Embryonic or foetal termination is the most common outcome of conception and observed as nature’s quality control for selecting genetically normal offspring. (Sudhir et al.
, 2016). Miscarriage is perhaps the most common obstetric complication of human conceptions (Silver and Warren 2006). Miscarriage is the spontaneous pregnancy loss without medical or mechanical means before the fetus is enough developed to survive or early pregnancy loss before 20th week of gestation, or 139 days (Li et al., 2014).The spontaneous miscarriage in India was reported to be approximately 10 % (Patki and Chauhan 2016). However, the recent studies revealed that the occurrence of spontaneous miscarriage among the Indian women is 32% (Patki and Chauhan 2016).
The comparative prevalence of recurrent miscarriages is much lower than spontaneous miscarriages, (Ford and Schust 2009). Recurrent miscarriage is classically defined as the occurrence of three or more consecutive losses of clinical pregnancies prior to the 20th week of gestation. However, this definition is variable according to many investigators. The American Society for Reproductive Medicine defines recurrent miscarriage as two or more failed pregnancies (Practice Committee of the American Society for Reproductive Medicine 2012). Clinically apparent recurrent miscarriage among the Indian women is observed to be 7.46 % (Patk and Chauhan 2016).The well-known causes of RPL include genetic abnormalities, immunological factors, anatomic defects, endocrinal factors, certain thrombophilias and infections. The specific treatment improves pregnancy outcome.
The identifiable causes accounted for 53% cases. Anatomical defects being commonest accounted for 21%, endocrinal factors for 20% and genetic factors contribute to 1% of recurrent miscarriages. They offered as first trimester abortions and history of Down’s syndrome.
Immunological factors accounted for 7% and Antiphospholipid syndrome (APS or APLA) contribute to 5% of recurrent miscarriages. They offered as late first trimester abortion and late second trimester abortion. Systemic lupus erythematosus accounted for 2% and infection for 1%.Medical causes accounted for 3% of recurrent miscarriages in women with history of chronic hypertension in second trimester abortion. However, 47% of RPL are still unexplained. (Singh A et al., 2017).
The frequency of chromosomal aberrations among Kashmiri couples with repeated fetal loss has been reported to be about 7.75% including numerical as well as structural chromosomal abnormalities. Males (2.
12%) as well as females (5.63%) had chromosomal aberrations with balanced translocations (4.22%), duplications (0.70%), deletions (0.70%) and inversions (2.11%) (Zargar et al., 2015). Factor V Leiden (FVL) G1691A and prothrombin G20210A mutations are not associated with recurrent miscarriage in Kashmiri women population (Mahrukh et al.
, 2017). Maternal age is identified as independent risk factor for miscarriage (Patk and Chauhan 2016). Indian women with 31–49 years age at ?rst birth are found more vulnerable for spontaneous miscarriage than those with less age at ?rst birth (Patki and Chauhan 2016). The incidence of miscarriage is reported to be 10 % in women aged 20–24 years and 51 % in women aged 40–44 years (Larsen et al., 2013).
A statistically signi?cant association has been found between age and spontaneous miscarriage. With the increased age of patients the incidence of more than or equal to three spontaneous miscarriages increases. Besides, the possibility of a subsequent miscarriage after the ?rst, second, and third miscarriage also increases. The percentage of patients with a subsequent miscarriage after the ?rst, second, and third miscarriage is reported as 24.97%, 34.04%, and 21.
88 %, respectively (Patki and Chauhan 2016).However, earlier studies reported that the risk of a subsequent miscarriage after one spontaneous miscarriage is approximately 22–25 %; after two spontaneous miscarriages, the risk of another is 25 %; and after three spontaneous miscarriages, this risk further increases to 30 % (Simpson and Carson 2013).Human reproduction is characterized by its inefficiency as large proportion of all conceptions fails to reach a live birth. Approximately 15-20% of all clinically recognized pregnancies worldwide result in spontaneous loss (Larsen et al., 2013; Hooker et al.
