1. Recurrent Pregnancy Loss
Dr.Narendra Gupta
Vivekanand hospital and fertility center, Jaipur

2. Vivekanand hospital and fertility center
Superspeciality center for the treatment of infertile couples
IUI
IVF
ICSI
Endoscopy
Sperm bank

3. Definition
A recurrent pregnancy loss is defined as 3 or more consecutive, spontaneous pregnancy losses. Pregnancy losses are in the form of abortions, rhesus isoimmnisation, cervical incompetence and recurrent preterm labor where the losses occur after 20 weeks of gestation.
Recurrent abortion or miscarriage where the pregnancy loss is always under 20 weeks gestation
Recently 2 or more spontaneous abortions/pregnancy loss have also been put in this category-
i. Since the risk of a recurrent loss is fairly high even after 2 losses (26%), we are justified to start work-up after 2 losses.
ii. Nowadays women start their reproductive career in their late twenties or early thirties.They do not have the time to wait for a third loss.
Recurrent miscarriage affects 1% (0.5-3 %) of all women

4. Impact of RPL
RPL results in great psychological trauma to the couple specially the woman.
They feel devastated and fear that this should not happen to them again.
It results in severe anxiety and depression.

5. Types of RPL
Preclinical or very early pregnancy losses- B-HCG positive pregnancies. This is due to poor implantation and LPD.
Clinical pregnancy loss- An ultrasound evidence of Gestation sac – %
First trimester loss- Almost 80% of RPL occur in the first 12 weeks
Midtrimester loss- 12 to 28 weeks
Late fetal loss- between 28 weeks to term

6. Approach to a patient with RPL
A detailed clinical history is useful. Every miscarriage and gestational age should be noted
Very early (< 6 weeks), 7-12 weeks and more than 12 weeks
Missed abortion or spontaneous live fetal expulsion

7. Clinical Approach
Try to find out a cause. In more than two third of the cases an etiological factor can be found.

8. Investigations Thyroid peroxidase antibody
Investigations should be directed to find out a cause
Male partner- Semen analysis-look for OAT and pyospermia
Female partner
Full blood count
Blood group
Thyroid function tests
HbA1C,Blood sugar/OGTT if needed
Karyotyping
Hormonal profile –LH,FSH,T1,PRL,DHEAS
LA and ACA IgG and AgM
Thrombophilia screen
Transvaginal sonography
Hysteroscopy
Thyroid peroxidase antibody
Autoantibody screen
Total homocysteine
Rubella status
Free androgen index
SHBG

9. Transvaginal sonography
TVS at 6 weeks is recommended to detect cardiac activity
Cervical length should be carefully assessed in patients with RPL
Color flow studies of corpus luteum and uterine artery are helpful
Role of 3 D scanning for anatomical defects of the uterus is undisputed

10. Recurent Miscarriage Explained Un-explained
Genetic
factors
Enviromental
factors
Infective
agents
Endocrine
Anatomical
factors
Immune
factors
Thrombophilic
defect
Bacterial
Vaginosis
Body
Cervix
APS
Paternal
karyotyping

11. Uterine Abnormalities
Uterine abnormalities detected on USG can be further investigated by 3 D scan, Hysteroscopy or HSG if necessary
The finding of uterine anomaly does not necessarily imply causation and surgical treatment may not be indicated

12. Diagnosis of Uterine Anomalies
Transvaginal sonography
3D Ultrasound
Laparoscopy
Hysteroscopy
MRI
Hysterosalpingogram (HSG)

13. Uterine anomalies
The reported prevalence of uterine anomalies in recurrent miscarriage populations range between 1.8% and 37.6%.
The prevalence of uterine malformations appears to be higher in women with late miscarriages compared with women who suffer early miscarriages but this may be related to the cervical weakness that is frequently associated with uterine malformation.
untreated uterine anomalies has a term delivery rate of only 50%.
Open uterine surgery is associated with postoperative infertility and carries a significant risk of uterine scar rupture during pregnancy. These complications are less likely to occur after hysteroscopic surgery but no randomised trial assessing the benefits of surgical correction of uterine abnormalities on pregnancy outcome has been performed.

