A site of Dr. Pankaj Desai

CHAPTERS CONTRIBUTED

RECURRENT PREGNANCY LOSS

By:

• DR. PANKAJ DESAI

Dean (Students) and Assoc. Professor [VRS]
Dept. Of Obstetrics & Gynecology
Medical College & S. S. G. Hospital
BARODA

• DR. MONA SHROFF

Fmr. Asst. Professor
Dept. Of Obstetrics & Gynecology
Surat Municipal Institute of Medical Education and Research
SURAT

INTRODUCTION:
A pregnancy loss (miscarriage) is defined as the spontaneous demise of a pregnancy before the fetus reaches viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation (20 weeks in few countries with advanced neonatal care infrastructure).Majority of these sporadic losses are due to random numeric chromosomal errors.

Recurrent pregnancy loss (RPL) is one of the most emotionally traumatic, disconcerting and challenging areas in reproductive medicine because the etiology is often unidentified and research on the etiology, evaluation, and management of RPL is often erroneous. Typical methodological shortcomings include failure to adhere to generally accepted criteria for RPL, improper selection of controls, ascertainment bias ,disparate monitoring of cohorts, no exclusion of aneuploid fetuses, lack of stratification for important factors such as number of previous losses, premature termination of study after interim analysis, and excessive post-randomization patient withdrawal [1].

DEFINITION:
The definition of RPL is varied which makes research on evaluation, management and counselling more challenging.

●Two or more failed clinical pregnancies as documented by ultrasonography or histopathologic examination [2].
●Three consecutive pregnancy losses, which are not required to be intrauterine [3-6].

Non-visualized pregnancy losses (biochemical pregnancy losses and/or pregnancies of unknown location) had the same negative impact on future live birth as an intrauterine pregnancy losses. These definitions also do not take into account the effect of maternal age or the gestational age at which the miscarriage occurred.

RPL can be further divided into primary or secondary. Primary RPL refers to pregnancy loss in women who have never carried to viability. Secondary RPL refers to pregnancy loss in a woman who has had a previous live birth. The prognosis for successful pregnancy is better with secondary RPL [7, 8]

Further classification can be Pre-embryonic (<4 weeks), Embryonic (5-9 weeks), and Fetal (>10 weeks)

INCIDENCE:
Approximately 15 percent of pregnant women experience sporadic loss of a clinically recognized pregnancy. Just 2 percent of pregnant women experience two consecutive pregnancy losses and only 0.4 to 1 percent have three consecutive pregnancy losses [9). At very early gestational ages (e.g., at less than 6 weeks of gestation) the risk of miscarriage is 22 to 57 percent versus 15 percent at 6 to 10 weeks and 2 to 3 percent after 10 weeks [10, 11]). The prevalence of miscarriage is higher with increasing maternal age, most likely due to poor oocyte quality (12)

TABLE I: Age and chances of Miscarriage
 

RISK FACTORS AND ETIOLOGY:
RPL is a heterogeneous condition, with numerous causes, diverse treatment options and enormous psychological implications. It is multidisciplinary, involving gynecology, genetics, endocrinology, immunology, pediatrics and internal medicine.

Two major concerns for the physician and the couple are: the cause and the risk of recurrence. The etiology can be identified in less than 50 percent of patients. General etiological categories of RPL include anatomic, immunological, genetic, endocrine, infectious, thrombophilic, male factors and environmental factors. Prognosis is based on the number of preceding pregnancy losses and female age.

Previous pregnancy loss — (13)

Table II: Number of previous Losses and risk of miscarriage
 

Genetic factors
• Parental chromosomal rearrangements [14, 15] in 2–5% of couples with recurrent miscarriage, one of the partners carries a balanced structural chromosomal anomaly, most commonly a balanced reciprocal or Robertsonian translocation less commonly, an inversion. Although carriers of a balanced translocation are usually phenotypically normal, their pregnancies are at increased risk of miscarriage or congenital malformations and/or mental disability secondary to an unbalanced chromosomal arrangement. The risk of miscarriage is influenced by the size and the genetic content of the rearranged chromosomal segments. Balanced translocations are more common in the females likely to result in pregnancy loss if the translocation is of maternal origin.

