Overview of Recurrent Pregnancy Loss

1. • Chairperson Designate ICOG –Indian College of OB/GY
• National Corresponding Editor-Journal of OB/GY of India JOGI
• National Corresponding Secretary Association of Medical Women, India
• Founder Patron & President –ISOPARB Vidarbha Chapter
• Chairperson-IMS Education Committee 2021-23
• President-Association of Medical Women, Nagpur AMWN 2021-24
• Nagpur Ratan Award @ hands of Union Minister Shri Nitinji Gadkari
• Received Bharat excellence Award for women’s health
• Received Mehroo Dara Hansotia Best Committee Award for her work as
Chairperson HIV/AIDS Committee, FOGSI 2007-2009
• Received appreciation letter from Maharashtra Government for her work in the
field of SAVE THE GIRL CHILD
• Senior Vice President FOGSI 2012
• President Menopause Society, Nagpur 2016-18
• President Nagpur OB/GY Society 2005-06
• Delivered 11 orations and 450 guest lectures
• Publications-Thirty National & Eleven International
• Sensitized 2 lakh boys and girls on adolescent health issues
Dr. Laxmi Shrikhande
MBBS; MD(OB/GY);
FICOG; FICMU; FICMCH
Medical Director-
Shrikhande Fertility Clinic
Nagpur, Maharashtra

2. Recurrent Pregnancy
Loss
Dr Laxmi Shrikhande
Nagpur

3. Overview
 Introduction
 Definition
 Incidence
 Aetiology
 Evaluation
 Management
 Summary & Recommendations

4. Introduction
• an emotionally traumatic experience, similar to that
associated with stillbirth or neonatal death
• It is one of the most frustrating and difficult areas in
reproductive medicine because the etiology is often unknown
and there are few evidence-based diagnostic and treatment
strategies.
• Studies on the etiology, evaluation, and management of RPL
are often flawed.

5. Why is studying RPL difficult?
• More than one factor may exist in the same couple
• Lacunae in literature
• Differences in definitions, evaluation protocols
• Variations in treatment regimens even with the same drug
• Randomized trials need to be very large to prove
statistical and clinically significant differences

6. DEFINITION
 The definition of RPL varies, which makes studying the
phenomenon, and determining which couples to counsel or
treat, more challenging.
 Two or more failed clinical pregnancies as documented by
ultrasonography or histopathologic examination .
 Three consecutive pregnancy losses, which are not required
to be intrauterine.

7. Non consecutive Pregnancy loss
There is no specific term for describing
women who have had multiple spontaneous
miscarriages interspersed with normal
pregnancies (ie, non consecutive pregnancy
losses).

8. When to start evaluation ?
 In our practice, we start investigation after two failed
clinical pregnancies, including biochemical pregnancies for
women undergoing IVF.
 Non visualized pregnancy losses (biochemical pregnancy
losses and/or pregnancies of unknown location) have the
same negative impact on future live birth as an intrauterine
pregnancy losses.

9. Types
 RPL can be further divided into primary or secondary
processes .
 Primary RPL refers to pregnancy loss in women who have
never carried to viability.
 In contrast, secondary RPL refers to pregnancy loss in a
woman who has had a previous live birth.
 The prognosis for successful pregnancy is better with
secondary RPL

10. INCIDENCE
 Approximately 15 percent of pregnant women experience
sporadic loss of a clinically recognized pregnancy.
 Just 2 percent of pregnant women experience two
consecutive pregnancy losses and
 only 0.4 to 1 percent have three consecutive pregnancy
losses .

11. Maternal age
 The prevalence of miscarriage is higher with increasing
maternal age and at very early gestational ages
 <6 weeks of gestation the risk of miscarriage is 22 to 57
percent versus
 15 percent at 6 to 10 weeks and
 2 to 3 percent after 10 weeks

13. RISK FACTORS AND ETIOLOGY
Couples who have had a pregnancy loss have two major
concerns:
the cause and
the risk of recurrence.
Unfortunately, the cause of RPL can be determined
in only 50 percent of patients

14. Causes-
General etiological categories of RPL include
 anatomic,
 immunological,
 genetic,
 endocrine,
 infectious,
 thrombophilic, and
 environmental factors.

