Recurrent Pregnancy Loss
INTRODUCTION
Recurrent pregnancy loss is three or more consecutive miscarriages. It affects approximately 1% of all women as against sporadic abortion which affects 25% of all women who conceive a pregnancy.
Most women with recurrent pregnancy loss have pre-embryonic or embryonic losses. Recurrent fetal loss is less common, and recurrent fetal loss at or beyond 14 weeks of gestation is very infrequent.
The risk of a further miscarriage increases after each successive pregnancy loss. The most significant increase occurs after the first miscarriage. The risk of further abortion is 20% after 1 abortion, 23% after 2 abortions, and 26% for women with 3 previous abortions. However, after 3 consecutive miscarriages, the majority of subsequent pregnancies will be successful.
AETIOLOGY
An identifiable cause can be found in 50 – 60% of cases. Causes include
GENETIC ANOMALIES
The reported incidence of chromosomal abnormalities among couples with repeated
Spontaneous abortion varies according to the population studied. Sant Cassia and Cooke (1981) found a frequency of 4.6% abnormal karyotypes among 182 couples with a history of 2 or more spontaneous abortions.
PARENTAL STRUCTURAL CHROMOSOME ABNORMALITIES
Couples in whom one or the other partner carries a chromosomal re-arrangement are at risk of repeated miscarriages with the loss of conceptuses with abnormal karyotypes.
The most common type of parental chromosomal abnormality is a balanced translocation( either Robertsonian or reciprocal) with a reported prevalence of 3-5% in couples with recurrent pregnancy failure in contrast to a prevalence of 0.2% in an unselected population. Other genetically balanced structural chromosomal abnormalities, such as chromosome inversions account for a small percentage of abnormal parental karyotypes among couples with recurrent pregnancy loss.
RECURRENT PRE-EMBRYONIC OR EMBRYONIC ANEUPLOIDY
Analyses of karyotypes in consecutive abortions suggest that recurrent aneuploidy in the conceptus may be a cause of RPL. Supportive evidence comes from genetic studies of women with RPL in which more than 50% of the embryos were found to have aneuploidy.
UTERINE ANOMALIES
The role of uterine factors in the etiology of reproductive failure is oftentimes difficult to define. Congenital anomalies of the uterus have been associated most often with second-trimester pregnancy loss. However, 10-15% of women with recurrent early pregnancy loss have congenital uterine anomalies.
The most common malformations associated with pregnancy loss are variations of the double uterus( bicornuate uterus, septate uterus, and uterus didelphys) with the septate uterus predominating. Poor vascularisation of the septum has been adduced as a cause of recurrent pregnancy loss.
Severe uterine synechiae(Asherman’s syndrome) is also associated with recurrent pregnancy loss. An association between submucosal fibroids and recurrent pregnancy loss is controversial
HORMONAL AND METABOLIC DISORDERS
LUTEAL PHASE DEFECT:
It has long been thought to be a cause of RPL but evidence linking Luteal phase defect to recurrent abortion is subject to criticism. Luteal phase defect results in failure of the corpus luteum to make enough progesterone to establish a mature endometrial lining suitable for placentation and poor follicular phase oocyte development leading to disordered estrogen and progesterone secretion. Some researchers believe that Luteal Phase defect is a common cause of RPL, accounting for 25 – 40% of cases
POLYCYSTIC OVARY SYNDROME:
36 – 56% of women with RPL have polycystic ovarian syndrome diagnosed by ultrasound4. More than half of women with ultrasound evidence of polycystic ovary syndrome also have hypersecretion of Luteinizing hormone and women with polycystic ovaries who miscarry have higher levels of circulating androgens5.
Pathophysiology
- Antagonism of Oocyte maturation inhibitor OMI by increased levels of LH leading to the premature resumption of meiosis in oocyte and physiologically aged oocytes.
- Altered endometrial function due to abnormal prostaglandin synthesis (women with PCOS have altered synthesis of endometrial prostaglandins which play an important role in implantation).
- Indirect effect on either the oocyte or endometrium via altered androgen production.
- Production of abnormal glycoforms of LH with a long circulating half-life but are low in bio-activity leading to abnormal signal transduction at the receptor level, anovulation, and possibly early pregnancy loss.
