Recurrent miscarriage

Pregnancy loss, also referred to as miscarriage or spontaneous abortion, occurs in up to 25% of pregnancies. Recurrent pregnancy loss occurs less frequently and it is estimated that 5% of women experience two consecutive pregnancy losses while only 1% experience three or more. == Etiology and risk factors ==

The cause of recurrent pregnancy loss is unknown in about 50% of cases. Risk factors that have been associated with RPL include parental and genetic factors (advanced maternal age, chromosomal abnormalities, sperm DNA fragmentation), anatomical conditions, lifestyle factors, endocrine disorders, thrombophila (bleeding disorders), immunological factors, and infections. Despite thorough evaluation for these risk factors, the exact cause for recurrent pregnancy loss is unknown in about 50% of cases. Parental and genetic factors • Advanced maternal age: Maternal age is associated with increased risk of miscarriage with a rate of 50% in women over 40 years of age. This higher likelihood of pregnancy loss can be attributed to the higher incidence of trisomies, a chromosomal abnormality, seen in women over the age of 35. Some research suggests that chromosomal abnormalities occur more frequently in sporadic pregnancy loss than in recurrent pregnancy loss, and the incidence of RPL is lower in women with 3 or more pregnancy losses. Previous studies produced conflicting results. Genetic evaluation of RPL is generally recommended in order to determine the need for genetic counseling and appropriate treatment. It is instead considered after individual risk assessment (ie. family history) and recommended to test parental chromosomes rather than the products of conception. The European Association of Urology Guidelines on Sexual and Reproductive Health therefore recommends SDF testing in cases of infertility or recurrent pregnancy loss. Anatomical conditions Fifteen percent of women who have experienced three or more recurring miscarriages have some anatomical reason for the inability to complete the pregnancy. The structure of the uterus has an effect on the ability to carry a child to term. Anatomical differences are common and can be congenital or acquired. • Congenital: Congenital uterine malformations include unicornuate, septate, bicornate, didelphic, and arcuate uteri. The relationship between uterine abnormalities that are present from birth and RPL is unclear, however, there is an association with pregnancy loss. These structural anomalies are a result of disruption of the Müllerian tract during development. These can be found in approximately 12.6% of RPL cases with the highest incidences occurring in patients with septate (44.3%), bicornuate (36%), and arcuate (25.7%) uteri. These Structural uterine abnormalities can be visualized by several imaging studies including, hysterosalpingography, ultrasound, and MRI. Lifestyle factors While lifestyle factors have been associated with increased risk for miscarriage in general, and are usually not listed as specific causes for RPL. These include cigarette smoking, caffeine intake, alcohol use, BMI, and stress. This review did not address e-cigarettes and vaping given that the authors did not find any studies that looked into the relationship between these forms of smoking and RPL. The relationship between smoking and the risk of miscarriage has been extensively researched. According to a systematic review and meta-analysis, there is some evidence that active cigarette smoking increases the risk of miscarriage and this risk is further increased the more cigarettes that a person smokes a day. This same review highlights that according to the Surgeon General's report in 2010, research supports that smoking during pregnancy can also lead to pregnancy complications such as placental abruption, preterm delivery, and low birthweight among other maternal health risks. • Caffeine: research regarding the association of caffeine intake and spontaneous pregnancy loss has produced inconsistent results in previous years due to the influence of multiple factors and limitations in data collection among the studies. The same systematic review that looked at the relationship between cigarette smoking and RPL in 2021 found that there was no increased risk of RPL with the consumption of caffeine. The harmful effects of caffeine during pregnancy can be attributed to its ability to absorb rapidly into the bloodstream and cross into the placenta, along with the slowed breakdown of caffeine that occurs during pregnancy which can expose the fetus to caffeine and its metabolites for a prolonged period of time. Caffeine consumption can also lead to maternal cardiovascular effects that reduce placental blood flow, putting the development of the fetus at risk. Similar to smoking and caffeine consumption, research studies assessing the relationship between alcohol use and pregnancy loss have produced inconsistent results. A systematic review that looked at several maternal lifestyle factors and the risk of recurrent pregnancy loss found no statistically significant increased risk in women that consumed any form of alcohol during pregnancy compared to those that did not. There is evidence that in women that drink 5 or less alcoholic drinks per week, there is a 6% increased risk of miscarriage with each additional alcoholic drink consumed when the specific trimester is not specified. Due to the inability to determine a safe range of alcohol consumption during pregnancy, multiple medical societies recommend avoiding alcohol to prevent the potential harm to the fetus. • BMI: Maternal obesity and an elevated Body mass index (BMI) has been associated with an increased risk of miscarriage, although no clear cause has been established. Studies suggest that pregnancy loss could be influenced by the downstream effects of the hormonal disruption of the HPA axis and insulin resistance that can be associated with obesity, on the reproductive system disrupting the development of oocytes, embryos, or the integrity of the endometrium (uterine lining). Despite this evidence, research studies aimed to establish a relationship between RPL and BMI, which incorporates height and weight, have produced inconsistent results. A systematic review found that women with a history of RPL had higher BMI's by an average difference of 0.9 kg/m² than women without. These findings, however, were not statistically significant and not exclusive to BMI's within the overweight and obese range. Another research review found that the risk of miscarriage is higher for women with a "history of exposure to psychological stress (OR 1.42, 95% CI 1.19–1.70)" However, the authors of these studies Endocrine disorders Women with hypothyroidism are at increased risk for pregnancy losses. Unrecognized or poorly treated diabetes mellitus leads to increased miscarriages. Women with polycystic ovary syndrome also have higher loss rates possibly related to hyperinsulinemia or excess androgens. Inadequate production of progesterone in the luteal phase may set the stage for RPL. • Luteal phase defect: The issue of a luteal phase defect is complex. The theory behind the concept suggests that an inadequate amount of progesterone is produced by the corpus luteum to maintain the early pregnancy. Assessment of this situation was traditionally carried out by an endometrial biopsy, however recent studies have not confirmed that such assessment is valid. Note that many women with thrombophilia go through one or more pregnancies with no difficulties, while others may have pregnancy complications. Thrombophilia may explain up to 49–65% of recurrent miscarriages. Immune factors A common feature of immune factors in causing recurrent pregnancy loss appears to be a decreased maternal immune tolerance towards the fetus. • Antiphospholipid syndrome: The antiphospholipid syndrome is an autoimmune disease that is a common cause of recurrent pregnancy loss. • Thyroid antibodies: Anti-thyroid autoantibodies are associated with an increased risk of recurrent miscarriage with an odds ratio of 2.3 with a 95% confidence interval of 1.5–3.5. • Increased uterine NK cells: Natural killer cells, a type of white blood cell, are present in uterine tissue. High levels of these cells may be linked to RPL but high numbers or the presence of these cells is not a predictor of pregnancy loss in women who have not have had a miscarriage. • Male-specific minor histocompatibility: Immunization of mothers against male-specific minor histocompatibility (H-Y) antigens has a pathogenic role in many cases of secondary recurrent miscarriage, that is, recurrent miscarriage in pregnancies succeeding a previous live birth. An example of this effect is that the male:female ratio of children born prior and subsequent to secondary recurrent miscarriage is 1.49 and 0.76 respectively. Infection There are numerous bacterial, fungal, protozoal, and viral infections that have been associated with risk of pregnancy loss, however, no direct link to recurrent pregnancy loss has been established. Infections known to increase the risk of miscarriage include bacterial vaginosis (M. hominis and U. urealyticum), syphilis, CMV, dengue fever, malaria, brucellosis, and HIV. There is mixed evidence regarding the risk of miscarriage with Chlamydia trachomatis, HPV, Hepatitis B, Toxoplasma gondii, HSV1/HSV2, and parvovirus B19. == Assessment ==

