Recurrent Pregnancy Loss

Introduction

Pregnancy loss has surprisingly common occurrence and is always an emotional trauma to the mother/ couples. Approximately 15% of all clinically recognized pregnancies result in spontaneous loss, there are many more pregnancies that fail prior to being clinically recognized. Only 30% of all conceptions result in live birth.¹

Recurrent miscarriage/ Recurrent pregnancy loss (RPL), defined as the loss of three or more consecutive pregnancies, losses prior to 20 weeks from the last menstrual period, occurs in approximately 1-2% of couples attempting to bear children.²   RPL may be of primary or secondary type. Primary RPL refers to couples who never had any live birth pregnancies and secondary refers to those who had repetitive losses following a successful pregnancy. The prognosis for successful pregnancy is better with secondary RPL.

RPL has been observed in the increased incidence among the women with previous history of miscarriages. Ogasawara et al. reported that women who had experienced miscarriage twice, 3 times, and 4 times in the past were likely to lose the next pregnancy with a probability of 43.7%, 44.6%, and 61.9%, respectively (Figure 1).³   Increasing number of past miscarriages is associated with further repetition of miscarriages and stillbirths attributable to factors in the mother or the father rather than the fetus (chromosomal aberrations).

Etiological factors for RPL and their management

There are various etiological factors for recurrent pregnancy loss. At present, there exist a small number of accepted etiologies for RPL (Figure 2).¹   These include parental chromosomal abnormalities, untreated hypothyroidism, uncontrolled diabetes mellitus, certain uterine anatomic abnormalities, and antiphospholipid antibody syndrome (APS).

Most of these etiological factors are treatable. Various diagnostic evaluation of RPL for different causative factors are enlisted in Table 1.

Genetic Etiologies

Chromosomal abnormalities of the embryo are the most common cause of sporadic miscarriage. Approximately 3% to 5% of RPL are caused by genetic defects, 7% are due to chromosomal derangement, most commonly balanced reciprocal or Robertsonian translocations. Additional structural abnormalities associated with RPL include chromosomal inversions, insertions, and mosaicism.⁴   Many patients consider chromosomal aberration to be a hopeless condition. However, patients with recurrent pregnancy loss have a good chance of achieving a live birth after a diagnosis of chromosomal aberration.

RPL patients with genetic etiologies should be evaluated using parental karyotyping. All cases of RPL associated with parental chromosomal abnormalities should undergo genetic counseling. Depending on the particular diagnosis, directed therapy may include in vitro fertilization with preimplantation genetic diagnosis.

Anatomic Etiologies

More than 10-15% of RPL cases have the etiology of anatomic abnormality and they are generally thought to cause miscarriage by interrupting the vasculature of the endometrium, prompting abnormal and inadequate placentation. The abnormalities which might interrupt the vascular supply of the endometrium are congenital uterine anomalies, intrauterine adhesions and uterine fibroids or polyps.

These uterine abnormalities are diagnosed using hysterosalpingography (HSG) and confirmed by MRI or other methods. The most frequently observed uterine abnormality is arcuate uterus, followed by septate uterus. Surgical management of these anomalies have been tried with 70-80% of success rate in live birth report following hysteroplasty, but some studies have also reported that patients maintain pregnancy at a rate of 70% without treatment, and there exist a controversy regarding the recommendation of surgical management of uterine abnormality for RPL treatment.⁵

Other abnormalities such as unicornuate or bicornuate uterus cause late second trimester loss and premature labour due to reduced volume of the uterine cavity.⁶   Diethylstilboestral (DES) exposure is associated with uterine and cervical hypoplasia causing second trimester pregnancy loss.

Uterine fibroids: Uterine fibroids, particularly beneath the endometrium, are the most commonly acquired anomaly. According to location fibroids are classified as submucus, intramural and subserous. Submucus fibroid located beneath the muscle layer, which deforms the cavity and endometrium covering them is usually thin and inadequate for normal implantation and is responsible for RPL. Intramural fibroid when distort the cavity causes pregnancy loss. Hence, location, size, and number of the fibroids have significant role in RPL. Larger and multiple fibroids are usually associated with adverse pregnancy outcome.

