Recurrent Miscarriage
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Elizabeth Taylor, MD, FRCSC, Mohammed Bedaiwy, MD, PhD, Mahmoud Iwes, MD Recurrent miscarriage Management of pregnancy loss includes investigating causes, addressing modifiable risk factors, and providing supportive care in the first trimester of pregnancy. ABSTRACT: Early miscarriages are arly miscarriage has been re Genetic causes those occurring within the first 12 ported to occur in 17% to 31% The risk of miscarriage increases completed weeks of gestation. Re- E of pregnancies,1,2 and is de with maternal age. At age 20 to 24 current miscarriage, defined as two fined as a nonviable intrauterine the risk is approximately 10%, with or more consecutive pregnancy loss- pregnancy with either an empty ges risk increasing to nearly 80% by age es, affects 3% of couples trying to tational sac or a gestational sac con 45.5 The relationship between mis conceive and can cause consider- taining an embryo or fetus without carriage risk and maternal age can be able distress. The risk of miscarriage fetal heart activity within the first explained by the increasing rate of oo increases with maternal age. Genet- 12 completed weeks of gestation.3 cyte aneuploidy that occurs as women ic abnormalities, uterine anomalies, Recurrent miscarriage occurs in 3% grow older. In one study, oocytes and endocrine dysfunction can all of couples trying to conceive. The examined during in vitro fertilization lead to miscarriage. Other causes of American Society for Reproductive (IVF) treatment had only a 10% risk miscarriage are autoimmune disor- Medicine (ASRM) defines recurrent of being aneuploid in women younger ders such as antiphospholipid syn- miscarriage as two or more failed than age 35, but by age 43 the risk of drome and chronic endometritis. clinical pregnancies as documented aneuploidy was 50%, and after age Unfortunately, in nearly 50% of cou- by ultrasound or histopathologic ex 45 nearly 100%,6 confirming that the ples no clear cause can be identified. amination,3 while the National Insti most frequent cause of miscarriage at Management includes investigating tute for Health and Care Excellence all ages is aneuploidy. causes, addressing modifiable risk (NICE) notes that miscarriages can Genetic factors that contribute to factors, and providing supportive cause considerable distress.4 miscarriage include structural and care in the first trimester of preg- Although common, recurrent numerical chromosome abnormali nancy. For some couples, in vitro fer- miscarriage is neither well defined ties that have arisen de novo in the tilization with embryo screening may nor well understood. Our understand be an option. ing of recurrent miscarriage has been Dr Taylor is a clinical assistant professor in limited by variable definitions of mis the Division of Reproductive Endocrinology carriage and a lack of standardization and Infertility at the University of British Co- in research. Recurrent miscarriage is lumbia. Dr Bedaiwy is a professor in the De- considered a primary or secondary partment of Obstetrics and Gynaecology at process, depending on whether the the University of British Columbia and head woman has experienced a live birth. of the Division of Reproductive Endocrinol- Nonconsecutive miscarriages have ogy and Infertility. Dr Iwes is a fellow in the unclear significance. Department of Obstetrics and Gynaecol- This article has been peer reviewed. ogy at the University of British Columbia. 258 BC MEDICAL JOURNAL VOL. 60 NO. 5, JUNE 2018 bcmj.org Recurrent miscarriage embryo or fetus or have been inher Surgical correction of most uterine Endocrine causes ited from the parents. These include anomalies does not improve pregnan Endocrine disorders are observed in trisomy, monosomy, and polyploidy. cy outcomes. The notable exception 10% of women with recurrent mis Trisomy is caused by unequal sepa is a uterine septum. Several studies carriage. The health and receptivity ration or disjunction of chromosome have analyzed the reproductive out of the endometrium is intimately re pairs during meiosis, events that in come before and after hysteroscopic lated to a woman’s thyroid, prolactin, crease with maternal age. Structural septum removal. The largest series androgen, and insulin regulation.4 chromosome abnormalities include reciprocal translocations, Robertso nian translocations, and pericentric and paracentric inversions. Balanced carriers of these translocations have a complete karyotype and a normal phenotype, but during meiosis unbal anced oocytes or sperm can be pro Recurrent miscarriage—defined as duced. Such gametes then result in an two or more failed clinical pregnancies embryo with an unbalanced karyo type predisposed to miscarriage. To as documented by ultrasound or identify parentderived chromosome histopathologic examination—occurs abnormalities, parental karyotyp ing is recommended. At the time of in 3% of couples trying to conceive. a miscarriage, genetic testing of the products of conception will help de termine whether the miscarriage is the result of a de novo chromosome abnormality of the embryo or fetus, which is unlikely to recur, or whether underlying maternal disease has led to showed a significant decrease in the Thyroid dysfunction the loss of a chromosomally normal early miscarriage rate from 89.6% to The presence of thyroid autoanti embryo or fetus, which might recur. 