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REVIEW ARTICLE
Recurrent Pregnancy Loss: A Tragic Reproductive Failure
*Mst. Rashida Begum1, Mariya Ehsan2, Mst. Sahina Begum3,
Hosne Ara Baby4, Maruf Siddiqui5, Suha Jesmin6
1Prof. Mst. Rashida Begum (Prof. AKMMC), 2Dr. Mariya Ehsan (Medical Officer ICRC) 3Dr. Mst. Sahina Begum (Embryologist ICRC), 4Prof. Hosne Ara Baby (Prof. AKMMC) 5Dr. Maruf Siddiqui (Assist. Prof. AKMMC), 6Dr. Suha Jesmin (Assist. Prof. AKMMC) *Corresponding Author
ABSTRACT
Three or more consecutive pregnancy losses are considered as recurrent pregnancy loss (RPL). About 1% of all pregnant women face this distressing problem and o.5% to 5% of spontaneous abortions are recurrent. Genetic, environmental, anatomic, hormonal, infectious and immunological factors are associated with RPL. Sometimes several factors might simultaneously be responsible for RPL. So diagnostic work up is to be extended. Life style changes, hormonal supplementation, anticoagulant and immunotherapy and surgical correction of certain uterine anatomic defects might help the couple to be parent. Genetic problem can be overcome by pre-implantation genetic diagnosis (PGD) and transferring good healthy embryos. Key Words: Recurrent Pregnancy Loss (RPL), Pre Implantation Genetic Diagnosis (PGD)

Introduction
increases with maternal age and may be as high as 50% to 80% for women who are older than 40 Recurrent pregnancy loss is (RPL) defined as three years5,6. In a few cases abnormality may be or more consecutive losses of pregnancy and this inherited and is responsible for about 2% to 4% of distressing problem affects approximately 1% of RPL. Although most frequent abnormality is all women. Infertility and spontaneous abortion or balanced translocation (3% to 5%), microdeletion, miscarriage are two forms of reproductive failure. Robertsonian translocations and structural Infertility affects about 10% to 15% of couples. chromosomal abnormality have also been detected. On the other hand the risk of abortion has been It can be of maternal and paternal origin. confirmed is about 15% to 20%. About 0.5% to
5% of spontaneous abortions are recurrent Toxins and Environmental Factors
miscarriage1,2. There is some debate about the
definition of RPL. Some feel that two rather than
Heavy alcohol consumption has been reported to three losses are sufficient to define RPL. So in be associated with an increased risk of miscarriage every day practice evaluation is usually initiated , though other studies have not shown the same. after the loss of two pregnancies specially if they Smoking has also been associated with RPL, have preceded by infertility treatment. which is positively related to the number of cigarette3,4. Caffeine and cocaine also have been Aetiology of Recurrent pregnancy Loss
linked to pregnancy loss10. Stress has also been shown to be associated with higher pregnancy loss Genetic factors
rate11. Body weight both high and low are Chromosomal abnormalities of the embryo are the associated with adverse pregnancy outcome. The most common cause of sporadic miscarriage. More risk of pregnancy loss is high in women with than half of early losses occur as the result of certain chronic maternal diseases e.g. liver, renal chromosomal abnormalities3-6. Most abnormalities and autoimmune diseases. Some medications such arise from errors in meiosis and advancing as nonsteroidal anti-inflammatory drugs and maternal age is associated with an increased risk of aspirin are linked to pregnancy loss12. Certain autosomal trisomy7,8. It occurs as a result of environmental effects like radiation and sporadic mutation and not inherited from the environmental toxin can also influence the parents. This mutation and rate of aneuploidy outcome of pregnancy13. AKMMC J 2011; 2(2): 29-35 34 █ AKMMC J 2011; 2(2) Mst Rashida Begum, Maryia Ehasan, Mst Sahina Begum et al Uterine defects
evidences that these organisms are associated with RPL are lacking. Anatomic defects can be identified in about 3% to 5% of women with RPL14,15. Uterine cavity can be Endocrine dysfunction
distorted by congenital and acquired defects. Some Hormonal problems can disrupt the implantation of these defects are associated with pregnancy process and the development of early embryo17. loss, but others are not. Septate uterus is a frequent Abnormal folliculogenesis due to effect of cause of loss where as arcuate uterus is associated different hormonal abnormality leads to with normal progression of a pregnancy. In septate development of inadequate corpus luteum and uterus the embryo supposedly implants over the luteal phase defect causing early abortions. Poorly septum which is poorly vascularized leads to controlled or uncontrolled diabetes mellitus do arrested development and early pregnancy failure. have an increased incidence of early pregnancy Both less nutrients due to reduced blood supply loss18 but there is no evidence that well controlled and reduced space available for the growing diabetes mellitus is associated with increased risk embryo is responsible for high loss rate. of early pregnancy loss19,20. Similarly severe Other abnormalities such as unicornuate or thyroid dysfunction is often cited as aetiological bicornuate uterus cause late second trimester loss factor for recurrent pregnancy loss21,22 but no and premature labour due to reduced volume of the direct evidence exists. It has been reported that the uterine cavity16. Diethyle stilboestral (DES) presence of thyroid autoantibodies is associated exposure is associated with uterine and cervical with an increased risk of miscarriage23, 24. hypoplasia causes second trimester pregnancy loss. Luteal phase defect
