RECURRENT PREGNANCY LOSS

Miscarriage is defined as the spontaneous loss of pregnancy before the fetus reaches viability. This definition includes all pregnancy losses from the time of conception until 24 weeks of gestation.
Recurrent miscarriage is defined as the loss of three or more consecutive pregnancies. It affects 1% of couples trying to conceive. It has been estimated that 1-2% of second trimester pregnancies miscarry before 24 weeks of gestation.

RISK FACTORS FOR RECURRENT PREGNANCY LOSS (CAUSES OF RECURRENT PREGNANCY LOSS)
1. EPIDEMOLOGICAL FACTORS: Maternal age and the number of previous miscarriages are risk factors. Advancing maternal age is associated with a decline in both the number and quality of the remaining eggs.
Age related risks of miscarriage are 12% for 20-29years, 15% for 30-34 years, 25% for 35-40 years, 51% for 40-45 years and 93% for over 45 years.
Advanced paternal age has also been identified as a risk factor for miscarriage. The risk of miscarriage is highest among couples where the woman is > 35 years of age and the man > 40 years of age.
The risk factor of further miscarriage increases after each successive pregnancy loss, and could reach up to 40% after three consecutive pregnancy loss, and the prognosis worsens with maternal age.
Maternal cigarette smoking and caffeine consumption is associated with an increased risk of spontaneous miscarriage in a dose dependent manner. Heavy alcohol consumption is toxic to the embryo and the fetus. Even moderate alcohol increases the risk of sporadic miscarriage.

2. ANTIPHOSPHOLIGIDSYNDROME
Antiphospholipid syndrome is the most important treatable cause of recurrent pregnancy loss.
Antiphospholiid syndrome refers to the association between antiphospholipid antibodies- Lupus anticoagulant, anticardiolipin antibodies and anti B2 glycoprotein-I antibodies and adverse pregnancy outcome. Adverse pregnancy outcome include
- Three or more consecutive miscarriage before 10 weeks of gestation
- One or more preterm birth before 34 weeks of gestation owning to placental disease.
Antiphospholipid antibodies are present in 15% of women with recurrent miscarriage. The effect of antiphospholipid antibodies can be reversed by heparin.
In women with recurrent miscarriage associated with antiphospholipid antibodies, the live birth rate with no drug treatment is reported to be as low as 10%.



3. GENETIC FACTORS
In approximately 2-5% of couples with recurrent miscarriage, one of the partners carries chromosomal abnormalities. In couples with recurrent miscarriage, chromosomal abnormalities of the embryo account for 30-60% of further miscarriages. The risk of miscarriage from chromosomal abnormalities increases with advancing maternal age.

4. CONGENITAL UTERINE MALFORMATIONS
The prevalence of uterine malfunctions appears to be higher in women with 2nd trimester miscarriage compared to 1st trimester miscarriage women with acute uterus tend to miscarriage more in 2nd trimester while women with septate uterus are more likely to miscarry in the 1st trimester.

5. CERVICAL WEAKNESS
Cervical weakness is a recognised cause of 2nd trimester miscarriage, but the true incidence is unknown since the diagnosis is essentially a clinical one. The diagnosis is usually based on a history of 2nd trimester miscarriage preceded by spontaneous rupture of the membrane or painless cervical dilatation.

6. ENDOCRINE FACTORS
Systemic maternal endocrine disorders such as diabetes mellitus and thyroid disease have been associated with miscarriage. However well treated and controlled diabetes and thyroid disease are not risk factors.
Polycystic ovarian syndrome (PCOS) is linked with an increased risk of miscarriage but the exact mechanism for this is not well known. It has been attributed to insulin resistance.

7. IMMUNE FACTORS
There is no clear evidence to support the hypothesis of antigen incompatibility between couples.

8. INFECTIVE AGENTS
Any severe infection that leads to severe bacteria or virus in the blood can cause sporadic miscarriage. The role of infection in recurrent miscarriage is unclear. For an infective agent to be emplaced as a cause of recurrent pregnancy loss, it must be capable of persisting in the genital tract and avoiding detection or cause sufficient symptoms to disturb women. Toxoplasmosis, rubella, cytomegalo virus, herpes and listeria infections do not fulfil these criteria and routine TORCH screen should be abandoned. The presence of bacterial vagmosis has been reported as a risk factor for for recurrent pregnancy loss and preterm delivery. Treatment with oral clindamycin significantly reduces the incidence of second trimester miscarriage and preterm birth in the general population.



INVESTIGATION OF RECURRENT PREGNANCY LOSS
Women with recurrent pregnancy loss should be looked after by health professional with necessary skills and expertise i.e obstetrician and gynaecologist. The loss of pregnancy at any stage can be a devastating experience. Ideally the couples should be seen together.
1. All women with recurrent pregnancy loss should be screened before next pregnancy
Antiphospholipid antibodies
2. Karyotyping: Cryptogenic analysis should be performed on products of conception of the third and subsequent consecutive miscarriages blood karyotyping of both parents should be performed too.
3. A pelvic ultrasound (vaginal ultrasound scan) to assess uterine anomalies may require further investigations to confirm diagnosis, using HSG, hysteroscopy, laparoscopy and 4 D ultrasound scan.
4. Women with 2nd trimester miscarriage should be screened for inherited trombophillia.

TREATMENT OPTIONS FOR RECURRENT PREGNANCY LOSS
Women with recurrent pregnancy loss should be referred to specialist clinics by GPs.
1. Women with antiphospholipid syndrome should be treated with low-dose aspirin plus heparin to prevent further miscarriage.
The treatment combination significantly reduces the miscarriage rate by 54%.
2. The finding of abnormal parental karyotype should prompt referral to a clinical genetist.
Genetic councelling offers the couple a prognosis for the risk of future pregnancies. Reproductive options include proceeding to a further natural pregnancy with or without prenatal diagnosis test, gamete donation (PGD) in an IVF cycle is a treatment option.
3. Congenial uterine malformations might benefit from surgical corrections.
4. Cervical weakness and cervical cerlage- Women with a history of second trimester miscarriage and suspected cervical weakness may be offered serial cervical sonograhic surveillance. An ultrasound indicated cerclage should be offered if a cervical length of 25mm or less is detected by transvaginal scan before 24 weeks gestation.
5. Endocrine Factors- Progesterone is necessary for successful implanation and maintenance of pregnancy. It offers a decreased miscarriage rate in recurrent miscarriage. There is insufficient evidence to evaluate the effect of metformin in pregnancy to prevent a miscarriage in women with recurrent miscarriage.
6. The use of various immune therapies in women with recumbent miscarriage does not implore the live birth rate. Immunotherapy is expensive with potential side effects. It should not be offered to women outside of formal research studies.
7. Unexplained recurrent miscarriage, the women can be reassured that the prognosis for a successful future pregnancy with supportive care alone is about 75%.


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