- Recurrent pregnancy loss (RPL), defined as two or more pregnancy losses, is a serious problem that impacts women psychologically and socially. - The causes of RPL are often unknown, but can include genetic factors, anatomical abnormalities, endocrine/metabolic issues, autoimmune disorders like antiphospholipid syndrome, and lifestyle factors. - Evaluation of RPL involves screening for causes like thyroid abnormalities, luteal phase defects, hyperprolactinemia, antiphospholipid syndrome, uterine anomalies, and counseling regarding lifestyle modifications. Treatment depends on the underlying cause but may include thyroid supplementation, progesterone, low-dose aspirin, anticoagulants, and surgery.

1. Recurrent
Pregnancy Loss
Dr Madhulatha Alexander, MD
Professor, Government Medical
College, Nizamabad

2. Background
• RECURRENT PREGNANCY LOSS (RPL), either early or late in the gestational
period, is a serious problem and has both psychological and social
impacts on the women who suffer from it
• Incidence before 20 weeks 8–20%, 80% of these occurring in the first
12 weeks of pregnancy
- The real rate of miscarriage may be much higher than reported
- Routine TORCH screening abandoned
Epidemiology and the medical causes of miscarriage.Regan L, Rai R
Baillieres Best Pract Res Clin Obstet Gynaecol. 2000 Oct;

3. Some Definitions
• A pregnancy loss (miscarriage) - the spontaneous demise of a
pregnancy before the fetus reaches viability.
• The term therefore includes all pregnancy losses (PLs) from the time
of conception until 24 weeks of gestation
• Primary RPL R-PL without a previous ongoing pregnancy (viable
pregnancy) beyond 24 weeks’ gestation, while secondary RPL is an
episode of RPL after one or more previous pregnancies progressing
beyond 24 weeks’ gestation.
• By definition, “recurrent” pregnancy loss is defined as the loss of
two or more pregnancies.

4. More definitions…..
• Pregnancy - confirmed by either serum or urine B-HCG, i.e. including non-
visualized pregnancy losses (biochemical).
• Clinical-clinical miscarriage is used when ultrasound examination or histological
evidence has confirmed that an intrauterine pregnancy has existed.
• Ectopic and molar pregnancies ❌
• Implantation failure❌
• Pregnancy losses after spontaneous conception and after ART treatments ✅.
• Recurrent “Early” Pregnancy Loss (REPL) is the loss of two or more pregnancies
before 10 weeks of gestational age

6. When to Investigate
The decision on when
to start investigations
will have to be
decided by the doctor
and the couple, as the
result of shared
decision-making, and
be compliant with
available resources.

7. Risk factors for RPL
20-35 years
> 40
Lowest
Rapidly ↑ after 40
Stress Yes - but no evidence
Occupation/ environment exposure ? Insufficient evidence
Chronic endometritis Further research needed
Endometrial decidualization More studies needed

8. Medical & Family history
• Number of preceding pregnancy losses and female age provide the
best available prognostic information
• (>40% risk after 3 losses)
• Risk of pregnancy loss rapidly ↑after 40 years

9. Screening for genetic risk factors
Genetic analysis – not routinely recommended – but explanatory
purposes
Cytogenetic analysis of products of conception of third and subsequent
consecutive miscarriages
For genetic analysis- array –CGH is recommended based on reduced
maternal contamination
• Parental genetic testing – not routinely recommended , could be
caried out after individual assessment of risk
• Parental peripheral blood karyotyping of both partners, especially
when POC reports unbalanced structural chromosomal abnormality

10. Treatment for RPL with genetic background
• All couples with results of abnormal fetal or parental karyotype
should receive genetic counselling
• All couples with results of abnormal fetal or parental karyotype may
be informed possible treatment options available including their
advantages and disadvantages
• No Treatment available

11. Thrombophilia screening - Hereditary
• Factor 5 Leiden mutation, Protein C , MTHFR mutation
• 2nd trimester abortion – ? screen for inherited thrombophilia ❌
• Unless Research background, / additional risk factors
• No treatment available

12. Acquired Thrombophilia –Anti Phospholipid
Syndrome
• Treatable cause
• Therefore, the authors concluded that it is justifiable to offer testing for
APS to all women with a history of two or more, consecutive or non
consecutive, pregnancy losses (van den Boogaard et al., 201 )
3 Antibodies
Lupus anticoagulant (LA),
Anticardiolipin antibodies ACA- IgG, IgM
β2 glycoprotein I antibodies
(aβ2GPI, IgG, IgM)