• Chromosomal abnormalities of the embryo [16-17]. — In couples with RPL aneuploidies account for 30–57% of further miscarriages. The risk of aneuploidy and association with the number of previous miscarriages is contradictory in several studies but mostly as the number of miscarriages increases, the risk of euploid pregnancy loss increases. The relationship between the karyotype of the abortus and risk of RPL requires further study to better define which abnormalities are likely to be recurrent. Recurrent aneuploid losses may be associated, in part, with the older age of the mothers.

The likelihood that RPL is related to parental karyotypic abnormality is higher when:
• Young maternal age at second miscarriage.
• History of three or more miscarriages.
• History of two or more miscarriages in a sibling or the parents of either partner
• A family history of stillbirth or an abnormal live--born.

Immunologic factors:
Antiphospholipid syndrome (APS) (18, 19) — several autoimmune diseases have been linked to poor obstetric outcome, but APS is the only immune condition in which pregnancy loss is a diagnostic criteria for the disease. Five to 15 percent of patients with RPL may have APS compared to 2% in normal obstetric patients. APS is the most important treatable cause of recurrent miscarriage

The mechanisms by which antiphospholipid antibodies cause pregnancy morbidity include inhibition of trophoblastic function and differentiation, activation of complement pathways at the maternal–fetal interface resulting in a local inflammatory response and thrombosis of the uteroplacental vasculature.

Other immunological factors (20-23) — allogeneic factors may cause RPL by a mechanism similar to that of graft rejection in transplant recipients. If the blastocyst is developmentally normal and intact, the embryo is entirely protected by trophoblast cells. In some pregnancies, the blastocyst is genetically deformed and not fully intact so paternally-derived antigens are exposed to the maternal immune system, leading to a rejection response. A secondary immune response would be expected to cause early rejection in cases of RPL.

Alternatively, some mothers with RPL may lack essential components of the networks that provide immunological protection to the embryos, such as appropriate expression of complement regulatory proteins. Deregulation of the normal immune mechanism, although not well defined, probably operates at the maternal-fetal interface and may involve increased activity of uterine natural killer (uNK) cells, which appear to regulate placental and trophoblastic growth, local immunomodulation, and control of trophoblastic invasion.

Thrombophilia and fibrinolytic factors[24-25] — Thrombosis of spiral arteries and the intervillous space on the maternal side of the placenta can impair adequate placental perfusion leading to late fetal loss, FGR, placental abruption, or preeclampsia. A relationship to early pregnancy loss is conflicting and may be restricted to specific thrombophilic defects that have not been fully defined, or the presence of multiple defects. A systematic review of the association between fibrinolytic defects and RPL found a significant association for factor XII deficiency.

Procoagulant microparticles can also contribute to the hypercoagulable state and likely to interfere with successful implantation and fetal growth. These were shown to be associated with early and late unexplained pregnancy loss.

Uterine factors [26-33]. — Acquired and congenital uterine abnormalities are responsible for 10 to 50 percent of RPL.

 Anomalies — Congenital uterine anomalies are present in 10 to 15 percent of women with RPL versus 7 percent of all women but there is a wide variability in diagnosis and inclusion criteria (first/second trimester) Pregnancy loss may be related to impaired uterine distention or abnormal implantation due to decreased vascularity in a septum, increased inflammation, or reduction in sensitivity to steroid hormones with possibly coexisting cervical weakness. The septate uterus is the most common uterine abnormality associated with RPL and the poorest reproductive outcome due mechanisms not clearly understood. The miscarriage rate in women with untreated septum in small observational studies is greater than 60 percent. The longer the septum, the worse the prognosis possibly due to poor blood supply and implantation. Arcuate uteri are more associated with second trimester losses.