, 2014) and many pregnancies are lost before a woman realizes that she is pregnant (Ford and Schust 2009). The total pregnancy loss including preclinical cases is estimated to be 30–50% (Stephenson 2011). Approximately 5% of couples trying to conceive have two consecutive miscarriages and only 1% experience three or more (Bulletti et al., 1996). Recurrent pregnancy loss (RPL) is defined by more than three consecutive miscarriages prior to 20 gestational weeks (Ford and Schust 2009) but now-a-days, even two consecutive miscarriages are considered for further evaluations (Jaslow and Kutteh 2013). The risk of subsequent miscarriage after the ?rst two, three and four successive pregnancy losses is 30%, 33 % and 40% respectively, in women without a history of live birth (Ford and Schust 2009). The prevalence of recurrent pregnancy losses including only clinical miscarriages occurring before 21 weeks of gestation is 0.
8–1.4 %. However, the prevalence of RPL taken as three consecutive pregnancy loses is high if biochemical losses are also included (Larsen et al., 2013).
The recognized potential etiologies of recurrent pregnancy loss include genetic factors, uterine anatomical defects, infection, endocrine, and immunological factors. The majority of early pregnancy losses (50%–60%) are the outcome of chromosomal abnormalities, which can be of parental origin, or arise de novo in the embryo from parents with normal chromosomes. Balanced translocation are the most common parental abnormalities found in 2%–4% RPL cases as compared to 0.
7% in the general population. Embryonic aneuploidy is established as the most common cause of early pregnancy loss. Uterine anomalies and chronic endometritis are reportedly found in up to 19% and 10%–27% women with RPL respectively.
The prevalence of Antiphospholipid antibody syndrome (APS or APLA) in women with RPL varies however, it is generally accepted to be 5%–20%. Polycystic ovarian syndrome is associated with an increased risk of miscarriage (Hachem et al., 2017). Many studies have shown a relationship between inherited thrombophilia and pregnancy failure and complications (Lissalde?Lavigne et al., 2005).
Maternal age and the number of prior spontaneous miscarriages are also associated with recurrent miscarriages (Li et al., 2002). Although a spectrum of causes is known for recurrent miscarriage but still etiology behind approximately 50% of RPL is unidentified. Such RPL is defined as unexplained recurrent miscarriage (Christiansen et al., 2008).
However, the chances for a future successful pregnancy in couples with unexplained recurrent miscarriage could be as high as 50%–70% and depend mostly on maternal age and the number of previous losses (Lund et al., 2012; Kling et al., 2016). Preferably, epidemiological studies of recurrent pregnancy loss should begin after three or more losses whereas clinical evaluation may be carried out subsequent to a second miscarriage (Bulletti et al., 1996). Immune dysregulation has been proposed as a possible etiology in unexplained recurrent miscarriage. Indeed, maternal immune tolerance of the fetus is essential for normal implantation and pregnancy, and is characterized by an induction of regulatory T cells and an anti-inflammatory Th-2 profile. Thus, a disruption of the normal CD4 T-helper cell (Th) and uterine natural killer (NK) activity, and a Th imbalance in the endometrium could lead to implantation failure and pregnancy loss.
(Mekinian et al.,2016). It is well recognized that at maternal-fetal interface equilibrium exists between Th1/ Th2 cells and the regulatory T (Treg)/Th17 cells where these cells secrete cytokines including IL-1?, IL-4, IL-10 and IL-17. These cytokines develop a complex network that maintains the pregnancy. An imbalance in these cytokines may result in spontaneous abortion (LeMaoult et al 2005). Recurrent pregnancy loss is associated with elevated level of pro-in?ammatory cytokine TNF-?. Recurrent pregnancy loss may be cured by blocking TNF-?. (Carpentier et al.
, 2011). New research studies correlate IL-23 and IL-17 with the pathogenesis of unexplained recurrent miscarriage (Sai?, et al., 2014).