13. Revised Sapporo classification criteria
for the APS
• Clinical criteria
• 1. Vascular thrombosis- confirmed by imaging or
HPE
2. Pregnancy morbidity
1. One /> unexplained deaths of a morphologically
normal fetus at or beyond the 10th week of gestation
2. One /> premature births of a morphologically normal
neonate before the 34th week of gestation because
of: (i) eclampsia or severe preeclampsia (ii)
placental insufficiency
3. Three /> unexplained consecutive spontaneous
abortions before the 10th week of gestation, .
•
- Laboratory criteria
- Two positive tests at least 12 weeks apart for
either LA or ACA IgG &/or IgM class present in a
medium or high titre over 40g/L or ml/L or above
99th percentile
•
--Anti-β2 glycoprotein-I antibody of IgG and/or
IgM isotype in serum or plasma, present on 2
or more occasions, at least 12 weeks apart,.
•
Definite APS is present if at least one of the clinical criteria and one of the
laboratory criteria are met, with the first measurement of the laboratory test
performed at least 12 weeks from the clinical manifestation

14. Treatment- Antiphospholipid syndrome

15. Immunological screening
• HLA determination in women with RPL is not recommended in clinical
practice
• Anti HV antibodies directed against male specific minor
histocompatibility antigens –NOT RECOMMENDED
• Cytokines testing, polymorphisms should not be used/tested in
women with RPL
• ANA –could be considered for explanatory purposes
• NK testing – insufficient evidence

16. Metabolic & Endocrine factors
1) Thyroid abnormalities
2) PCOS
3) Prolactin deficiency
4) Luteal Phase Insufficiency
5) Androgens
6) Vitamin D
7) Luteinizing Hormone
8) Hyperhomocysteinemia

17. Metabolic & Endocrine
factors
• Thyroid peroxidase (TPO)
antibodies (TPO-Ab) - disturbed
folliculogenesis, spermatogenesis,
fertilization and embryogenesis
• In the RPL group, the incidence of
subclinical hypothyroidism was
significantly higher in the TPOAb
positive group compared to the
TPOAb negative group (52 vs
16%).

18. Thyroid autoantibodies
• In women with RPL, thyroid peroxidase autoantibodies (TPOAb) are
mostly studied, and shown to be more relevant than antibodies
against the thyroid gland (Marai et al., 2004).

19. Isolated hypothyroxemia
• Defined as a normal TSH concentration in conjunction with FT4
concentrations in the lower 5th or 10th percentile of the reference
range (Stagnaro-Green et al., 2011).
• Associated with an increased risk of obstetric complications and child
neurocognitive impairment, although other studies reported no
association (Lazarus et al., 2014).
• A recent meta-analysis found an association of isolated
hypothyroxinaemia with placental abruption, but not with pregnancy
loss (Chan and Boelaert, 2015).

20. Hyperthyroidism
• Hyperthyroidism-sporadic pregnancy loss, pre-eclampsia, preterm
delivery, and congestive heart failure.
• However, no studies were found that described or searched for an
association between hyperthyroidism and recurrent pregnancy loss
(RPL).

21. Recommendations – Thyroid abnormalities
Treat/ not Evidence
Overt Hypothyroidism (
Before/early preg)
Treat – levothyroxine Strong
Subclinical hypothroidism Conflicting results
If Sub clinical hypothyroidism and
RPL – get pregnant, check TSH
If hypothyroid - treat GPP
Euthyroid, with thyroid antibodies No evidence to treat

22. PCOS
Uncertainty for an association between PCOS and pregnancy loss could
be explained by several factors suggested to be associated with both
PCOS and pregnancy loss, including obesity, hyperinsulinemia, LH
hypersecretion, hyperandrogenism, and thrombophilia (Homburg,
2006, Kazerooni et al., 2013, Ke, 2014).

23. Metformin/ insulin

24. Prolactin deficiency
Prolactin may play an important role in maintaining corpus luteum
function and progesterone secretion, although the mechanism is still
unclear (Li et al., 2013).

25. Bromocriptine for RPL with
hyperprolactinemia

26. Luteal phase insufficiency
• Insufficient progesterone exposure to maintain a regular secretory
endometrium and is allowed for normal embryo implantation and
growth (Palomba et al., 2015).
• Progesterone is essential for secretory transformation of the
endometrium that permits implantation as well as maintenance of
early pregnancy. Luteal phase insufficiency can be caused by several
endocrinopathies, including stress, PCOS, and prolactin disorders (Ke,
2014).

