1. Recurrent pregnancy loss
Recurrent pregnancy loss (RPL) can be defined as more than 2 to 3 consecutive miscarriages before 24 wk. gestation . which had a traumatic experience for the patient & is also one of the most difficult areas in reproductive medicine .Its incidence is 1-3% , which is more higher in the early gestations . The majority occurring in the first trimester of pregnancy.

2. Risk factors for RPL
1. Genetic factors : Embryonic chromosomal (structural & numerical) abnormalities may account for 30-57% of miscarriage .
2. Anatomical disorders such as:
congenital uterine abnormalities.
Leiomyoma.
Intrauterine adhesion.
cervical in competence .
3- Thrompophilic factors.
4- Antiphospholipid syndrome.
5- Immunological factors
6- Endocrinal factors such as:
a. PCOS
b. Diabetes mellitus.
c. Thyroid Abs & thyroid disease . (Thyroid perioxidase antibodies).

3. Both hyper& hypothyroidism can cause RPL.
D-Luteal phase defect & progesterone deficiency ٠
7- Environmental factors.
8- Infections : untreated syphilis , genital T.B.
However , 50 ؛% of the couples with RPL , the cause of it remains unexplained.
Women with unexplained RPL still have an excellent prognosis for future pregnancy outcome with a live birth rate of over 50% .

4. Thyroid disease & RpL
The American thyroid association recommends measuring serum thyroid hormones in the following cases:
Symptomatic for thyroid disease .
from an area known with iodine deficiency .
family or personal Hx. of thyroid disease .
thyroid perioxidase Abs. test is positive.
type I diabetes .
History of preterm delivery or miscarriage .
history of neck or head radiation.
morbid obesity(BMI more than 35 kg/m2)
Infertility (primary or secondary)
older than 30 years.

5. Normal maternal physiological changes during pregnancy lead to complex endocrine and immune modifications. Thyroid gland volume enlarges and serum levels of thyroxine (T4) and triiodothyronine increase, whereas serum TSH levels reduce .
These modifications are related to TSH-like activity of HCG, rise in thyroxin-binding globulin (TBG) due to hyperestrogenemia and resultant altered TBG glycosylation which increases TBG half life , elevated glomerular filtration rate (GFR), and transplacental passage of FT4. Ten to 20% of pregnant women are positive for thyroid peroxidase (TPO) or thyroglobulin antibodies and euthyroid, of whom 16% will develop high TSH values during pregnancy and 35–50% will develop postpartum auto- immune thyroiditis.

6. During pregnancy, thyroid disease could be associated with a lack in thyroid hormone concentrations or a poorer ability of the thyroid gland to sufficiently conform to the requests of pregnancy. Treatment of thyroid insufficiency, caused by auto antibodies, during pregnancy is important in avoiding hostile maternal and fetal outcome .
The exact mechanism of an association of thyroid outoimmunity with miscarriage remain largely unknown.
Generally, enhanced autoimmune reactivity against the feto-placental unit as a consequence of hypothyroidism is the most reliable mechanism . The presence of thyroid autoantibodies can cause infertility and delay pregnancy. Women with high concentration of thyroid autoantibodies in their blood circulation usually become pregnant in older age and encounter with a higher risk of pregnancy loss .

7. .
Pregnancy loss in women with positive thyroid autoantibodies occurs within the first trimester of gestation, when the fetus is dependent on maternal thyroid hormones. Following implantation, the preservation of the pregnancy is reliant on a mass of immunological events that will assistance in the successful growth and development of the fetus.

8. Thyroid peroxidase or thyroperoxidase (TPO) is an enzyme expressed
mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase
oxidizes iodide ions to form iodine atoms for addition onto tyrosine residues
on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3),
the thyroid hormones. Inhumans, thyroperoxidase is encoded by the
TPOgene .

9. The prevalence of TPOAb is even higher in women with a history of recurrent pregnancy loss, at around 17–33%, and in women with a history of subfertility, at around 10–31%.
TPOAb constitutes a risk factor for hypothyroidism, miscarriage, preterm delivery, perinatal death, postpartum thyroid dysfunction and impaired motor, and intellectual development in the offspring. Miscarriage, or spontaneous pregnancy loss before the 24th week of gestation, is a common pregnancy complication affecting one in five pregnant women (17–33% of gestations)

10. Given the potential of thyroid autoimmunity and adverse pregnancy outcomes , it is of prime importance to screen pregnant woman for thyroid autoimmunity and to manage thyroid euthyroid women during pregnancy , when necessary .  
As women with elevated anti-TPO antibodies are at increased risk for progression of hypothyroidism , if such women identified before conception require monitoring for hypothyroidism during pregnancy based on guidelines , ATA recommends that serum TSH should be evaluated every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation .
However the reduction of these complications by treatment with LT4 supplementation is less robust .

11. Recurrent pregnancy loss & PCOS
There is high correlation between thrombophilia & RpL in patient with
polycystic ovarian syndrome.
PCOS is common endocrinopathy characterized by oligo-&/or anovulation , clinical or biochemical hyperandrogenemia , & polycystic ovaries on ultrasonography (Roterdam criteria 2003) , affects ؛ % of women in reproductive age . This syndrome is described by stein - leventhal in
In some research , there is high correlation between RpL due to pcos & elevated level of thromlophilia parameters & high testestaseronc level & dehydroepiond- rosterane sulfate with fasting insulin level.

12. Thore, the ratio of RpL with PCOS is increased in patient with abnormal thrembophilic study, specially factor 5-Leiden mutation. Immune dysregulation in PCOS- cause or effect is still unknown????????
The state of estrogen excess has been linked to different autoimmune disease . During normal ovulatory menstrual cycle , follicular phase is characterized by elevation ofIL-6 where as . its level is decreased in the luteal phase which is also characterized by negative correlation with progesterone ٠
The stimulatory effect of Estrogen to immune system can be inhibited by progesterone.
Patient's with PCOS present with low level of progesterone due to oligo and/or anovulation , therefore the immune system could be over -stimulated leading to production of auto - anti bodies in these patients
eref

13. Antiphospbolipid syndrome
All women with RPL should be screened for APS before the next pregnancy , which include the testing for ACA IgG , IgM .
Lupus Anticoagulant IgG , IgM.
It should be done twice 6-8 wk. apart to rule out false positive result.
APS is most important treatable cause of EpL . It is the only autoimmune condition in which pregnancy loss is part of its diagnostic criteria .
Its adverse pregnancy outcome are:
1. Three or more consecutive unexplained miscarriage before 10 wk. gestation.
2. One or more deaths of morphologically normal fetuses after the 10th wk ٠ gestation.
3. One are more preterm births before 34 wk . gestation due to severe preeclampsia, Eclampsia & placental insufficiency. Of patients with RpL , % may have APS .
Fetal loss rate in untreated pregnancies may be as high as 90%.