 Leiomyoma — Submucous leiomyomas that protrude into the endometrial cavity can impede normal implantation as a result of their position, poor endometrial receptivity of the decidua overlying the myoma, or degeneration with increasing cytokine production but no clear association has been proven.

 Endometrial polyps — there have been no data showing a relationship between endometrial polyps and RPL.

 Intrauterine adhesions — intrauterine adhesions or synechiae lead to pregnancy loss because there is insufficient endometrium to support fetoplacental growth. The main cause of intrauterine adhesions is intrauterine interventions traumatizing the basalis layer, leading to menstrual irregularities (hypomenorrhea, amenorrhea), cyclic pelvic pain, infertility, and RPL.

 Cervical insufficiency — cervical insufficiency could lead to recurrent midtrimester, but not early pregnancy loss. True incidence remains unknown due to essentially a clinical diagnosis and no specific inter-pregnancy test

 Defective endometrial receptivity — Estrogen and progesterone prepare the endometrium for pregnancy. Normal endometrial receptivity allows embryo attachment, implantation, invasion, and development of the placenta. These processes are likely to be disturbed when endometrial receptivity is defective, resulting in unexplained infertility and RPL. Causes of defective endometrial receptivity and biomarkers for evaluation of endometrial receptivity are under research. RPL may be associated with primary receptor defect, uterine stem cell deficiency and enhanced cellular senescence, which then results in abnormal endometrial preparation leading to RPL.

Environmental chemicals and stress (21, 34)—There is no high-quality evidence showing a relationship between RPL and occupational factors, stress, or low level exposure to most environmental chemicals. Chemicals that have been associated with sporadic spontaneous pregnancy loss include anesthetic gases, arsenic, aniline dyes, benzene, ethylene oxide, formaldehyde, pesticides, lead, mercury, and cadmium.

Other
Personal habits [1, 35] — the association between RPL and obesity, smoking, alcohol use, and caffeine consumption is unclear. These factors may act in a dose-dependent fashion or synergistically to increase the rate of sporadic pregnancy loss.

Male factor [36-38]. — There is a trend toward repeated miscarriages in women whose male partner has abnormal sperms (e.g., poor morphology, sperm chromosome aneuploidy, high DFI) advanced paternal age may be a risk factor for miscarriage.

Infection[39-41] — Some infections, such as Toxoplasma gondii, cytomegalovirus, and primary genital herpes, are known to cause sporadic pregnancy loss, but no infectious agent has been proven to cause RPL. The presence of bacterial vaginosis in the first trimester of pregnancy has been reported as a risk factor for second-trimester miscarriage and preterm delivery, but the evidence for an association with first trimester miscarriage is inconsistent.

Decreased ovarian reserve[42] — Women with unexplained RPL have a higher incidence of abnormal ovarian reserve tests, than women with a known cause of RPL Women with RPL and elevated day 3 FSH or low AMH may have poor quality oocytes that fail to develop after fertilization.

Future research [43-45] — A meta-analysis of studies evaluating whether there is an association between cytokine polymorphisms and RPL concluded there was no more than a mild non-significant association. Progesterone receptor gene polymorphisms, as well as other gene polymorphisms, may play a role in RPL.

HISTORY AND PHYSICAL EXAMINATION:
The minimum diagnostic workup of couples with RPL consists of a complete medical, surgical, genetic, and family history and a physical examination.

History — the history should include
• The gestational age and characteristics (e.g., anembryonic pregnancy, live embryo) of all previous pregnancies. Gestational age is important because RPL typically occurs at a similar gestational age in consecutive pregnancies and the most common causes of RPL vary by trimester. E.g. Miscarriages related to chromosomal and endocrine defects tends to occur earlier in gestation than losses due to anatomic or immunological abnormalities; however, there is significant overlap.
• Abnormalities in menstrual cycle length may be due to endocrine dysfunction. Presence of galactorrhea, which also suggests endocrine dysfunction (hyperprolactinemia)
• Does the family history display patterns of disease consistent with a strong genetic influence? Is consanguinity present?
• Was embryonic/fetal cardiac activity ever detected? RPL prior to detection of embryonic cardiac activity also suggests a chromosomal abnormality
• Is there exposure to environmental toxins, which may be lethal to developing embryos?
• Is there a personal/family history of venous or arterial thrombosis suggestive of antiphospholipid syndrome?
• History of uterine instrumentation, which may have caused intrauterine adhesions.
• What information is available from previous laboratory, pathology, and imaging studies?

