overview of recurrent pregnancy loss

1. Recurrent Pregnancy Loss
Dr. Shobhana Mohandas. MD.DGO.FICOG

2. Recurrent pregnancy loss.
Europeans and
British
2 or more clinical pregnancy
losses (USG or HP) but not
necessarily consecutive. Americans
Biochemical pregnancy loss (+ve hCG, no USG
done, or no pregnancy found even if it is done) .
3 consecutive pregnancy losses,
including nonvisualized ones

3. It is reasonable to find the cause
of pregnancy loss after 2
pregnancy losses. Specially
when the woman is more than 35
years of age, or when the couple
have difficulty in conceiving.
BMJ2000:320:1708-12.

5. Uterine
factors
Endocrine
factors
Inherited
thrombophilias
Environmental
and
psychological
factors
Genetic
factors
Antiphospholipid
syndrome

8. Uterine factors
Adhesions

9. Polyps
Fertil Steril 2011;95:1156–8.
Endometritis often co-exists with endometrial polyps.
Antibiotic administration alone or in combination with hysteroscopic
polypectomy was found effective .

12. uterine fibroids increase the risk for
pregnancy loss by affecting implantation or
calcium metabolism in the myometrial
myocytes, resulting in abnormal uterine
contraction .
The rate of pregnancy loss was found to
be reduced significantly following
myomectomy
Reviews in Gynaecological Practice 3 (2003) 75–80

13. Endocrine disorders
Well controlled diabetes is not a risk factor
Anti Thyroid Antibodies ?????
PCOD: Metformin reduces abortion rate

14. PCOS
1st Qtr 2nd Qtr
40%
Continue Metformin in patients with PCOS to prevent
miscarriage.

15. HYPERINSULINEMIA AND INSULIN RESISTANCE
Recurent Abortion + abnormal GTT Metformin is useful

16. Obesity
Independantly
Along with insulin resistance and PCOS
Recurrent miscarriage

17. HYPERPROLACTINEMIA
Rate of successful pregnancy is higher in hyperprolactinemic women
with RSA who are treated with bromocriptine

19. Progesterone
Quiescence of the uterus by suppressing myometrial contractility
via upregulation of nitric oxide synthesis in the endometrium

20. Leuteal phase defect
Decreased progesterone production by
corpus luteum
Seen in 35% of RSA

21. Peripheral
mononuclear
cells from R A
T2 cells
T1 cells
Progesterone and
Dydrogesterone
Natural
Killer
cells(NK)
Inhibits release of Arachidonic acid
Favours protection of pregnancy protecting Antibodies

22. Progesterone
Progesterone-induced blocking factor
Th 1
TNF-α
IFN-γ
IL-2
IL-12
IL-18
Th2
IL-3
IL-4
IL-5
IL-6
IL-10
IL-13
Shift to Th2dominance
Decidual NK
Activity
Asymmetric ABs
• Blocking ABs
• Without effector
functions
• ‘Mask fetal antigens’
Given the crucial immunomodulatory effect of progesterone,
treatment should start immediately at the time of the implantation

23. “Progestogen supplementation is available as
Vaginal suppositories (the authors use 0.4 g/day, preferably in the evening
because natural progesterone can cause tiredness),
Intramuscular injection (250 mg hydroxyprogesterone weekly)
or Oral intake (e.g. 2 × 10 mg dydrogesterone, the stereo-isomer of natural
progesterone).”
KaTharina T. Walch: Best Practice & Research Clinical Obstetrics and Gynaecology : Vol. 22, No. 2, pp.
375–389, 2008

24. Hyperthyroidism is associated with an elevated
rate of fetal loss. (uncommon cause)
In women with subclinical hypothyroidism, gestational age is low at
the time of abortion

25. Immunological causes of recurrent pregnancy failure
Autoimmune causes
(Directed to self)
Alloimmune causes
(Directed to foreign
cells/tissues
Systemic Lupus
Erythymatosus
Anti phospholipid
Antibody syndrome
An abnormal immune
response
to fetal or placental
antigen

26. Acute/subacute cutaneous lupus rash
• Malar rash
• Subacute cutaneous Lupus
erythematosus (SCLE) rash
• Palpable purpura or urticarial
vasculitis
• Photosensitivity
Discoid lupus erythematosus (DLE) rash
or hypertrophic Lupus rash
Non-scarring frank alopecia d
Oral/nasal ulcers
Joint disease
Pleurisy and/or pericarditis
Psychosis and/or seizure and/or acute
confusion
Kidney involvement
• proteinuria≥ 3+ or ≥ 500 mg/day or
urinary casts
• Biopsy-proven nephritis compatible
with SLE
2015 ACR/SLICC Revised Criteria for Diagnosis of
Systemic Lupus Erythematosus
Hematologic
• WBC count < 4000/mm3 or lymphocyte
count < 1500/mm3 on ≥ 2 occasions
or WBC count < 4000/mm3 along with
lymphocyte count < 1500/mm3 in
one occasion
• Thrombocytopenia < 100,000/mm3
• Hemolytic Anemia
Serologic tests
• Low titer positive ANA
• High titer FANA with homogenous or rim
pattern
• Positive anti-ds DNA
• Positive anti-Sm
• Anti-phospholipid antibodies (aPLs)
• Low serum complement (Cand/or
C4and/or CH50)