DIABETES MELLITUS AND THYROID DISORDERS:
Poorly controlled diabetes mellitus has been implicated as a cause of RPL.
Thyroid dysfunction is also often cited as an aetiological factor but no direct evidence exists.
INFECTIONS
Certain infectious agents such as Listeria monocytogenes are known to cause sporadic pregnancy loss but no infectious agent has been proven to cause RPL. Toxoplasmosis Gondi, and some viruses(rubella, Herpes simplex, cytomegalovirus)have all been linked to sporadic abortion.
Bacterial vaginosis has been implicated in the etiology of preterm labor but its role in early pregnancy loss is doubtful. Isolation of ureaplasma urealyticum from the genital tract has been associated with recurrent early miscarriage but this organism is highly prevalent in the general population.
THROMBOPHILIA
The most common inherited thrombophilic disorders are Factor V Leiden and G20210A mutations. These mutations are associated with approximately 25%of isolated thrombotic events and approximately 50% of familial thrombosis. Other less common thrombophilias include deficiencies of the anticoagulants Protein C, Protein S and antithrombin 111. One or more of these thrombophillic mutations are associated with RPL.
IMMUNOLOGICAL DISORDERS
This can be autoimmune or alloimmune.
AUTOIMMUNE:
This is associated with an abnormal immunologic response of the mother to a pregnancy.
Antibodies that have been implicated include Antiphospholipid antibodies, antithyroid and antinuclear antibodies.30% of patients with unexplained RPL will test positive for autoimmune antibodies.
ANTIPHOSPHOLIPID ANTIBODIES:
Phospholipids act like glue that holds the dividing cells together and are necessary for the growth of the placenta into the wall of the uterus. They also serve as a filter between the maternal and fetal compartments. The most common APAs are anticardiolipin antibodies and Lupus anticoagulants. Others are antibodies to phosphatidylserine, phosphatidylinositol, etc.
Antiphospholipid antibodies inhibit endothelial prostacyclin production. They also increase platelet activation leading to thromboxane release and reduced antithrombin 111 productions. This leads to thrombosis and deposition of fibrin in many vessels including the uteroplacental circulation.
The primary antiphospholipid syndrome is the presence of antiphospholipid antibodies with recurrent pregnancy loss, arterial and venous thrombosis, and thrombocytopenia. Fetal demise can occur at all stages of pregnancy and there is an association with severe preeclampsia, intrauterine growth restriction, and abruptio placenta. Miscarriage tends to occur at progressively lower gestational age and there is a fetal loss rate of about 80% with lupus anticoagulant or anticardiolipin antibodies.
ANTITHYROID ANTIBODIES:
Thyroid antibodies increase the risk of miscarriage 2-fold. The antibodies involved are thyroglobulin and thyroid microsomal(thyroid peroxidase) antibodies.
ANTINUCLEAR ANTIBODIES:
A significant percentage (15%) of women with RPL have detectable antinuclear antibodies. Without treatment, subsequent pregnancy outcomes among women with a positive ANA result are similar to those among women with a negative ANA test result.
AUTOIMMUNE DISORDERS
It has been suggested that maternal recognition of the embryo, leading to a protective immune response is a necessary prerequisite to a successful pregnancy. A failure to mount the appropriate maternal immune response will lead to RPL. Based on this hypothesis, immunization treatment was developed. The female partner is immunized with the paternal, third-party, or fetal material in order to potentiate the maternal immune response. The most common method of treatment utilized is paternal leucocyte immunization.
The development of a detectable amount of anti-paternal cytotoxic antibodies APCAs is also considered necessary for the normal progression of pregnancy. However, it has now been demonstrated that the presence of APCA is not necessary for the maintenance of pregnancy: the majority of women who have successful pregnancies do not develop APCA and those that do produce the antibody in the third trimester become antibody-negative following delivery. Natural killer cells NK have also been implicated in the etiology of RPL. Some types of NK cells produce tumor necrosis factor which is toxic to the developing fetus. Patients who have high levels of these cells are at high risk of implantation failure and miscarriage.
Certain cytokines are embryo-toxic and embryo-toxic factors have been identified in as many as 60% of women with recurrent, unexplained miscarriages.