Physical examination — Physical assessment should include signs of endocrinopathy (e.g., hirsutism, galactorrhea) and pelvic organ abnormalities (e.g., uterine malformation, cervical laceration).
Mental health evaluation — screening for severe stress and depression should be an integral part of the RPL work-up.

EVALUATION:
Parental Karyotype [16, 21, 46] — Karyotyping of couples is part of the evaluation of RPL, despite the low yield of abnormality, cost, and limited prognostic value. The purpose is to detect balanced reciprocal or Robertsonian translocations or mosaicism that could be passed to the fetus unbalanced.

Karyotype of the abortus or products of conception [16, 47] -- Chromosomal abnormalities detectable in parental peripheral blood preparations are an indirect and limited indicator of fetal karyotype vis-a-vis the fetal karyotype.

• Knowledge of the karyotype of the products of conception allows an informed prognosis for a future pregnancy outcome
• To differentiate whether it was sporadic due to abnormal embryo or treatment failure per se and need for further evaluation
• A normal karyotype suggests (but does not prove) a maternal factor as the cause of pregnancy loss, while an abnormal karyotype is usually a sufficient explanation for a nonviable pregnancy
• If the karyotype of the miscarried pregnancy is abnormal(Aneuploidy), there is a better prognosis for the next pregnancy(except unbalanced translocations)

Pitfalls of conventional POC karyotype are: - [48-50].
• Failure to cultivate: Cells from chromosomally abnormal abortuses, are less likely to grow in culture, thereby skewing the results of cohort studies maternal tissue contamination. Array comparative genomic hybridization (aCGH) does not require dividing cells, and therefore can be useful in fetal demise with culture failure.
• Failure to seek other coexisting causes if cytogenetic study reveals chromosomal abnormality.
• Occurrence of non-cytogenetic embryonal abnormalities.
• Type of laboratory and analysis: In some cases, karyotype analysis of the abortus indicates a normal chromosomal pattern, but more detailed Acgh demonstrates major abnormalities.
• Need for surgical evacuation.

Fig I: Flow Chart for Evaluation of Chromosomal Anomalies in RPL

Uterine assessment [51-57].— Anatomic causes of RPL are usually diagnosed using hysterosalpingography (HSG) , sonohysterography.(SHG) or 3D ultrasound(USG) .3D USG and SHG are more accurate than HSG in delineating internal contours along with outer. Ultrasound (especially 3D) is useful for making the diagnosis of a septate/arcuate/bicornuate uterus ,renal abnormalities associated, the presence and location of uterine myomas and, in pregnancy, the possibility of cervical insufficiency and assessment of fetal viability.

Hysteroscopy, laparoscopy, or magnetic resonance imaging (MRI) due to invasiveness and /or cost, are used as second-line tests when additional information or therapeutic intervention is required.

Anticardiolipin antibodies and lupus anticoagulant [58-60]— The minimum immunology work-up for women with RPL is measurement of anticardiolipin antibody (IgG and IgM) and lupus anticoagulant, done twice, six to eight weeks apart, because a low to mid positive level can be due to viral illness and revert to normal. The anticardiolipin antibody titre is considered elevated if medium or high titres of both IgG and IgM isotypes are present in blood. The detection of the lupus anticoagulant is generally based upon an activated partial thromboplastin time, kaolin plasma clotting time, or dilute Russell viper venom test time

Table III: Clinical and Laboratory Findings in Reproductive Autoimmune Syndrome
 

Thyroid function [61-63] — Thyroid function should be assessed if positive history or symptoms. Screening asymptomatic women for subclinical thyroid dysfunction is controversial but recommended since there is evidence of an increased risk of miscarriage in women with subclinical hypothyroidism and in euthyroid women with thyroid peroxidase (TPO) antibodies.