14. Fibroids
If fibroids are detected on the inside of the uterus (termed submucous fibroids) and distort the uterine lining, they are a significant cause of reproductive problems and should be removed hysteroscopically

15. Uterine anomalies
Mullerian anomalies particularly the Bicornuate and unicornuate uterus are associated with RPL
Septum resection, release of intrauterine synechiae and removal of polyp under hysteroscopic guidance have a better prognosis

16. Cervical incompetence
Cervical incompetence is common in patients of RPL due to repeated D & C’s
TVS diagnosis of cervical length is diagnostic
Cervical cerclage offers a good pregnancy outcome

17. Genetic factors Chromosome Testing on Fetal (Miscarriage) Tissue
This can only be done right at the time of miscarriage.
It is an analysis of the genetic makeup of the fetus.
It can indicate genetic problems that lead to RPL.
Many miscarriages are caused by chromosomal abnormalities that are unlikely to repeat. To know if the problem is likely to recur, it is necessary to study the genetics of both parents as well.
Karyotyping of Parents
each Chromosome analysis of blood of both parents.
It can show if there is a potential problem with one of the parents that leads to miscarriage, but often has to be done in conjunction with fetal testing to provide answers.
These tests help rule out the 3% or so of partners that carry a "hidden" chromosomal problem called a balanced translocation.

18. Karyotyping It is a display of an individual’s chromosome pairs.
Process : Sample of blood is taken.
Cells are chemically stimulated to undergo mitosis. Mitosis is stopped at metaphase.
Chromosomes are separated out, viewed with a microscope and photographed.
The photograph is then rearranged to show the paired chromosomes. Size, shape and banding pattern are used to pair up the chromosomes.

19. Karyotyping

20. Polycystic ovaries
PCOS are associated with increased incidence of pregnancy loss.
Evidence suggest that hypersecretion of LH, hyperandrogenemia and luteal phase defects is associated with poor reproductive outcome.
Treatment is HCG, metformin and progesterone supplementation

21. Endometriosis
Endometriosis not only is responsible for infertility, it also causes RPL.
Though exact role is uncertain, probably it relates to poor egg quality seen in patients of endometriosis

22. Immunology of RPL 40 % of losses in RSA could be due to immunology
1. Alloimmune
2. Auto immune

23. Pregnancy and immunological miracle of immune tolerance
Why should the mother tolerate the fetus?
How does the mother tolerate the fetus ?

24. Alloimmune
A conceptus of 3000 gms is tolerated, protected and nourished by the mother for 280 days
after birth even 30 gms of say renal tissue of that conceptus is not tolerated and immune rejection occurs why?
Husband’s renal tissue transplanted in the mother during pregnancy is not accepted
How his conceptus is accepted?

25. Alloimmune response
At fetomaternal interface when the mother’s immune system senses that a different system has arrived it mounts a protective response.
This is through the syncitiotrophoblast
Functioning of trophoblast is such that it will sense only immunologically distinct identity.
In fact if it is immunologically similar the syncitiotrophoblast will not sense and the mother’s immune sysyem will destroy it.
This can occur repeatedly and results in RPL.

26. This can be applied to renal transplants or any other transplant.
If transplant scientists can create an artificial trophoblast like shield around the donated organ, once again the receptor will protect it and there will be no rejection.
In fact HLA testing will become obsolete because you will require the donor and the recipient to be different and not similar as in the case of the conceptus.

27. HCG The role of HCG is believed to be much beyond hormones
It is believed to have a very strong role that generates changes in the endometrium.
This explains the abrupt and graded rise of HCG levels as soon as blastocyst is formed.
Some perceive HCG as the master of the orchestra that brings about the entire process of nidation
Immune substance first thought to be similar to growth factor
Subsequently proved to be growth factor itself

28. progesterone Progesterone plays an important role in immuno-modulation
Micronised progesterone in varying doses have proven to be successful in reducing spontaneous abortion rate

29. Auto immune Many syndrome antibodies are implicated
But most influential and consistent have been anti phospholipid antibody syndrome.

