Obstetrics & Gynecology: Recurrent Miscarriage Mala Arora, Siladitya Bhattacharya, Vijaya Kumari
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fm1World Clinics Obstetrics and Gynecology: Recurrent Miscarriagefm2
fm3World Clinics Obstetrics and Gynecology: Recurrent Miscarriage
Editor-in-Chief Mala Arora, FRCOG FICOG FICMCH Guest Editors Siladitya Bhattacharya, MD FRCOG Vijaya Kumari, MD FACOG
June 2011 Volume 1 Number 1
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WORLD CLINICS Obstetrics and Gynecology: Recurrent Miscarriage
June 2011, Volume 1, Number 1
9789350254226
Printed in India
fm5List of Contributors  
Editor-in-Chief
 
Guest Editors
 
Contributors
fm11Editorial
Mala Arora, frcog (uk) ficog ficmch
Editor-in-Chief
Recurrent miscarriage (RM) poses a challenge for the treating clinician. The cause of RM may be identified in the embryo, endometrial environment, or both. Diverse etiological factors are responsible in some cases, while an extensive investigative work-up may not reveal an underlying cause in many others. Besides, different etiologies may be responsible for successive miscarriages in the same woman. The emerging field of psychoneuroimmunology elucidates how subtle factors like stress may alter the immune response in the mother and contribute to a second and third miscarriage. The definition of RM itself is poised for a major change. Percy Malpas from Liverpool, in 1939, coined the term “habitual aborters” for women with three or more miscarriages, and predicted that they had a poorer pregnancy outcome. However, as discussed in chapter 1, various academic bodies have lowered the threshold for investigations to two or more consecutive miscarriages. This is important in women who start their reproductive career late, as age adds to the risk of infertility and miscarriage.
In our understanding of etiological factors we are moving away from the traditional Pie model to a Threshold model. The Pie model, where different causes are compartmentalized was discarded when it became clear that several risk factors could operate simultaneously in the same individual.
The Threshold model is based on the premise that “a number of risk factors that are in themselves not sufficient to cause disease, but when these intrinsic and extrinsic factors come together in the same individual, the risk exceeds a critical threshold and a miscarriage occurs.” For example, when a patient with advanced maternal age, has an endocrinal factor like polycystic ovaries and a uterine malformation like endometrial polyp, the risk exceeds a threshold and miscarriage ensues (Figure 1).
Figure 1: Threshold model.
The Threshold model illustrates the need for a comprehensive work-up of patients with RM. This will elucidate the probable etiological factors (Figure 2).
It is recommended by the RCOG green top guideline no. 17 (April 2011) that all patients with RM should be screened for:
Alloimmune rejection of the fetus by the mother is a concept that has been extensively studied. The fetus being a foreign allograft, the mother makes adjustments in her immune system to accommodate its growth during pregnancy. Many systems come into play including regulation of T and B cell immunity as well as expression of histocompatibility antigens (HLA) G in the trophoblast instead of A and B, which are the major HLA antigens.
Figure 2: Etiological factors in RM.
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Activation of the fas/fas ligand system causes apoptosis of B cells that recognize fetal antigens as foreign. There is an increase in the numbers of T regulator cells in the uterus and reduction in natural killer cells. The immune acceptance is orchestrated in the endometrium by production of anti-inflammatory cytokines interleukins 4, 6, and 10 along with suppression of proinflammatory cytokines, interleukin 2, interferon, and tumour necrosis factor alpha (TNF). Progesterone has an immunomodulatory role in the endometrium. Some studies show that dydrogestrone may alter the T helper cell 1 response to T helper cell 2 response in the endometrium thus favouring implantation and growth of the embryo (evidence level 2++). Recently identified molecules like uteroglobin and glycodelin A may play a role. There may be other mechanisms that are as yet unidentified. Unfortunately there are no tests currently available to the clinician to confirm the diagnosis of alloimmune rejection. Hence, they are lumped under “etiology unidentified” group. Immune potentiation in the mother is an interesting concept but has not been proven to be of benefit by a Cochrane review.
Acquired thrombophilia, i.e., antiphospholipid syndrome (APLS) should be screened for in all patients with RM. In fact, the association between the two is so strong that RM is a clinical criterion for diagnosing APLS. Clinically, the commonest presentation is missed miscarriage, and in many cases the fetal cardiac activity is documented in an early scan, before it dissappears. These patients are best treated with low-dose aspirin and low-molecular weight heparin.