27. Maternal HLA Paternal HLA
Disparity
Maternal rejection of Fetal cells

28. Antiphospholipid Antibody syndrome

29. Foetal causes (Anti Phospholipid antibody syndrome)
Clinical obstetric criteria
• Three or more consecutive spontaneous losses before the
10th week of gestation.
• One or more premature births before 34 weeks for severe
pre-eclampsia or impaired fetal growth.
• One or more unexplained intrauterine deaths beyond 10
weeks’ gestation.

30. Presence of lupus anticoagulant (LA) in plasma on two
or more occasions at least 12 weeks apart
Presence of moderate to high levels of anticardiolipin
(aCL) (IgG or IgM) in serum or plasma (ie, >40 IgG
phospholipid units (GPL)/mL or IgM phospholipid units
(MPL)/mL or >99th percentile) on two or more
occasions at least 12 weeks apart
Presence of moderate to high levels of anti–beta-2
glycoprotein I antibodies (IgG or IgM) in serum or
plasma (>99th percentile) on two or more occasions at
least 12 weeks apart

31. Protein C,
antithrombin
Protein S,
Pro
coagulants
Anti
coagulants
factorsXII,XI,
X,VII,V,IX etc

32. Abnormality in the system of coagulation
Propensity to form clots
Thrombophilia

33. The factor V Leiden
gene polymorphism
Antiphospholipid
Antibody syndrome
Hyperhomocysteneimia
Prothrombin
Gene mutation
Anti thrombin Deficiency Protein C deficiencyProtein S deficiency.
Increased
PAI
Aquired thrombophilias

34. Deficiency of cystathionine beta-synthase or
5,10-methylenetetrahydrofolate reductase (MTHFR )
Reduced folate, vitamin B12, and B6 intake;
Increased methionine intake
Smoking, coffee drinking;
Renal impairment; thyroid deficiency;
Drugs : methotrexate,
anticonvulsants, cyclosporine, or steroids
Folic acid at a dose of 0.5 to 5 mg daily reduced HCY levels by 25%,
Vitamin B12 at a dose of 0.5 mg/d reduced HCY levels by an additional 7%.

36. Unfractionated Heparin
5000IU 12 hourly
Does not cross the
fetus–placental barrier.
Side effects:
Immune-mediated
thrombocytopenia.
Osteoporosis

37. Low molecular weight heparin
Longer half life
Predictable anticoagulant activity
Enoxaparin 20mg/day, 40mg/day,
40mg twice a day.
Nadroparin 0.3ml/day .

38. Low molecular weight heparin +
Aspirin
IVIG : 400 mg/kg
every 28 days
until 32 weeks of gestation.
Low molecular weight heparin +
Aspirin had more live births

39. Immunomodulation

41. Basis of Immunomodulation

43. Monthly IVIG at 0.4 g/kg/month from eight weeks gestation..
A beneficial effect of IVIG in treatment of RM was not observed. IVIG
treatment is not justified outside the context of properly designed RCTs.
(Fertil Steril 2011;95:1080–5.2011 by American Society for Reproductive Medicine.)
IVIG increased the rates of live birth in secondary recurrent
miscarriage, but there was insufficient evidence for its use in
primary recurrent miscarriage.
Hutton B, Sharma R, Fergusson D, Tinmouth A, Hebert P, Jamieson J, Walker M. Use of intravenous
immunoglobulin for treatment of recurrent miscarriage: a systematic review. BJOG 2007;114:134–142.

44. Corticosteroids
APS complicated by clinically important thrombocytopenia
or coexistent SLE ,gestational diabetes or hypertension
Passaleva et al. reported a cohort-controlled trial and Hassegawa et al. a
case-controlled trial in which the successful pregnancy rate was significantly
increased by steroid treatment of women with APLA’s.
Continuing prednisone past the first trimester was associated
with maternal and fetal morbidity.
Clark DA. Immunological factors in pregnancy wastage: fact or fiction. Am J
Reprod Immunol 2008; 59: 277–300

45. Tempfer et al. (2006) Journal of Reproductive Immunology 93 (2012) 41– 51
Prednisone 20mg/day
Progesterone 20mg/day
Aspirin
Placebo
40/52 18/52
1992