Hypercoagulable state —Evaluation for an inherited thrombophilia can be considered in rare cases of recurrent, unexplained late fetal loss (after nine weeks of gestation) associated with evidence of placental ischemia and infarction and maternal vessel thrombosis.

Culture and serology [21]. — Routine cervical cultures are not useful in the evaluation of RPL among otherwise healthy women.

Autoantibodies and immune function [64-74]. — Many studies have reported the presence of autoantibodies in women with RPL .The pregnancy outcome of women with and without antinuclear antibody (ANA) is the same hence routine testing for ANA not recommended. Peripheral blood NK cells are phenotypically and functionally different from uterine NK (uNK) cells. There is no clear evidence that altered peripheral blood NK cells are related to recurrent miscarriage. Examining the relationship between uNK cell numbers and future pregnancy outcome remains a research field. Selection of appropriate tests for diagnosis of immune-based RPL (HLA typing, mixed lymphocytotoxic antibody tests, CD56+ cells and cytokine polymorphism) also requires further investigation and validation.

Screening for diabetes — limited to women with clinical manifestations of the disease.

Progesterone level [75] — Single or multiple serum progesterone levels are not predictive of future pregnancy outcome.

Endometrial biopsy [76] for luteal phase defect is not predictive of fertility status and not recommended.

MANAGEMENT:
RPL is an inhomogeneous condition and hence specific guidelines cannot be applicable in general to all. The development of an optimal investigation and management protocol depends on reaching a correct diagnosis of etiology and directing specific treatment. Therapeutic recommendations are largely based upon clinical experience and data from observational studies. The overall live birth rates after normal and abnormal diagnostic evaluations for RPL are 77 and 71 percent, respectively [77].In all cases, psychological support is vital[78,79].

• PARENTAL KARYOTYPE ABNORMALITY [80-85] — Couples in whom chromosomal abnormalities are discovered in one or either partners or the abortus are generally referred for genetic counselling. They should receive information regarding the probability of having a chromosomally normal or abnormal conception in the future... The magnitude of these risks varies according to the specific chromosomal abnormality and the sex of the carrier parent.

Management options for these couples
• Prenatal genetic studies (amniocentesis or chorionic villus sampling)
• In vitro fertilization (IVF) with preimplantation genetic screening(PGT-A) Gamete donation (egg or sperm)
• Adoption

UTERINE ABNORMALITIES [86-91] — Uterine abnormalities are managed surgically (hysteroscopically) if correctable cause, such as a uterine septum, intrauterine adhesions, or submucosal myoma.

There are no randomized trials evaluating pregnancy outcome after surgical correction of uterine anomalies. In a classic observational series, repair of septate uteri reduced the abortion rate from 84 percent (before surgery) to 12 percent (after surgery) using patients as their own controls The value of prophylactic cervical cerclage in women with a uterine anomaly, but no history of second trimester pregnancy loss, is controversial. Cervical cerclage is associated with potential hazards related to the surgery and the risk of stimulating uterine contractions and should be considered only in women who are likely to benefit. Women with a history of second-trimester miscarriage and suspected cervical weakness should be monitored closely by serial cervical scans. In women with a singleton pregnancy and a history of one second-trimester miscarriage, an ultrasound-indicated cerclage should be offered if a cervical length of 25 mm or less is detected by transvaginal scan before 24 weeks of gestation. A gestational carrier (surrogate) is an option for women with irreparable uterine defects.

ANTIPHOSPHOLIPID SYNDROME [92]. — Aspirin and heparin improve pregnancy outcome in women with APS with RPL. LMWH appear to have additional qualities in preventing adverse pregnancy outcome by their anti-inflammatory and proangiogenic properties.