As per recently conducted study, submucosal fibroid location and distortion of the endometrial cavity (either submucosal or deeply infiltrating intramural fibroids) are most predictive of impaired fertility and probable benefit of surgical removal, and consideration of myomectomy in the subfertile patient is also justified.⁷

Decreased ovarian reserve with increasing age: Decrease in quality of oocyte has been observed with increasing age of the female, leading to increased miscarriages. This age-related decrease of oocyte quality is accompanied by a decrease in oocyte quantity. Process of female reproductive ageing is attributed to a decrease in both oocyte quantity, eventually resulting in menopause, and oocyte quality.⁸

Asherman’s syndrome/endometrial fibrosis: Asherman’s syndrome is an acquired condition which is due to the presence of post-traumatic intrauterine adhesions, partly or completely obliterating the uterine cavity. In this syndrome endometrial response to steroid hormones is reduced in areas affected by the endometrial fibrosis. Severity of adhesions present in the endometrial fibrosis have an inverse relation with endometrial responsiveness, which means more the adhesions lower is the responsiveness of endometrium. Successful division of the intrauterine adhesions in cases without extensive fibrosis may restore the responsiveness of the endometrium and lead to regular menstruation. Presence of extensive and dense fibrosis has poor prognosis.⁹

Endocrine etiologies

Hormonal problems can disrupt the implantation process and the development of early embryo. Hormonal abnormality leads to the abnormal folliculogenesis which further results in the development of inadequate corpus luteum and luteal phase defect causing early abortions. Patients with poorly controlled diabetes mellitus, thyroid dysfunctions have increased risk of RPL. It has been reported that the presence of thyroid autoantibodies is associated with an increased risk of miscarriage.^10,11

17-20% of RPL are result of luteal phase defect (LPD), polycystic ovarian syndrome (PCOS), diabetes mellitus, thyroid disease, and hyperprolactenimia.¹

Hence, all the patients of RPL should be evaluated for endocrine dysfunctions namely, thyroid-stimulating hormone (TSH) level. Other testing that might be indicated based on the patient’s presentation include insulin resistance testing, ovarian reserve testing, serum prolactin in the presence of irregular menses, antithyroid antibody testing, and, very rarely, luteal phase endometrial biopsies.

Luteal phase defect: Patients with RPL commonly present with luteal phase defect. Inappropriate corpus luteal function causes decreased release of progesterone and inadequate endometrial preparation. Luteal phase deficiency (LPD), as diagnosed by endometrial biopsy, is not a single disorder but rather a spectrum of dysfunction that reflects both endometrial cycle and ovarian cycle abnormalities.¹²   Progesterone is required to induce secretory changes that prepare the endometrium for the arriving embryo. Previous observations also suggest that the majority of cases of luteal phase defect are associated not with suboptimal progesterone but with an abnormal response of the endometrium to progesterone. It seems therefore that a logical treatment is targeted at improving the responsiveness of the endometrium to progesterone by enhancing priming of the endometrium in the follicular phase.

hMG (Human menopausal Gonadotropin)

This is hypothesized that controlled ovarian stimulation by gonadotropins, which enhances estrogen priming, is of beneficial value in the treatment of endometrial defects associated with recurrent miscarriage. A retrospective, randomized study was conducted to evaluate the use of human menopausal gonadotropins in the treatment of endometrial defects associated with recurrent miscarriage.¹³   In this study 21 subjects with otherwise unexplained recurrent miscarriage who had retarded endometrial development in the mid-luteal phase were included. Endometrial biopsies were timed by the luteinizing hormone surge. Controlled ovarian stimulation using human menopausal gonadotropins and repeat endometrial biopsy in the treatment cycle in 13 subjects was done.

Results of this study demonstrated that 85% (11 out of 13) biopsies in the treatment cycle were normal. The miscarriage rate in the treatment group was 15% (2 out 13) and in nontreatment group was 58.33% (7 out of 12) (chi2 5.0, p<.05) (Figure 3).

This study concluded that controlled ovarian stimulation by human menopausal gonadotropins in the follicular phase is an effective treatment for luteal phase defect associated with recurrent pregnancy loss.

Progesterone and hCG (Human Chorionic Gonadotropin)

The use of human chorionic gonadotropin (hCG) and exogenous progesterone may prolong the health of the luteal phase in women with infertility or recurrent pregnancy loss. Significantly, the use of these agents has been associated with decreased cellular apoptosis, which may be important in preserving endometrial function, and thus promoting implantation.