12.4%, as well as an increase in term bodies is associated with an increased delivery rate from 1.4% to 74.4%.9 risk of both sporadic miscarriage and Anatomic causes Uterine fibroids and endometri recurrent miscarriage. A metaanaly Uterine anomalies are observed in al adhesions may also be associated sis found an increase in the miscar 13% of women with recurrent miscar with recurrent miscarriage. Submu riage rate in the presence of thyroid riage, compared with 5.5% of women cosal fibroids affect implantation by autoantibodies: OR 3.90 for cohort in the general population.7 Congenital altering vascularization of the endo studies (95% CI, 2.486.12); OR 1.80 uterine anomalies result from the ab metrium and reducing fluid cytokine for casecontrol studies (95% CI, normal formation, fusion, or resorp concentrations.10 An association be 1.252.60).12 tion of the Müllerian ducts during tween miscarriage and intramural or Several studies have suggested embryological development. Com subserous fibroids is less clear, having that levothyroxine treatment of eu mon congenital uterine anomalies are been demonstrated in some, but not thyroid women who have thyroid uterus didelphys, unicornuate uterus, all, studies.10 Recurrent miscarriage autoantibodies decreases the risk of bicornuate uterus, and septate uterus.8 may occur in women with intrauter miscarriage. Two large randomized These anomalies are diagnosed using ine adhesions as a result of implanta trials are underway to examine the the following imaging techniques, tion abnormalities in areas of denuded role of thyroid hormone therapy in either alone or in combination: endometrium or insufficient vascular women with recurrent miscarriage.13 hysterosalpingography, saline in ization. The impact varies with the se fusion sonohysterography, hysteros verity of adhesions. Research on the Hyperprolactinemia copy, 2D and 3D ultrasonography, impact and treatment of adhesions is Hyperprolactinemia alters the and magnetic resonance imaging. limited.11 hypothalamicpituitaryovarian axis BC MEDICAL JOURNAL VOL. 60 NO. 5, JUNE 2018 bcmj.org 259 Recurrent miscarriage leading to impaired folliculogenesis Other causes lature is associated with fetal growth and/or a short luteal phase. One study Although early pregnancy loss most restriction, fetal death after 20 weeks of women with recurrent miscarriage commonly has a genetic, anatomic, or gestation, and preeclampsia. While found a significant decrease in preg endocrine cause, miscarriage may also there is no association between throm nancy loss with suppression of hyper result from an autoimmune disorder, bophilias and recurrent early miscar prolactinemia using the dopamine chronic infection, or a lifestyle factor. riage, it may be prudent to screen agonist bromocriptine.14 women at high risk of thrombosis Autoimmune disorder based on their personal or family Polycystic ovary syndrome Antiphospholipid syndrome (APS) history.21 Women with polycystic ovary syn is characterized by venous or arterial drome (PCOS) have an increased thrombosis and/or an adverse preg Infection risk of miscarriage, although the nancy outcome in the presence of Acute infection or asymptomatic col incidence rate is uncertain. The persistent laboratory evidence of an onization of the cervix or vagina with underlying mechanism may involve tiphospholipid antibodies. Commonly mycoplasma, chlamydia, listeria, ureaplasma, or other pathogens does not increase the risk of miscarriage, and routine screening for such patho gens in women with recurrent miscar Although early pregnancy loss riage is not recommended. Unlike acute infection, however, most commonly has a genetic, chronic endometritis is associated anatomic, or endocrine cause, with pregnancy loss. One study iden tified chronic endometritis in 9% of miscarriage may also result from women with recurrent miscarriage, an autoimmune disorder, chronic and found a perpregnancy live birth rate of 7% before and 56% after treat infection, or a lifestyle factor. ment with antibiotics.22 While the causative organism is rarely identified in cases where endo metritis is suspected, the presence of plasma cells