Recurrent Pregnancy Loss (RPL) constitutes for 1-5% of infertile couple and 12-15% of all pregnancies. True incidence of RPL cannot be estimated as most of the losses occur either before they have been clinically recognized or sometimes even before the first missed period. Out of the total pregnancies 70% female fail to report as 50% tend to undergo spontaneous miscarriage before first cycle and 20% are clinically unrecognized. Only 30% are recognized either by clinically, radiological (appearance of intrauterine gestational sac), histopathological or biochemical evaluation (viable levels of b-HCG) Off late, all the existing guidelines have been updated based on evidence. American College Of Obstetricians and Gynaecologists (ACOG) guidelines have been substituted by guidelines released by American Society of Reproductive Medicine (ASRM, 2012). Royal College of Obstetricians and Gynaecologists (RCOG) guidelines for RPL which were first released in 1998 have been updated from time to time with most recent update in 2012 The most recent are the guidelines by European Society of Human Reproduction and Embryology (ESHRE) They were first published in 2006, but later updated and finally replaced by new guidelines in November, 2017. The updated guidelines have even changed the definition of RPL to “two or more pregnancy losses” in place of “three or more pregnancy losses” On-going through these guidelines, it is found that a series of experience, consensus and evidence based investigations and management protocols have been described considering RPL as a single entity. Thus these guidelines leave the treating obstetricians in management dilemma while dealing such cases. It should be understood that they should tailor the diagnostic investigations according to patient and follow management protocols accordingly, thus should stress on “patient–specific approach”.

RISK FACTORS AND MANAGEMENT

Thrombophilia Inherited Thrombophilia: Screening for inherited thrombophilia can only be done for research purposes and not routinely or in women with additional risk factors for thrombophilia (family members with hereditary thrombophilia, or previous VTE) {ESHRE (LEVEL C); ASRM. Low risk thrombophilia (factor V Leiden heterozygous, Prothrombin G20210A heterozygous, Protein C or Protein S deficiency): They are just managed with antepartum surveillance without the need of anticoagulants or Prophylactic low molecular weight heparin (LMWH) or Unfractionated Heparin (UFH). Postpartum anticoagulation is needed in cases with simultaneous risk factors like obesity, prolonged immobilization or first degree relative with history of thrombotic episode in first degree relative or history of Venous thromboembolism in self High risk thrombophilia (Antithrombin deficiency, double heterozygous for Prothrombin gene mutation G20210A and Factor V Leiden mutation homozygous or Prothrombin G20210A mutation homozygous): These cases need to be given prophylactic antepartum anticoagulation therapy along with postpartum anticoagulation therapy with LMWH/UFH for 6 weeks.

Acquired thrombophilia: Antiphospholipid Antibody Syndrome is the most common acquired thrombophilia.

Immunological factors Antinuclear antibodies (ANA) testing can be done only for explanatory purposes. But HLA determination, measurement of anti-HY antibodies, cytokine testing or cytokine polymorphisms, NK cell testing and anti-HLA antibodies testing is not recommended.

Congenital Endometrosis:  Septate, bicornuate and arcuate uterus has been seen to be related with 44.3%, 36% and 25.7% loss of pregnancy (ASRM 2012). Though no randomized control trials are there but few studies have shown beneficial effect of hysteroscopic septum resection (improving Live Birth Rate and reducing pregnancy loss rates) Hysteroscopic resection of septum in septate uterus have shown significant fall in abortion rate by 70% leading to successful pregnancy outcome.

Acquired Abnormalities:  Based on observational studies, in Asherman sydrome/ intrauterine synechiae, hysteroscopic removal of synechiae in women with RPL can be done with care to prevent recurrence. For intramural fibroids not distorting the cavity and endometrial polyp less than 1cm, surgical treatment is not recommended. Infact women with fibroids not distorting the uterine cavity can achieve high live birth rates without intervention.

Endocrine Dysfunction: Any clinical or subclinical endocrine dysfunction calls for investigation and treatment. The symptomssuggestive of endocrine dysfunction are irregular cycles, galactorrhoea, on and off headaches and vision disturbances. Uncontrolled diabetes mellitus, obesity, Luteinising hormone hypersecretion, luteal phase insufficiency and metabolic syndrome are important contributory factors for RPL.

Unexplained rpl:  Half of the cases of recurrent pregnancy loss remain unexplained. In these cases, there may be a contributory role of immunological causes like presence of cytotoxic antibody, absence of maternal blocking antibodies, disturbances in Natural Killer (NK) function and role of inflammatory mediators in and around pregnancy.

Role of progesterone: Progesterone is indispensable for the establishment and continuation of a normal pregnancy. Thus, luteal phase insufficiency has been suggested as a causative factor in RPL. In a study conducted by Stephenson et al. in 2017 vaginal progesterone tend to improve endometrial milieu as was assessed by cyclin-D levels. As per the European guidelines there is insufficient evidence to recommend the use of progesterone to improve live birth rate in women with RPL and luteal phase insufficiency.

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Eliza Grace
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Journal of Basic and Clinical Reproductive Sciences

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