In a controlled, prospective, and randomized study, Lovely et al examined the effects of exogenous hCG and progesterone on apoptosis in late luteal-phase endometrial biopsies of 12 healthy fertile women (aged 20 to 34 years) with regular menstrual cycles.¹⁴   The women received luteal doses of either intravaginal progesterone, 200 mg (on days 18 to 27), or a single IM injection of hCG, 10,000 IU, on day 19. At 26 days, a second endometrial biopsy was performed and serum was collected. Evidence of apoptosis was reduced significantly with both luteal-phase treatments. Serum progesterone levels were higher in the hCG-treated group; however, the difference between groups was not statistically significant. These findings suggest that luteal-phase support may prolong the health of the luteal phase in part by preventing programmed cell death.

Allylestrenol

It is a synthetic progesterone derivative that is used to treat threatened pregnancies and to support in early pregnancy. It can prevent premature labor and can help in women give birth to a healthy child. It is usually indicated in patients with threatened abortion, habitual abortion or threatened premature delivery.

The trophoblastic effect of allylestrenol stimulates the trophoblasts to release hCG which acts on corpus luteum and progesterone is released, relaxes uterus and thus helps in better fetal growth. This also has placentotrophic action which stimulates placental enzymes and hormones for a better fetal development. Selective β 2 adrenergic action of allylestrenol relaxes myometrium and increases blood flow to placenta, which in turn increases fetal metabolism and results in a better fetal growth. The pharmacological actions of allylestrenol are very similar to naturally occurring progesterone. It prepares the uterus for receiving the fertilized ovum and makes the endometrial lining thicker. Thus, it supports implantation to sustain pregnancy. Uterine motility is suppressed by the action of allylestrenol which helps in the maintenance of pregnancy.¹⁵

PCOS: Polycystic ovary syndrome is a heterogeneous endocrine condition that affects approximately 5% to 10% of women in the reproductive age group. The polycystic ovary syndrome (PCOS) affects some 10% of women during their reproductive life span and it is linked to an increased risk of early recurrent miscarriges. In PCOS patients, proper diagnosis and treatment according to the Thessaloniki guidelines (Figure 4) should be offered prior to conception.¹⁶

Clomiphene citrate in PCOS

Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy. Clomiphene citrate has been used as a first-line ovulation induction agent for over 40 years.¹⁹   It is a selective estrogen receptor modulator that stimulates endogenous FSH production and secretion by interrupting estrogen feedback to the hypothalamus and pituitary.

According to the guidelines, the starting dose of clomiphene citrate should be 50mg/day for 5 days, commencing between day 2 and 5 of menses. Dosages can be lowered to 25 mg, if multiple follicular development is observed with 50 mg. Dosages can be increased in cases which are unresponsive to the given dosage. Cycle monitoring should be considered in at least the first cycle and when the treatment dose has to be increased because of failure to ovulate.²⁰

Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy. Patients should be informed that there is an increased risk of multiple pregnancy with ovulation induction using clomiphene citrate.²⁰

Metformin should be combined with CC for infertility instead of persisting with further treatment with CC alone, in women with PCOS who are CCR, anovulatory, and infertile, but with no other infertility factors.

Clomiphene citrate is recommended as a first line of drug therapy in PCOS. Clomiphene plays a significant role in ovulation induction, thereby increasing chances of pregnancy. Metformin has also been used in PCOS. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior.

Legro RS, et al conducted a study to compare the efficacy of clomiphene and metformin alone or in combination.²¹   626 patients with PCOS were administered with clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery.

Results of the study demonstrated improved live birth rate and conception rate following CC administration (Figure 5).

This study concluded that Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication.

Infectious etiologies

Certain infections, including listeria monocytogenes, toxoplasma gondii, rubella, herpes simplex virus (HSV), measles, cytomegalovirus, and coxsackie viruses, are known or suspected to play a role in sporadic spontaneous pregnancy loss. Those particular infections speculated to play a role in RPL include mycoplasma, ureaplasma, Chlamydia trachomatis, L monocytogenes, and HSV. Although their role in RPL is not clear, the proposed mechanism by which they cause RPL is:

• Direct infection of the uterus, fetus, or placenta
• Placental insufficiency
• Chronic endometritis or endocervicitis
• Amnionitis
• Infected intrauterine device

Immunologic etiologies

In an otherwise unexplained pregnancy loss dysregulation of the immune system could be responsible factor for RPL. During pregnancy, immune response modifiers are produced, among them Th1, TNF alpha, TNF beta, gamma interferon are considered to be toxic for developing embryo. Th1 cytokines may directly damage the placenta and possibly activate immune cells that induce reaction.