The most common acquired anomaly of the uterus It is a common finding in patients of recurrent is fibroids particularly beneath the endometrium. pregnancy loss. Inappropriate corpus luteal function According to location fibroids are classified as causes decreased release of progesterone and submucus, intramural and subserous. Submucus inadequate endometrial preparation. Progesterone fibroid located beneath the muscle layer, which plays an important role during implantation and deforms the cavity and endometrium covering pregnancy. Progesterone is required to induce them is usually thin and inadequate for normal secretory changes that prepare the endometrium implantation and responsible for RPL. Intramural for the arriving embryo. Besides progesterone also fibroid when distort the cavity causes pregnancy has an immunomodulatory effect. It stimulates the loss. So, location, size, and number of the fibroids production of progesterone induced blocking make a difference in this case. Larger and multiple factor that suppresses natural killer cell activity fibroids are usually associated with adverse and increases the Th-2 response. This suppressive pregnancy outcome. effect favours implantation and the progress of early development25. Hyperprolactinemia has often Benign hyperplasia of endometrium called been diagnosed among women with recurrent endometrial polyp acts as foreign body within the pregnancy loss. In these cases the luteal phase is endometrial cavity induce chronic inflammatory shortened. Prolactin may interfere the normal changes that makes endometrium unfavourable for activity of the developing placenta and therefore pregnancy. Fibroid which protrudes into the cavity could affect the progress of pregnancy. causes same as endometrial polyp. Intrauterine
synachea may develop as a result of surgical Hypersecretion of LH
procedure like curettage or severe endometrities
There is now good evidence that polycystic interfere with normal implantation process and can ovarian syndrome (PCOS) is associated with both be responsible for pregnancy loss7. subfertility and early pregnancy loss26-28. The link between PCOS and early pregnancy loss would Infections
appear to be hypersecretion of luteinizing hormone The role of viral and bacterial infections in the (LH). The mechanism by which LH exerts an pathogenesis of recurrent abortion is controversial. adverse effect is not clear. But it has been Maternal infections with TORCH, mycoplasma, postulated that raised follicular phase LH may Listeria can cause sporadic pregnancy loss but cause premature resumption of meiosis, has lead to Pregnancy Loss: A Tragic Reproductive Failure the concept of the production of physiologically circulating APAs are found in association with aged oocyts13,29. LH may cause endometrial defect recurrent pregnancy loss, arterial and venous leading to suboptimal implantation and poor thrombosis and thrombocytopenia in the absence reproductive outcome. LH causes increased of overt autoimmune disease is now well –secretion of androgen from the ovary. Elevated documentated33-35. androgen levels are associated with early Haematological causes
pregnancy loss30,31. Hypersecretion of LH may therefore act both directly on the oocyte or on the Intensive angiogenesis,coagulation and fibrinolysis endometrium or both and indirectly through accompany implantation. Coagulation and increasing secretion of androgen. fibrinolysis are simultaneously ongoing process in the body. A healthy balance is disrupted during Immunological causes
pregnancy. Occlusion of the placental vessels may Autoimmune causes
results, which could lead to spontaneous abortion. It has been suggested that a necessary prerequisite Diagnosis
for successful pregnancy involves maternal Several factors might simultaneously be recognition of the embryo leading to protective responsible for the recurrent reproductive failure. immune response. The implanting embryo inherits So diagnostic work-up has to extended. Detailed its antigens from both mother and the father. The history about previous pregnancy losses may yield paternal antigens are identified as foreign by important clues. The etiology differs in the first maternal immune system. In order to prevent the and second trimester. Thorough physical rejection of the pregnancy this immune response examination can reveal important factors. Height, needs to be modulated. It has been proposed that in weight need to be measured, signs of otherwise unexplained pregnancy loss dysregulation hyperandrogenism should be looked for and breast of the immune system could be responsible for the should be checked for the presence of factor. Many cytokines that modify the immune galactorrhoea. The pelvic examination can identify response are produced during pregnancy. Some of congenital and acquired genital tract lesions like then favor pregnancy like Th2,11,3, 11,4, 11,5, 10-11, 11-13 vaginal septum, duplicated cervix, uterine and other are toxic to it like Th1, TNF alpha, TNF abnormality and adnexal masses. beta, gamma interferon, 11-2. A shift to Th1
dominance increases the risk for pregnancy loss. Investigations
Th1 cytokines may directly damage the placenta Imaging studies