SUSPECTED IMMUNOLOGIC DYSFUNCTION [93-101]— No alloimmune mechanism has been proven to cause RPL .Immunologic treatments for unexplained RPL are not effective, and may even be harmful as proven in systematic reviews and should use only in the setting of a clinical trial regulated by an Institutional Review Board.

• Paternal cell immunization
• Third party donor cell immunization
• Trophoblast membrane infusion
• Intravenous immunoglobulins (IV Ig)
• Glucocorticoids— Glucocorticoids have several anti-inflammatory effects, including suppression of NK cell activity, but do not appear to be effective for preventing RPL. Steroids for treatment of RPL has been abandoned because of uncertain efficacy and increase in complications, such as preterm premature rupture of membranes, gestational diabetes, and maternal hypertension

THYROID DYSFUNCTION AND DIABETES MELLITUS [102,103]. —
• Women with overt thyroid disease or diabetes mellitus should be treated, as medically appropriate, since these disorders can result in serious sequelae.
• Women with elevated serum thyroid peroxidase antibody concentrations are at high risk of developing hypothyroidism in the first trimester and autoimmune thyroiditis postpartum, and should be followed appropriately
• Euthyroid women with high serum thyroid peroxidase antibody concentrations may benefit from treatment with levothyroxine (50 mcg daily) during pregnancy as it may reduce the risk of miscarriage and preterm birth although more trials are required.

POLYCYSTIC OVARY SYNDROME [104]. — The miscarriage rate in women with polycystic ovary syndrome (PCOS) is 20 to 40 percent, higher than the baseline rate in the general obstetric population Metformin has been used in women with PCOS to decrease this risk, but the effectiveness of this approach is unproven.

HYPERPROLACTINEMIA [105]. — Normal levels of prolactin may play a significant role in maintaining early pregnancy. A study of 64 hyperprolactinemic women with RPL randomly assigned to bromocriptine therapy or no bromocriptine found treatment was associated with a significantly higher rate of successful pregnancy (86 versus 52 percent Prolactin levels during early pregnancy were significantly greater in women who miscarried.

THROMBOPHILIA — Anticoagulation of women with certain inherited thrombophilias may improve maternal outcome (e.g., prevention of venous thromboembolism), but controversial in RPL.

TREATMENT OPTIONS FOR UNEXPLAINED RPL — [106]. A significant proportion of cases of RPL remain unexplained despite detailed investigation. These women can be reassured that the prognosis for a successful future pregnancy with supportive care alone is almost 75%.

Several unproven treatments are often offered for unexplained RPL
• Lifestyle modification — Eliminating use of tobacco products, alcohol, and caffeine and reduction in body mass index (for obese women) may improve chances of live birth

• Progesterone [106-110] — Therapeutic effect of progesterone may be related to immune modulation it is possible that earlier initiation of progesterone, such as during the luteal phase, may improve outcome as shown by small studies.

Older metaanalysis including smaller heterogeneous studies confounded by fetal factors showed a beneficial effect but a large trial comparing first-trimester vaginal progesterone therapy or placebo showed no significant difference

• Human menopausal gonadotropin [111] — an observational study reported that controlled ovarian stimulation with human menopausal gonadotropin (hMG) appeared effective for endometrial defects in women with RPL likely by correction of a luteal phase defect or a thicker endometrium, leading to a better implantation.

• Human chorionic gonadotropin (118) — HCG is critical to early pregnancy, ensuring active maintenance of steroid production from the corpus luteum and for endometrial preparation to facilitate implantation. Although HCG has shown to improve LBR in systematic reviews but there is insufficient evidence to recommend the use of hCG to prevent pregnancy loss in women with a history of unexplained RPL. However hCG also had detrimental effects on decidualization in vitro. There are evidences both for and against its use, so it should be offered to women only within a research trial. Large randomized controlled trials to identify subgroups which are likely to benefit are needed.