UNEXPLAINED PREGNANCY LOSS
In about 50% or more of couples with RPL, an evaluation including parental karyotype,
Hysterosalpingography or hysteroscopy, antiphospholipid antibody testing will be negative. Informative and sympathetic counseling serves an important role in this situation.
Live birth rates between 35 and 85% are commonly reported in couples with unexplained RPL who undertake an untreated or placebo-treated subsequent pregnancy10.60 – 70% of women with unexplained RPL will have a successful next pregnancy.
ENVIRONMENTAL AND OCCUPATIONAL FACTORS
Occupational exposure to certain products such as organic solvents has been linked to sporadic pregnancy loss. However, no association between occupational exposure and RPL has been established.
Smoking and heavy alcohol consumption have also been implicated in the etiology of RPL. The risk of smoking appears to increase with the number of cigarettes smoked and alcohol.
THE MALE FACTOR
The role of the male factor among couples with RPL is not clear. Rehan et al (1975) found an incidence of polyspermia( sperm count > 250 million per ml.) of 1.2% among fertile couples while Ghazerman et al (1982) found an incidence of 4.2% among infertile couples. They reported an abortion rate of 25% among 30 couples where the man had polyspermia.
EVALUATION
ACOG recommends the commencement of evaluation after 2 losses especially when the patient is older than 35 years.
1. GOOD HISTORY
Family and Social History
Past Obstetric and Gynaecological History
Past Medical History
2. EXAMINATION
3. INVESTIGATIONS
Chromosomal: Parental karyotyping, karyotyping of products of the conceptus
Radiological: Hysterosalpingogram, Pelvic Ultrasound, Hysteroscopy
Endocrinological: Glucose tolerance test, thyroid function test, serum LH, Urinary LH
Hematological: Lupus anticoagulant( dilute Russell’s viper venom time, KCT, APTT), anticardiolipin assay.
TREATMENT
Depends on the cause.
- Genetic: Parental counseling
- Uterine malformation: Counseling, surgery
- Autoimmune: Preconception Low dose Aspirin 75mg, Subcut. Heparin 5,000 I.U 12 hours and Prednisolone 40 – 60mg daily(for women who do not respond to aspirin and heparin therapy)
- Intravenous immunoglobulins IV Ig throughout pregnancy
Alloimmune: Immunization with husband’s WBC(10% increase in the chance of live birth)for women with low LAD levels.IV Ig is also effective.
IV Ig is also the treatment of choice for women with elevated LAD, circulating NK(CD56+), elevated circulating embryotoxic, and unexplained recurrent miscarriage.
- Endocrine: Elevated LH: Suppression of LH with clomiphene, LH-releasing hormone analog,pre-pregnancy treatment with progesterone, and the use of analogs to somatostatin, ovarian diathermy
- Diabetes mellitus: periconceptual glycaemic control
PROGNOSIS
- 60% successful in their next pregnancy even without treatment
REFERENCES
- Progress in Obstetrics and Gynaecology volume 11, Chapter 6, page 97
- Progress in Obstetrics and Gynaecology Volume 5, Chapter 16
- Obstetrics and Gynaecology Secrets 2nd Edition
- Tulpala et al British Journal of Obstetrics and Gynaecology 1993; 100, 348 – 352
- Lejeune et al British Journal of Obstetrics and Gynaecology 1983;100: 669 – 672
- Winkoff D., Malinek M et al . The predictor value of thyroid test profile in habitual abortion. British Journal of Obstetrics and Gynaecology 1975; 82: 760 – 766
- Carey J.C. Blackwelder W.C. et al Antepartum cultures for Ureplasama urealyticum are not useful in predicting pregnancy American Journal of Obstetrics and Gynaecology 1991; 164: 728 – 733
- Rai R. Regan L. et al British Journal of Haematology 1996; 92 : 489 – 490
- Harger J.H., Archer D.F. et al Etiology of Recurrent Pregnancy loss nad outcome of subsequent pregnancies Obstetrician and Gynaecologist 1983; 6 : 574 – 581
- Cauchi M.N. Lim D. et al Treatment of recurrent aborters by immunization with paternal cells