27. Treatment for RPL with Luteal phase deficiency

28. Role of Progesterone in RPL
• “Pregnancy hormone”, is crucial in the maintenance of pregnancy
• In early pregnancy, progesterone is responsible for preparing the
endometrium for implantation and maintenance of the gestational sac
in the uterus
• Start during the luteal phase and continue

29. Dydrogesterone
• Dydrogesterone could be effectively used to prevent miscarriage in women with a
history of idiopathic recurrent miscarriage
• Available evidence is insufficient to recommend the use of vaginal progestogens
(capsule, suppository, micronized, or gel) for the treatment of threatened or
recurrent miscarriage.
• There is insufficient evidence to support the use of injectable progestogens in
miscarriage prevention and treatment.
• There is no evidence to support the use of combination progestogens in the
prevention and treatment of threatened and idiopathic recurrent miscarriage.
Progestogen monotherapy administered in the appropriate dose is recommended
• Manufacturer dosage: 10–20 mg daily, until the 20th week of pregnancy. Treatment should preferably start before
conception.

30. Androgens
• Elevated androgen levels are associated with the retardation of
endometrial development in luteal phase, and have been assessed as
a possible cause of (recurrent) pregnancy loss.

31. Vitamin D
• Vitamin D deficiency has been studied extensively in relation to
obstetric complications and was described as a risk factor for
gestational diabetes, small for gestational age infants and
preeclampsia in systematic reviews

32. Vitamin D

33. Luteinizing hormone
• High serum concentrations of luteinizing hormone (LH) (≥10 IU/L) in
the early to mid-follicular phase, with or without PCOS, have been
associated with an increased prevalence of pregnancy loss in several
reports, both after spontaneous conception and ART (Kaur and
Gupta, 2016).

34. Hyperhomocysteinemia
• Hyperhomocysteinemia (HHcy), - a risk factor for venous
thromboembolism, and adverse pregnancy outcomes (neural tube
defects, pre-eclampsia, and placental abruption).

35. Ovarian reserve testing
• Ovarian reserve can be assessed with measurements of FSH, estrogen
(E2), inhibin B, and anti-Müllerian hormone (AMH), or ultrasound
investigation to determine antral follicle count (AFC) and ovarian
volume.

36. Male factor
• Since there is also clear evidence that sperm DNA damage is caused
by unhealthy lifestyles (such as smoking, obesity and excessive
exercise), clinicians could make couples aware of these risks.
• Antioxidants- no ↑ live birth
• Prospective studies are needed to elucidate these trends further.
• From the literature searched on male factors and RPL few studies
were retrieved, therefore, the search was extended to include studies
on single miscarriage.

37. Anatomical Investigations
• Three-dimensional US allows visualization of the internal and external
contour of the uterus, has high sensitivity and specificity, non-invasive
(Saravelos et al., 2008, Caliskan et al., 2010). STRONG
• It appears to be very accurate for the diagnosis and classification of
congenital uterine malformations and may conveniently become the
only mandatory step in the assessment of the uterine cavity in
women with a history of RPL, although further studies are required
for confirmation (Ghi et al., 2009)

38. Other investigations
• 1) Sonohysterography – uterine malformations, tubal factor
• 2) Mullerian anomaly- Kidneys , Urinary tract needs evaluation
• 3) MRI- not recommended as 1st line, but alternative – 3D USG not
available
CONDITIONAL

39. Treatment of RPL with uterine abnormalities
Treatment Recommendations
Hysteroscopic resection improves outcome Needs further evaluation
Metroplasty – bicorporeal uterus with normal cervix(
Bicornuate Uterus)
NO – Strong
Uterine reconstruction for hemi uterus ( Unicornuate) NO – Strong
Metroplasty – bicorporeal uterus with double cervix(
Didelphic Uterus)
Insufficient evidence
Hysteroscopic removal of sub mucosal fibroids or
endometrial polyps
Insufficient evidence
Intramural fibroids ( distort cavity) Insufficient evidence
Surgical removal of intrauterine adhesions,
precautions for recurrence
Insufficient evidence

40. Role of cerclage
2nd trimester PL with suspected
cervical weakness- offered serial
sonographic surveillance
STRONG
Singleton pregnancy , RPL, history
suggestive of cervical incompetence/
weakness
No evidence that cerclage ↑ perinatal
survival

41. Treatment of Unexplained RPL
Lymphocyte immunization therapy No May have serious adverse effects
IV Ig No
Prednisolone NO Some adverse effects
Folic acid No Prevents NTD , not RPL
Anticoagulants/ aspirin No
Vaginal progesterone No No ↑ live birth rates
Intralipid therapy No Insufficient evidence
Granulocyte colony stimulating
factor
No Insufficient
Endometrial scratching – in luteal
phase , prior to IVF/ICSI
NO

42. Multivitamins

43. Health behavior modifications
FACTOR
Smoking cessation Yes
BMI Obesity
Caffeine Not all studies, unclear
Exercise Conflicting results
Alchohol Xs--yes
Other lifestyle changes Intercourse, soft drugs – cannabis , Xray's

44. Organization of care- RPL
Clinic
Staffing
First visit
Equipment / location
Appropriate evaluation
Care – psychological needs
Treatment plan
Research

45. THANK YOU