• In vitro fertilization and preimplantation genetic diagnosis (PGT-A) [112-116]. — Studies evaluating the value of in vitro fertilization (IVF) in women with RPL have yielded mixed results. Embryos of women with unexplained RPL have a higher incidence of aneuploidy. In a retrospective cohort study of 300 women with RPL, the pregnancy, live birth, and miscarriage rates were similar for women who underwent IVF with preimplantation screening (PGS) and women who elected expectant management other drawbacks include need for IVF, cost involved and issues related to PGT-A like mosaicism.

• Oocyte donation [117] — Poor quality oocytes may be responsible for 25 percent of pregnancy losses Ovum donation can overcome this problem and has been associated with a live birth rate of 88 percent in women with RPL.

• Surrogacy — a gestational carrier may be considered in RPL not associated with recurrent embryonic aneuploidy or obvious intrinsic gamete factors (e.g., single gene defects, diminished oocyte and embryo quality).

FUTURE PREGNANCY PROGNOSIS
• Continued pregnancy loss [119,120] — the greatest risk of recurrent loss occurs during the period up to the time of previous miscarriage. The likelihood of successful pregnancy in women with a history of recurrent pregnancy loss (RPL) was 67-75 percent at 5 years. Increasing maternal age and number of miscarriages are associated with a poorer prognosis.

• Other obstetric issues. [121,122].— Women with a history of RPL who become pregnant may be at higher risk for developing fetal growth restriction and premature delivery, but not for gestational hypertension or diabetes

Table IV: Comparison of Guidelines for the Investigation and Treatment of Recurrent Pregnancy Loss
 

ASRM: American Society of Reproductive Medicine; RCOG: Royal College of Obstetricians; ESHRE: European Society of Human Reproduction and Embryology

SUMMARY AND RECOMMENDATIONS
●Recurrent pregnancy loss (RPL) refers to the occurrence of three or more consecutive losses of clinically recognized pregnancies prior to the 20th week of gestation (excluding ectopic, molar, and biochemical pregnancies). It may be primary or secondary.
●0.4 to 1 percent of women have three consecutive pregnancy losses.
● Chromosomal abnormalities are the most common cause of sporadic early pregnancy loss (50 %). 3 to 5 % of couples with RPL have a major chromosomal rearrangement (vs. 0.7 percent of the general population); usually a balanced translocation.
●Uterine abnormalities, both acquired and congenital have been reported to be responsible for 10 to 50 percent of RPL in small studies.
●Pregnancy loss is one of the diagnostic criteria for antiphospholipid syndrome.
●Endocrine factors may account for some cases of RPL.
●There is no strong evidence showing a relationship between RPL and occupational factors, stress, or mild exposure to most environmental chemicals.
●RPL typically occurs at a similar gestational age in consecutive pregnancies. The recurrence risk increases as gestational age at the time of loss increases.
●Evaluation of women for RPL may be recommended after two or three consecutive miscarriages depending on other factors like age.
●A detailed history and physical examination should guide the clinician regarding probable etiology and tailor diagnostic investigations and management in RPL.

●The following initial evaluation may be recommended as per need:
•Sonohysterography/3D USG for assessment of uterine abnormalities
•Anticardiolipin antibody (IgG and IgM) titre and lupus anticoagulant performed twice, six to eight weeks apart
•Thyroid stimulating hormone (TSH) and thyroid peroxidase antibodies
•Parental karyotype and karyotype of the abortus if the above examinations are normal.
Additional testing depends upon the diagnosis suggested by the history, physical examination, and laboratory results.
• Couples with chromosomal abnormalities in one or both partners or the abortus are generally referred for genetic counselling.
• Correctable uterine abnormalities such as a uterine septum or intrauterine adhesions may be managed hysteroscopically.
• For women with unexplained RPL, there is not enough evidence that use of vaginal progesterone or HCG improves live birth rates.
• Immunotherapy or glucocorticoids are not effective for RPL and may be harmful.
• Women with hyperprolactinemia and RPL should be treated.
• For unexplained RPL low risk, simple, and less expensive interventions should be preferred over more complex and expensive options.
• Women with a history of RPL who become pregnant may be at higher risk for developing fetal growth restriction and premature delivery.

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