Transvaginal ultrasonography has become the primary method of assessment of the health of an early pregnancy. In non-pregnant patients who are evaluated for recurrent pregnancy loss the following tests are usually performed. Parental chromosome testing (karyogram) is generally recommended after 2 or 3 pregnancy losses. Blood tests for thrombophilia, ovarian function, thyroid function and diabetes are performed. == Treatment ==

If the likely cause of recurrent pregnancy loss can be determined treatment is to be directed accordingly. In pregnant women with a history of recurrent miscarriage, anticoagulants seem to increase the live birth rate among those with antiphospholipid syndrome and perhaps those with congenital thrombophilia but not in those with unexplained recurrent miscarriage. One study found that in many women with chronic endometritis, "fertility was restored after appropriate antibiotic treatment." For women with unexplained recurrent pregnancy loss, research suggests that specific antenatal counseling and psychological support may result in a higher chance of pregnancy success. Some research finds that for these patients psychological support and ultrasound in early pregnancy "gives 'success rates' of between 70% and 80%". However, each additional loss worsens the prognostic for a successful pregnancy and increases the psychological and physical risks to the mother. Aspirin has no effect in preventing recurrent miscarriage in women with unexplained recurrent pregnancy loss. Immunotherapy has not been found to help. In certain chromosomal situations, while treatment may not be available, in vitro fertilization with preimplantation genetic diagnosis may be able to identify embryos with a reduced risk of another pregnancy loss which then would be transferred. However, in vitro fertilization does not improve maternal-fetal tolerance imbalances. == Psychological Impact ==

Experiencing pregnancy loss can have a significant and at times prolonged psychological impact, including higher levels of stress anxiety, and depression. There is evidence that women struggling with recurrent pregnancy loss in particular may be affected to a greater degree. Grief is a normal and expected response to the loss of a pregnancy. In heterosexual couples, men also experience grief as a result of pregnancy loss and have reported feeling obligated to disregard their feelings in order to support their partner. Consequently, there has been a rise in antidepressant (ie. SSRI) use during pregnancy over the last few years with a prevalence of 1-8%. This decision should be made with the guidance of a medical provider given the teratogenicity and potential adverse effects of antidepressants on the fetus. In addition to psychotherapy, psychological care for people experiencing recurrent pregnancy loss can include counseling and other supportive services. There is some evidence to support that women that received bereavement counseling (based on the Guidelines for Medical Professionals Providing Care to the Family Experiencing Perinatal Loss, Neonatal Death, SIDS, or other Infant Death) after pregnancy loss were able to cope better, with women reporting 50% less despair than those that did not receive this intervention. == Prognosis ==

Recurrent miscarriage in itself is associated with later development of coronary artery disease with an odds ratio of approximately 2, increased risk of ovarian cancer, increased risk of cardiovascular complications, and an increased risk of all-cause mortality of 44%, 86%, and 150% for women with a history of 1, 2, or 3 miscarriages, respectively. Women with a history of recurrent miscarriage are at risk of developing preeclampsia in later pregnancies. == References ==