and possibly activate immune cells that induce reaction7,23. Natural killer cells can be found in Imaging studies play an important role in large numbers in the uterus. They are thought to diagnostic work up. A transvaginal ultraso alter the humoral response to pregnancy and nography is usually the primary investigative tool induce the Th1 dominance that would lead to for pelvic pathologies. It can evaluate size and pregnancy loss8. position of the uterus, fibroids and adenomyoma of the uterus, duplicate cervix, uterine septum, Autoimmune disease
unicrnuate and bicornuate uterus, endometrial The association between raised circulating polyps and scarring of the endometrium. Saline antiphospholipid antibodies (APAs) and recurrent infusion into the cavity can improves the pregnancy loss is now well established. The diagnostic accuracy of the ultrasound by creating a knowledge that some women with systemic lupus filling defect by polyps and fibroids in the uterus erythematosus have a poor reproductive outcome and lack of distension helps to diagnose the led to the discovery that the presence of circulating scarring due to Asherman's syndrome. APAs is a marker for the poor outcome of X-ray like hysterosalpingography (HSG) also can pregnancy32. APAs are immunoglobulin that bind identify the filing defects, scarring and septum. strongly to negatively charged membrane Cervical canal length and competency can be phospholipids. The most common antibodies are identified by HSG. Funneling of cervical canal anticardiolipin antibodies and lupus anticoagulant indicates cervical incompetency which causes 2nd though other types of APA exist. The primary trimester abortions. antiphospholipid syndrome in which raised 34 █ AKMMC J 2011; 2(2) Mst Rashida Begum, Maryia Ehasan, Mst Sahina Begum et al Hysteroscopy offers a more precise evaluation of pregnancy but which will not give any benefit to the cavity. During the procedure intracavitary subsequent pregnancy management.
structures can be directly visualized. Though Treatment
hysteroscopy alone cannot differentiate between a
septate and a bicornuate uterus. Laparoscopy is Life style changes
required to complete the evaluation. Laparoscopy
Life style changes might have some role in the allows to assess the outer surface of the uterus and management of recurrent pregnancy loss. Weight other pelvic structures. Magnetic resonance should be as close to the normal range as possible. imaging (MRI) is an accurate non-invasive Dieting and exercise may be an appropriate technique for evaluation of uterine anomalies but recommendation for PCOS patients. Smoking and expense limited its use. Intravenous pylography is other harmful habit should be given up. Caffine recommended if congenital anomaly of uterus is intake should be reduced as much as possible. diagnosed as congenital anomaly of the uterus is Pregnant women need to avoid occupational associated with urinary tract abnormality. exposure (radiation) and exposure to Laboratory Testing
environmental toxins (teratogen medications). Laboratory investigations like hormonal, Medical treatment
hematologic, genetic and immunologic testing are
required to identify the specific causes.
Hormonal treatment
Hormones
Diabetes, hypothyroidism and hyperprolactinaemia should be treated by insulin, thyroxin and Hormonal testing is used to evaluate ovarian bromocriptine. Bromocriptine should be admini function and to screen endocrinological abnormalities that might influence follicu stered after dinner to avoid gastrointestinal upset logenesis, corpus luteum function, implantation and hypotension. Cabergolin is another drug for and preservation of pregnancy. Ovarian reserve the management of hyperprolactinaemia, which test is done by measuring D3 FSH and E2. Along requires less frequent doses. with these LH, prolactin and thyroid hormone should be tested. If prolactin level is raised MRI of For inadequate luteal phase ovulation induction is pituitary gland is require to rule out pituitary an option to produce multiple follicles and more lesions. Serum progesterone on D21 gives clue progesterone. Ovulation induction also has an about corpus luteum defect. impact on endometrial development. Another Blood sugar two hours postparandial is to be done. option is to supplement progesterone to support If raised or there is family history of diabetes the luteal phase. mellitus OGTT is to be done. Vaginal or intramuscular preparations are used and The diagnosis of antiphospholipid syndrome started in the luteal phase when pregnancy follows. requires antibody testing on two separate Progesterone is continued up to 12 weeks of occasions at least 6 weeks apart. IgG or IgM gestation. A meta-analysis evaluating progesterone anticardiolipin antibodies need to be present in supplementation for the prevention of miscarriage medium or high titer and the test for lupus anticoagulant needs to be positive. failed to find a significant benefit. When the analysis was limited to those studies involving Though immunological factors are responsible for women with recurrent loss, however, there was a repeated abortions, routine use of immunological significant reduction in the loss rate37. testing (eg natural killer cells, interleukins, TNF alpha) is not recommended unless the patient Metformin have been widely used for the participates in a clinical study36, 24. management of women with