Inherited thrombophilias like factor V leiden mutation, prothrombin gene mutataion, antithrombin III deficiency, activated protein C resistance, protein C, and protein S deficiency lead to a thrombogenic state and have the potential to cause adverse pregnancy outcomes. They should be screened for in cases of unexplained intrauterine death and growth restriction in the second and third trimesters. Thrombophilia screening is currently recommended in women with miscarriages and a history of thrombotic events in the past, even though the evidence linking inherited thrombophilia with RM is weak.
Hyperhomocysteinemia is associated with fusion defects in the fetus like spina bifida, cleft palate, but has also been implicated in women with RM and adverse late pregnancy outcomes. Hyperhomocysteinemia may show racial variations and is more prevelant in the Indian subcontinent. Screening for homocysteine should be considered in the work-up of RM. Treatment with folic acid (vitamin B9), pyridoxal 5’ phosphate (vitamin B6), and cyanocobalamine (vitamin B12) can lower homocysteine levels. Reduced red cell folate levels potentiate the adverse effects of hyperhomocysteinemia.
Infections of the genital tract like endometritis, bacterial vaginosis may cause RM, and TORCH group of infections are not implicated in recurrent miscarriages. Screening and treatment of:
is recommended during the pre-pregnancy period.
Anatomical factors like endometrial polyps, submucous fibroids, and uterine septae are associated with RM. Hysteroscopy will identify and treat these conditions. However, there are no randomized controlled trials to assess the effect of surgical correction of uterine anomalies and pregnancy outcome.
Evidence is emerging that obesity may be linked to miscarriages as discussed in chapter 5. The importance of fitness for fertility has been recognized by most infertility clinics. However, the importance of weight loss prior to embarking on a pregnancy has not been emphasized in the routine pre-pregnancy counselling clinics. This is a concept that needs to be encouraged in the obese women with a BMI over 30. Endocrinological factors like uncontrolled diabetes and hypothyroidism should be identified and treated.
fm14Genetic abnormalities will result in anembryonic pregnancies or early pregnancy wastage. Karyotyping of products of conception (POC) is only recommended after three or more miscarriages, but practically may not be feasible in many patients. Fluorescence in situ hybridization (FISH) analysis (for chromosomes 13, 16, 18, 21, X, and Y) on POC is less expensive and does not require culture. Parents may be carriers of balanced translocations which may get unbalanced in the offspring. Parental karyotyping should be performed if aneuploidy is detected in the POC. Skewed inactivation of X chromosome and single gene disorders are difficult to diagnose by routine karyotyping.
The role of in vitro fertilization (IVF) is emerging in mothers with advanced maternal age and/or poor ovarian reserve where ovum donor cycles give good results. Women that are carriers of balanced translocations or have recurrent hydatidiform mole will also benefit from ovum donor cycles. Furthermore, IVF gives us a chance to screen the embryos by PGS for aneuploidy. The role of PGS currently has practical limitations that are discussed in chapters 11 and 12.
In conclusion, management of patients with unexplained RM poses a dilemma. According to current evidence, the use of human chorionic gonadotropin, corticosteroids, intravenous immunoglobulins, and paternal leucocyte transfusion does not improve live birth rates and may potentially be harmful (evidence level 1+). There is no randomized controlled trial to evaluate the use of metformin in patients with PCOS and RM. However, progesterone is used in patients with unexplained RM based on a meta-analysis with three small controlled trials (evidence level 1+). A large prospective double blind trial (progesterone in recurrent miscarriage PROMISE, http://www.medscinet.net/promise) has started in the UK and Netherlands to evaluate the use of natural micronized progesterone in the first trimester and its results are eagerly awaited. The use of aspirin and low-molecular weight heparin in the group of unexplained miscarriages has not shown any benefit (evidence level 1+). Women with unexplained RM have a good chance of live birth with supportive care alone (evidence level 1+). There is dire need for future research in establishing etiological factors, evaluating the effect of therapy and unravelling the mystery of unexplained RM.
Table 1   Key to Classification of Evidence Levels
1+ Well conducted meta-analysis
2++ High quality systematic reviews of case control or cohort studies
3 Non-analytical studies like case reports, case series
4 Expert opinion
Reproduced from RCOG guidelines (www.rcog.org.uk/GTG17recurrentmiscarriage.pdf)
Mala Arora, FRCOG (UK) FICOG FICMCH
Director, Noble IVF Centre, Faridabad 121001, India
Consultant, Fortis La Femme, Greater Kailash,
New Delhi 110048, India