30. Diagnosis Negative < 10 GPL units Low positive 10-20
Moderately positive
Strongly positive > 100
Once the diagnosis is well established treatment plans are instituted
Mainstay is heparin, low dose aspirin

31. Protocol In interval period-
For low and moderate – aspirin in a dose of 1-2 mg/kg/day till conception. Allow conception- continue aspirin from 12 weeks upto 36 weeks
For high positive-aspirin in a dose of 1-2 mg/kg/day till conception in the interval period. Allow conception. Continue aspirin upto 36 weeks
add heparin in a dose of 1000 IU/day from conception till 36 weeks
Low molecular weight heparin is also being used effectively- convenience of dosing schedule and less bleeding episodes.
In pregnancy-
for these cases we give only the post conception protocol of aspirin or aspirin + heparin as specified.

32. Lymphocyte Immnunization therapy (LIT therapy) and IV Immunoglobulins
Indications- Unexplained infertility
For two-thirds of the known causes," he said, "there is a specific treatment. Then you have about 40 percent where you don't know exactly what has caused it. So there are some empirically unproven treatments out there that are highly debatable."
One theory explaining why some women repeatedly miscarry is that the immune system somehow fails to recognize and protect a pregnancy, and instead mounts antibodies to attack it.
This idea has led doctors to try two treatments intended to to restore normal immune function. One is intravenous immunoglobin therapy, a blood product pooled from thousands of donors and used to regulate abnormal responses of the immune system. The other is lymphocyte immune therapy, which uses blood from a woman's partner to prompt her immune system to recognize a pregnancy.
A report in the literature (THE LANCET Vol. 354, July 31, 1999, 365) indicates that women who have received LIT may have a higher incidence of subsequent miscarriage than women who did not receive such cellular products.
Whether LIT uses cells/cellular products from the woman's partner or from other donors, the manufacturing/preparation and administration of such cells/cellular products presents risks to the recipient (e.g., administration of non-sterile cellular products, transmission of communicable diseases).

33. Immunotherapy for recurrent miscarriage TF Porter, Y LaCoursiere, JR Scott Cochrane Database of Systematic Reviews 2008 Issue 3
Objectives- The objective of this review was to assess the effects of any immunotherapy, including paternal leukocyte immunization and intravenous immune globulin on the live birth rate in women with previous unexplained recurrent miscarriages
Main results
Twenty trials of high quality were included. The various forms of immunotherapy did not show significant differences between treatment and control groups in terms of subsequent live births: paternal cell immunization (12 trials, 641 women), Peto odds ratio (Peto OR) 1.23, 95% confidence interval (CI) 0.89 to 1.70; third party donor cell immunization (three trials, 156 women), Peto OR 1.39, 95% CI 0.68 to 2.82; trophoblast membrane infusion (one trial, 37 women), Peto OR 0.40, 95% CI 0.11 to 1.45; intravenous immune globulin, Peto OR 0.98, 95% CI 0.61 to Authors' conclusions
Paternal cell immunization, third party donor leukocytes, trophoblast membranes, and intravenous immune globulin provide no significant beneficial effect over placebo in improving the live birth rate.

34. Diabetes and thyroid disorders
Routine screening for occult diabetes and thyroid disease with oral glucose tolerance and thyroid function tests in asymptomatic women presenting with recurrent miscarriage is uninformative
well-controlled diabetes mellitus is not a risk factor for recurrent miscarriage, nor is treated thyroid dysfunction

35. Hyperprolactinemia
There is insufficient evidence to assess the effect of hyperprolactinaemia as a risk factor for recurrent miscarriage.

36. Hyperhomocysteinemia
Hyperhomocysteinemia is associated with an approximately 2-fold to 3-fold increased risk for pregnancy-induced hypertension, abruptio placentae, and intrauterine growth restriction. Cobalamin deficiency is associated with HELLP syndrome, abruptio placentae, intrauterine growth restriction, and intrauterine fetal death.
Deficiencies of the vitamins folic acid, pyridoxine (B6), or B12 can lead to high homocysteine levels.
Supplementation with pyridoxine, folic acid, B12 or trimethylglycine (betaine) reduces the concentration of homocysteine in the bloodstream.
Normal fasting homocysteine plasma levels are between 5,0 and 15,9 mmol/l.

