Evaluation and Management of Recurrent Pregnancy Loss
Recurrent pregnancy loss (RPL) is commonly defined as two or more clinical miscarriages. RPL is generally estimated to occur in approximately 1% to 5% of women trying to conceive. An identifiable cause for RPL can be identified in only half of cases. Therefore, unexplained RPL is very common. Among the known causes are genetic abnormalities in embryos, abnormalities of the uterus, hormone disorders, autoimmune abnormalities, clotting abnormalities and environmental toxins.
GENETICS
Human cells carry 46 chromosomes, and each chromosome is composed of hundreds to thousands of genes containing the DNA that are a blueprint of a person’s physical traits, tissues and organs. During the formation of eggs and sperm abnormalities in chromosomes may occur resulting in extra or missing chromosomes that are either incompatible with life or may result in severe intellectual and functional abnormalities in offspring. Chromosome abnormalities and certain single gene mutations are the leading cause of miscarriages. Even when the number of chromosomes is normal, structural abnormalities in the chromosomes of one parent can be passed on to her or his child again leading to pregnancy loss or abnormalities in the child.
UTERUS
Another common cause for recurrent miscarriages is a uterine abnormality. It is estimated that 10-15% of miscarriages are the result of uterine abnormalities. Such abnormalities can develop during embryological or fetal development (congenital) or can be acquired during a woman’s lifetime. During fetal development the uterus is transformed from a solid ball of tissue into a hollow structure with room for future fetal growth. Sometimes this transformation is faulty resulting in an abnormal uterine cavity less receptive to embryo implantation and fetal growth than a normal uterus. During adult life, lesions and masses can develop in the uterus including polyps and uterine fibroids. If these abnormalities appear in the uterine cavity they can diminish implantation and lead to miscarriages.
IMMUNE
Embryos contain cells from the mother and cells from the father. The father’s cells are foreign to the mother which, if not for special adaptations in the maternal immune system, would lead to maternal rejection of the embryo. These adaptations involve the development of cells, proteins and chemicals that promote immune tolerance. In some women, however, abnormalities occur in the immune tolerance adaptations leading to fetal rejection and pregnancy loss. Some women develop antibodies to fetal tissue that lead not only to pregnancy loss but in some pregnancies poor intrauterine growth, diminished perfusion of blood through the placenta, and maternal blood pressure elevations.
ENDOCRINE:
Thyroid: The most common cause of hypothyroidism is called Hashimoto’s thyroiditis. Hypothyroidism is strongly associated with RPL, infertility and preterm birth. In women with hypothyroidism and RPL, replacing thyroid hormones (e.g. Levothyroxine) may reduce the rate of miscarriage.
Prolactin: Hyperprolactinemia (elevated prolactin hormone levels in maternal blood) is associated with disturbances in ovulation and decreased progesterone secretion thereby contributing to infertility and pregnancy loss. In hyperprolactinemic women with two or more pregnancy losses, medications that lower prolactin levels may reduce the miscarriage rate and improve live birth rates.
Diabetes: Women with pre-gestational diabetes have been shown to have higher miscarriage rates than women without diabetes. However, the increased risk of miscarriage appears in women with uncontrolled diabetes, not in women with well-controlled blood glucose levels.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age. Women with PCOS may have irregular menstrual cycles, hyperandrogenism (acne, scalp hair loss, or excess body hair, or high testosterone levels) and polycystic-appearing ovaries on ultrasound. Having even two of these characteristics is sufficient for a diagnosis of PCOS. Approximately 10% of women with RPL have PCOS, and some studies reported a higher rate of pregnancy loss among women with PCOS than in normal women.
CLOTTING ABNORMALITIES
An increase in blood clotting is seen in pregnant women than in non-pregnant women. Circulating levels of proteins responsible for clotting increase during pregnancy. Genetic mutations found in some women lead to excessive clotting and an increased risk of miscarriage. Some studies show that blood thinners (e.g. Heparin) lower miscarriage rates in women with such mutations but other studies do not show that treatment with blood thinners is efficacious.
ENVIRONMENTAL FACTORS
Environmental toxins including organic solvents, radiation and pesticides have been linked to pregnancy losses but the data are limited. Many studies indicate that smokers, and even women exposed to secondary smoke, have higher miscarriage rates than non-smokers. Increased miscarriages have also been reported in women who consumed >300 mg per day of caffeine as compared to non-caffeine users. Moderate alcohol consumption may also increase miscarriage rates. Studies performed to date have not confirmed which environmental factors are responsible for pregnancy losses, or how much exposure to these factors is problematic.
A standard diagnostic evaluation for the causes of RPL include checking the chromosomes of the parents (Karyotypes) and, if available, testing miscarriage tissue to determine its chromosome content. A careful evaluation of the uterus (saline sonogram) is performed in which saline solution is instilled through the cervix into the uterine cavity to look for congenital anomalies or acquired abnormalities like fibroids or polyps. Testing the woman’s blood for the presence of autoimmune antibodies and other immune cells should be performed. Hormone testing and testing for abnormal blood clotting should also be completed.
Treatment of RPL depends on the cause and is focused on correction of anatomical, autoimmune and/or endocrine factors. When causative factors are unable to be identified or are chromosomal, continued intercourse is an option. However, some but not all studies support the use of in vitro fertilization (IVF) in which cells from embryos can be tested to determine if they have the proper number and structure of chromosomes. Normal embryos can therefore be selected for transfer back to the uterus.