Progesterone and recurrent pregnancy loss: Immunologic effects

Progesterone, as well known is essential for supporting a pregnancy and has significant effect in successful pregnancy. Progesterone also exerts some non-hormonal immunologic effects. Progesterone induces an immunomodulatory blocking factor critical in suppressing T-helper 1 cytokines and thus preventing miscarriages through the exertion of antiabortive effect. In the 1^st trimester the ratio of Th1 to Th2 is critical. The relation between these cytokine, and potential effects of spontaneous abortion, has been examined. According to the studies, increased levels of mean cytokines were observed in patients with RPL when compared to that of normal pregnancy. Association between the Th1 type and pregnancy loss was observed in this study.²²

In 2005, Gruber and Huber²³   reviewed the evidence regarding the administration of progesterone and dydrogesterone in the prevention of habitual abortion. When peripheral mononuclear cells from women who have recurrent pregnancy loss were incubated with progesterone or dydrogesterone in vitro, T-helper 1 cytokine interferon-gamma decreased, while T-helper 2 cytokines such as interleukin-4 and interleukin-6 markedly increased, further documenting the importance of this cytokine ratio. One more review study, demonstrated that progesterone reduced the risk of miscarriage in women with recurrent losses.  ²⁴

Antiphospholipid syndrome:

This syndrome is diagnosed in patient who has thrombosis with history of 3 or more episodes of miscarriage earlier than 10 weeks of gestation, 1 or more episode of miscarriage or stillbirth after 10 weeks of gestation, or premature delivery earlier than 34 weeks of gestation due to pregnancy induced hypertension syndrome, eclampsia or placental dysfunction, in addition to a positive test result of b2GPI-dependent anti-cardiolipin antibodies or lupus anticoagulant.²⁵   While low-dose aspirin (LDA) has been used in the treatment of recurrent pregnancy loss presenting positive antiphospholipid antibodies, the combined use of heparin and LDA has been shown to achieve higher effectiveness in preventing miscarriage.²⁶

Environmental etiologies

Environmental factors such as exposure to organic solvents, medications, ionizing radiation and toxins have been linked to RPL. Most widely accepted factors linked to RPL are smoking, alcohol, and caffeine. All these factors can be avoided by the female which indirectly reduces the risk of miscarriages. 80-90% of infertility factors are related to the individual’s lifestyle and thus considered to be preventable.

Unexplained RPL

Approximately 50% of women with RPL remains unexplained despite thorough investigations. This unexplained RPL has high psychological impact on the patient as well as it is challenging for the attending clinician due to lack of definite etiology. But majority of these patients have excellent prognosis without any treatment as most of these women are healthy individuals, with no underlying pathology and have suffered previous miscarriages purely by chance.²⁷

Types of Unexplained RPL

Type 1 unexplained RPL: This occurs by chance in women who have no underlying pathology and this has a good prognosis.

Type 2 unexplained RPL: This occurs due to an underlying pathology which is currently unidentified with regular clinical investigations and this has poor prognosis.

Paternal lymphocyte immunization has been proposed as an efficient treatment for unexplained recurrent spontaneous abortion (RSA), however precise mechanism that underlie the benefits of this immunotherapy are still unclear.²⁸

Conclusion

Causes of recurrent miscarriage are multiple, ranging from genetic, environmental, infectious, metabolic, and endocrine to purely anatomic ones. After two consecutive clinical pregnancy losses, RPL should be evaluated. Patient should be evaluated for genetic factors, antiphospholipid syndrome, any uterine anatomical abnormality, hormonal and metabolic factors, as well as life style related causes. Using karyotyping of parents, screening for lupus anticoagulant, anticardiolipin antibodies and anti-b2 glycoprotein 1 antibodies, sonohysterogram, hysterosalpingogram and hysteroscopy patient of suspected RPL should be evaluated. Once the cause of RPL is determined, treatment should be initiated targeting the cause, like in treating antiphospholipid syndrome, combination of prophylactic doses of unfractionated heparin and low-dose aspirin should be used. Treating various causes of RPL has various treatment regimens as outlined in Table 2. All the couples with RPL should be supported emotionally with proper and timely psychological counseling.

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