37. Infections
TORCH (toxoplasmosis rubella, cytomegalovirus and herpes simplex virus), other [congenital syphilis and viruses], screening is unhelpful in the investigation of recurrent miscarriage.
For an infective agent to be implicated in the aetiology of repeated pregnancy loss, it must be capable of persisting in the genital tract and avoiding detection or must cause insufficient symptoms to disturb the women. Toxoplasmosis, rubella, cytomegalovirus, herpes and Listeria infections do not fulfill these criteria and routine TORCH screening should be abandoned.

38. Bacterial vaginosis
Screening for and treatment of bacterial vaginosis in early pregnancy among high risk women with a previous history of second-trimester miscarriage or spontaneous preterm labour may reduce the risk of recurrent late loss and preterm birth.

39. Environmental factors
Exposture to noxious or toxic substances are known to be associated with recurrent miscarriage ( social drugs, cigarettes, alcohol and caffeine ,anesthetic gases, petrolium products )

40. One stop Recurrent miscarriage clinic
Dedicated clinic governed by evidence based guidelines
More extensive investigations and tailored treatment
Supportive care

41. Investigations Full blood count Thyroid function tests HbA1C
Karyotyping
Hormonal profile –LH,FSH,T1,PRL,DHEAS
LA and ACA IgG and AgM
Thrombophilia screen
TVS
Hysteroscopy
TORCH profile
Thyroid peroxidase antibody
Autoantibody screen
Total homocysteine
Rubella status
Free androgen index
SHBG

42. Frequency of possible etiological factors in 189 couples
No. (%)
No.of pregnancies
Live birth rate (%)
Idiopathic
103 (54) 75
56 (75)
Thrombophilia
26 (14) 22
14 (64)
Antiphospholipid syndrome
20(11) 19
10 (53)
PCOS
3 (1.6) 7
5 (71)
Abnormal karyotype
9 (4.8)
4 (57)
Hyperhomocysteinemia 15
8 (53)
Hypothyroidism
8 (4.2) 6
3 (50)
Autoimmune antibodies
7 (3.7)
5(83)
Thyroid peroxidase antibody
2 (1.1) 2
2 (100)
Ashermann’s syndrome
1(0.5)
Uterine septum
1 (0.5)
Total
189
159
107 (67)

43. For unexplained RPL
For those women with no documented abnormality, supporting care, including USG is valuable.
Studies have shown this type of therapy to improve the prognosis,with the rate of live birth in the subsequent pregnancy upto 86 %,although the outcome is age related.

44. Obstetric outcome in patients with H/O recurrent pregnancy loss
Patients with H/O RPL are more likely to have
threatened abortion
APH
preterm labour
depressed APGAR at 1 minute
IUGR

45. Management of pregnancy
These patients should be followed up in a specially dedicated facility
Round the clock assistance should be available

46. Last but very important !
RPL management should have a back-up of very efficient and modern neonatal care unit. It should have a good track record of salvaging infants weighing more than 1 Kg.
A sympathetic and caring attitude along with pediatric care can fulfill the desire of parenthood of many of these couples.

47. Some new messages for clinical practice
Past performance is important in prognosticating the outcome.
Live abortion indicate the anatomical cause. Cervical encerclage has a very important role in treating incompetent cervix.
Chromosomal causes are not always gloomy
Immunological causes are most prevalent
APA syndrome has a oxidative stress complex but is easy to treat.
Corticosteroids are not used anymore. Aspirin- heparin combination give best results.
Pregnancy following treatment of RSA are still high risk pregnancies
These patients should be followed very closely and possibility of them undergoing preterm labor should be kept highest in our mind. Timely administration of Betamethasone is a must for fetal lung maturity.

50. Thank You !