PCOS. When Finally a karyotype of both partner should be done continued during pregnancy it has been associated to exclude any chromosomal defects in either with a lower rate of spontaneous abortions. partner. Karyotype of product of conception also can give clue of chromosomal defect of that Pregnancy Loss: A Tragic Reproductive Failure is achieved with the latter procedures, though thermal injury might lead to scar formation. Antiphospholipid syndrome is a cause for recurrent Reproductive outcome significantly improves after abortion. It causes thrombosis of placental hysteroscopic resection of septum (76% after vasculature leads to reduced placental circulation. surgery vs. 20% before surgery)45. Polyps are Aspirin is used to prevent thrombocyte aggregation removed by forceps or by gentle curettage and sub and thromboxane release. Though aspirin alone has mucous fibroids are usually respected during not been shown to improve outcome among women hysteroscopy. Intramural and sub serous fibroids with early recurrent pregnancy loss38. For women are removed via abdominal approach. The with antophospholipid antibodies but no previous laparoscopic approach gained popularity more history of thrombosis, prophylactic heparin use is recently. Bicornuate uterus is usually associated recommended. Usual dose is 5000 IU with problem during the third trimester. So in unfractionated heparin twice a day or 30-40 mg much selected cases with recurrent 2nd or third low molecular weight heparin daily in combination trimester abortion bicornuate uterus is to be with 81 mg aspirin a day. Patients with a history of thrombosis need to be anticoagulated. Women with Genetic screening
hyperhomocysteinemia require vitamin B and folic
acid supplementation. The patients with Preimplantation genetic diagnosis (PGD) allows
genetic screening of the embryos before hyperhomocystineinemia and history of thrombosis transferring during IVF. Several research groups should be anticoagulated. Those with inherited have assessed whether PGD is beneficial for thrombophilias and recurrent loss require women with recurrent pregnancy loss, as a great prophylactic-dose heparin during pregnancy 27, 39, 40. proportion of losses are due to chromosomal anomalies. A small hole is made on the zona pellucida in the cleavage stage embryo to remove The role of immunotherapy is controversial. 1 or 2 blastomeres for genetic analysis. Flurescent Active immunization with third party or paternal in situ hybridization (FISH) is used to detect leukocytes and passive immunization using numeric and structural chromosomal anomalies intravenous gammaglobulins (IvIG) have been and polymerase chain reaction (PCR) is used to evaluated. The infusion of lymphocytes is detect monogenic disorders. A significant supposed to induce blocking antibodies that would reduction in the loss rate among women over the hide the pregnancy from the maternal immune age of 35 was reported by one group46. But others system. IvIG is supposed to shift the cytokine failed to observe a benefit with IVF-PGD among production to induce favorable humoral immune women with recurrent spontaneous abortion47. So response during pregnancy. Meta-analysis of the PGD may not be appropriate for all women with trials failed to find a significant benefit with recurrent pregnancy loss, but there may be subgroups for whom its use is justified. Further immunotherapy41. Only one randomized controlled studies need to identify these subgroups. Donor trial of immunotherapy has shown benefit gametes can be considered for couples with a following treatment42. More recent randomized known genetic defects. trials have failed to confirm these findings43, 44. Conclusion
Recurrent pregnancy loss is a tragic situation for a Some anatomic defects require surgical correction. couple, which has got tremendous psychological But it is very important to know the exact burden. Though in certain cases cause can be anomaly. Endoscope procedures are most identified, in about 50% cases the exact aetiology commonly used to correct the defect. Intrauterine remains unknown even after a thorough work-up. pathologies eg septum, fibroids, polyps can be Patients with known causes should be treated removed during hysteroscopy. Septum should be accordingly. Couples for whom the exact cause is excised with scissors or laser. Better homeostasis not identified require emotional support and 34 █ AKMMC J 2011; 2(2) Mst Rashida Begum, Maryia Ehasan, Mst Sahina Begum et al should be counseled about their chances of normal 14. Propst AM. Hill JA 3rd. Anatomic factors in recurrent pregnancy without specific treatment. Some pregnancy loss. Semin Reprod Med. 2000; 18: 341-350. therapies are widely used without any scientific 15. Devi Wold AS, Pham N, Arici A. Anatomic factors in support. Patients usually are agreed to do anything recurrent pregnancy loss. Semin Reprod Med. 2006; 24: 25-32. to improve their chances. But we should be very 16. ProctorJA, Haney AF. Recurrent first trimester careful not to offer such empirical treatments pregnancy loss is associated with uterine septum but not without sufficient scientific evidence supporting with bicornuate uterus. Fertil Steril. 2003; 80: 1212- their use rather those are expensive and may be 17. Arredondo F, Noble LS. Endocrinology of recurrent pregnancy loss. Semin Reprod Med. 2006; 24: 33-39. References
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