The most common etiology of pregnancy loss is genetic. Sixty to seventy percent of first-trimester pregnancy losses are genetically not normal. The most common class of abnormality is autosomal trisomies. In such pregnancies, one extra chromosome is present in the developing pregnancy, causing it to fail. Not all trisomies are lethal, however. For example, trisomy 21 (also known as Down syndrome) can result in a live birth, and children with Down syndrome are fairly well recognized by the population at large. However, most trisomy pregnancies undergo spontaneous miscarriage.

Couples who have suffered two or three consecutive losses are recommended to have their blood tested for karyotype analysis to ensure that they, themselves, are genetically normal. Certain chromosomal rearrangements in the parents can predispose to pregnancies possessing abnormal chromosome arrangements, leading to an increased rate of pregnancy loss or fetal abnormalities. The most common of these parental chromosomal rearrangements is a balanced translocation, in which two different chromosomes (for example, chromosomes 14 and 21) break and exchange genetic information. This rearrangement may lead to unbalanced chromosomal arrangements in the egg or the sperm, subsequently predisposing the pregnancy to miscarriage. Although patients with balanced translocations may successfully conceive and deliver healthy babies without assistance, many consider fertility treatments up to and including IVF with preimplantation genetic diagnosis (PGD) to reduce the risk of pregnancy loss. The fact that a couple has previously experienced a successful pregnancy and delivery does not preclude the possibility of a chromosomal balanced translocation.