46. Intralipid infusion
Intralipids are a fat emulsion containing soy oil,
glycerine, egg phospholipids and used as parenteral
nutrition in patients unable to take an oral diet.
100 mL of 20% product diluted in 250 or 500 mL of normal
saline infused over 1 to 2 hours.
The initial rate of infusion in adults should be 1 mL/minute for
the first 15 to 30 minutes of infusion.
If no untoward reactions occur the infusion rate can be
increased to 2 mL/minute.
Intralipid has been proposed to be equivalent to IVIg
in its ability to reduce NK cell cytotoxicity and reduce the
release of pro-inflammatory cytokines such as TNF.
A.S. Bansal et al. /
Journal of
Reproductive
Immunology
93 (2012) 41– 51

47. Granulocyte-Colony-Stimulating Factor (G-CSF)
1microgram/kg/day SC, after the ovulation until the recurrence of
menstruation or until the 9th weeks of gestation
A cytokine which stimulates neutrophilic granulocyte proliferation.
Anti-abortive role of G-CSF was found in animal models and trophoblast
of patients with recurrent miscarriage failed to express G-CSF
34 MU/weeks or 2 9 13 MU/weeks until 12 weeks

48. Tumour Necrosis Factor Alfa Therapy
TNF has been shown to inhibit
Extra Villous Trophoblast invasion
When used in conjunction with IVIg, the TNF inhibitors etanercept (Enbrel®)
or adalimumab (Humira®) were found to be significantly helpful in
improving the live birth rate in women with RM compared with those
receiving anticoagulation alone .
A.S. Bansal et al. / Journal of Reproductive Immunology 93 (2012) 41– 51

49. Patients who were treated with Humira underwent an initial two injections of 40 mg
each separated by a 2-week interval.
Approximately 2–3 weeks following the second injection, a second Th1 ⁄ Th2 assay
was performed.
If the initial elevation persisted, an additional two injections were started
approximately 3–4 weeks following the second injection.
The embryo transfer was done a mean of 2 months following the last injection of
Humira.

50. Pregnancy loss classification
Type of loss Typical gestation (weeks) Fetal heart activity
Pre-embryo <6 Never identified
Embryo 6–8 Never identified
Fetal >8–10 Cessation of fetal heartbeat

51. Embryonic losses
Karyotypic abnormalities
Endometrial and
Immunological factors
Anti adhesion molecule
CD56+ , LGL(NK cells)
More T1, less T2
Oligomenorrhoea
Decreased oestrogen
in luteal phase
Role for HCG

52. Who killed
Soumya?
Who killed
T.P.Chandrasek
haran?

53. Bacterial vaginosis
Eliminating even mild microbial infection and used well
before artificial or natural implantation . Drugs with
a strong history of safety in pregnancy and action against
Chlamydia and Mycoplasma in particular would appear
to be best, particularly if they also have additional antiinflammatory
action.
Eliminating/reducing candidal infection/colonisation as an
additional means of reducing endometrial inflammation.

54. Vitamin D
Measuring and correcting subnormal levels of vitamin D
should certainly be undertaken with a view to normalising
an unhelpful pro-inflammatory T cell environment.
Journal of Reproductive Immunology 93 (2012) 41– 51

55. Stress
Increase mucosal permeability for small
molecules.
Bacteria are necessary to maintain
T – cell immune response.
Probiotics can restore microbial
homeostasis in the intestine.
It can improve immune response
The International Journal of Biochemistry & Cell Biology 40 (2008) 2348–2352
Enhance the uptake of bacteria/bacterial
products

56. Karyotypic abnormalities
Only structural abnormalities like translocations
or inversions can be transmitted
Foetal karyotyping?
Parental karyotyping?

57. Male factor
Perhaps, antioxidants will not only help reduce sperm DNA fragmentation
rates but will also lower pregnancy loss rates.
Greco E, Iacobelli M, Rienzi L, et al. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant
treatment. J Androl 2005; 26:349–353. A prospectively randomized trial using oral vitamin C and E reduced
sperm DNA fragmentation that did not affect basic semen analysis parameters. A well done
study.

58. Age
< 35 years No effect
> 35 years 75% Increase
> 40 years 5 fold increase
Weight Underweight : 72% increase
Nausea 70% less risk
Folic acid, vitamins
Vitamins reduced risk by 50%
Specially, folic acid, multivitamins
and iron
Fresh fruits, vegetables, diary products
Work
Stress at work incresed risk
Long standing or lifting heavy
Weights did not
Staying Happy 60% reduction in odds
Air travel No risk
Intercourse No increased risk
Double increase in bleeding cases

59. Anti oxidants
Impaired antioxidant defence may be responsible for
recurrent abortions,
The recurrent abortions may result in oxidative stress and
depletion and weakness of antioxidant defence.
P. Vural et al. / Clinica Chimica Acta 295 (2000) 169 –177
albumin, ascorbic
acid
a-
tocopher
ol,
, total
thiols
cerulopla
smin,
uric acid,
erythrocyte
glutathione
(GSH

60. HSG, 3-D USG,Hysteroscopy
Rule out PCOD
Prolactin levels, Thyroid testing, antithyroperoxidase antibody levels
Hb1Ac levels,GTT
Parental karyotyping

61. Sujat
Torchnil