recessive: both copies must be altered. The parents are carriers, unaffected or only mildly affected, and each pregnancy carries a 25% chance of an affected child. Sickle cell disease is the familiar example.
• X-linked: these conditions present predominantly in males, who have a single X chromosome, while females have two.

There is also a maternal genetic cause that operates through the woman herself. Some women are homozygous or compound heterozygous for variants in genes that govern oocyte quality or embryo implantation, meaning both of their copies of the gene are altered. They are prone to repeated implantation failure and recurrent pregnancy loss regardless of the partner.

Karyotype findings that do not cause miscarriage: qh+ and inversion Y

Some karyotype findings look alarming but do not cause recurrent pregnancy loss, so reading the report correctly is part of the evaluation. When both partners are karyotyped, the report sometimes describes polymorphic variants, especially on chromosomes 1, 9 and 16, often written as "qh+". The notation means an increase in heterochromatin, a region of DNA made up largely of repetitive sequence with few genes. These variants are common in the general population and are well established not to cause recurrent pregnancy loss.

The same applies, on balance, to inversion of the Y chromosome, which is seen in many men. Some studies have suggested an association, but the consensus is that it is not a cause of recurrent loss.

Pre-implantation genetic testing (PGT) for recurrent pregnancy loss

Pre-implantation genetic testing is performed on the embryo during IVF, most commonly at the blastocyst stage (about five days after fertilisation), and the result is used to select the most appropriate embryo for transfer to the uterus. Dr. Singh distinguishes four forms: PGT-A, PGT-M, PGT-SR and PGT-HLA. For couples weighing IVF, the cost of IVF and fertility treatment is set out separately.

PGT-A: who should have aneuploidy screening?

PGT-A screens the embryo for an abnormal chromosome number. It is not recommended routinely in all IVF cycles, but it may be done:

• in advanced maternal age, where the high rate of chromosomal abnormality means an untested IVF pregnancy may simply end in miscarriage
• in severe male factor infertility
• in some couples with normal karyotypes but recurrent miscarriage who are already undergoing IVF, to select the embryo with the best potential for survival

Its benefit in these groups is unproven: ESHRE does not recommend PGT-A for unexplained recurrent pregnancy loss, and ASRM finds the evidence insufficient to support its routine use.

PGT-M: testing for single-gene conditions

PGT-M tests the embryo for a specific single-gene condition. It can be used for conditions that cause recurrent loss, such as genetic causes of hydrops or arthrogryposis, and equally for conditions such as thalassaemia and sickle cell anaemia.

PGT-SR: the test for translocation carriers

PGT-SR is the form most relevant to recurrent pregnancy loss. It is used for couples in whom one partner carries a balanced translocation, allowing a chromosomally balanced or normal embryo to be selected for transfer.

PGT-HLA: selecting a matched sibling donor

PGT-HLA is used when PGT is already being performed for a condition such as thalassaemia or sickle cell anaemia and the family has an affected first child who needs a bone marrow transplant. The embryo is selected to be both unaffected and an HLA (tissue-type) match for that child.

Dr. Singh sees this as clearly preferable to the alternative of testing HLA type in an ongoing pregnancy. Deciding the fate of a baby on the basis of whether it can serve as a donor for a sibling is, in her view, not right. Selecting at the embryo stage avoids that dilemma altogether.

Does a PGT result need confirming?

Yes. Dr. Singh is emphatic on one point that applies to every form of PGT: the result must be confirmed by prenatal testing, in the third month or the fifth month of pregnancy. PGT is not yet a gold-standard test, and it is not 100% accurate.

Genetic causes of recurrent pregnancy loss in the wider evaluation

The genetic evaluation is the first step in the first trimester, not the whole workup. When the chromosomal and genetic tests are normal, attention turns to the uterus, the immune and clotting systems, hormones and the male partner, covered in the article on recurrent pregnancy loss treatment by cause. The full testing sequence, including chromosomal microarray of the pregnancy tissue, is set out in the complete guide linked above.