15. Uterine anomalies : How Common ?
General population 6.3%
Infertile women 7.6%
Women with reproductive failure 16.1%
Saravelos H et al, Hum Rep Update 2008
Acquired and congenital uterine abnormalities are
responsible for 10 - 50 % of RPL

16. Saravelos H et al, Hum Rep Update 2008

17. Possible Mechanisms
 Small cavity, less suitable areas for
implantation
 Vascular compromise
 Mechanical constraints of space
 Cervical incompetence

18. Diagnosis of uterine
anomalies
 Hysteroscopy with laparoscopy is the gold
standard
 Sonosalpingography and 3D ultrasound have
more than 90% accuracy
 Hysteroscopy is the only one which allows a
“see-and-treat” approach

19. Septate Uterus
 The septate uterus is the uterine anomaly
associated with the poorest reproductive
outcome and the most common uterine
abnormality associated with RPL .
 The fetal survival rate in women with
untreated septate uterus is 6 - 28 % and the
miscarriage rate is > 60%.
 The longer the septum, the worse the
prognosis .

20. Reproductive outcome with a T-
shaped uterus
 Of cycles where a T-shaped uterus was demonstrated, none out of 11
(0%) resulted in pregnancy
 Noyes N et al, Hum Reprod 1996
 Women with a T-shaped uterus had the highest rate of first trimester
losses (47%) and lowest rates of term deliveries (21%)
 Golan A et al, J Reprod Med 1992
 Favorable outcomes have been reported after lateral wall metroplasty
 Katz Z et al, Hum Reprod 1996
Garbin O et al, Hum Reprod 1998

21. E C
UT
 Excess of tissue leads to constriction rings around
the proximal uterine segment giving rise to a T
shaped uterus
 Fibrotic tissue is a result of infection (TB), or
trauma

22. The T Shaped Uterus
• Modality for incising
• Monopolar current v/s scissor
• Laparoscopy guidance

23. Leiomyoma —
 Submucous leiomyomas that protrude into the
endometrial cavity can impede normal implantation as
a result of their position, poor endometrial
receptivity of the decidua overlying the myoma, or
degeneration with increasing cytokine production .
An association between pregnancy loss and
intramural or subserous myomas is less clear, having
been demonstrated in some, but not all, studies.

24. Hysteroscopic Myomectomy
Inclusion criteria to
excise a fibroid
hysteroscopically
GnRH agonists before
procedure?
Two stage procedure

25. Intrauterine adhesions —
 Intrauterine adhesions or synechiae lead to pregnancy loss
because there is insufficient endometrium to support
fetoplacental growth.
 The main cause of intrauterine adhesions is curettage for
pregnancy complications.
 Curettage of the endometrium, especially within the first
four weeks postpartum, traumatizes the basalis layer, which
then heals via formation of granulation tissue.

26. Intrauterine Adhesions
Modality
Laparoscopic control
Should they take AKT ?
Placental adhesion

27. Cervical insufficiency —
 Cervical insufficiency is a cause of recurrent mid
trimester, but not early, pregnancy loss

28. Cervix
• Most neglected part of obstetric
sonography !!

29. Incidence
It is estimated that cervical incompetence will
complicate anywhere from 0.5% - 2% of all
pregnancies
CI is responsible for approximately 15% of habitual
immature deliveries between 16 and 28 weeks of
gestation

30. Summary-Anatomical factors
Hysteroscopic surgery is the modality of choice
for treating most cases
Postoperative measures to prevent intrauterine
adhesion formation should be taken
Anatomical causes are a potentially rewarding
etiology to diagnose and treat

31. Immunologic factors —
 Each step in the establishment of normal pregnancy has
been implicated as a possible site of immune-mediated
reproductive failure.
 Both autoimmune and alloimmune mechanisms have been
proposed.
 Since the mechanisms that allow a mother to tolerate her
semi-allogeneic conceptus are not well defined, it is difficult
to assess the role of aberrant immunologic factors in
reproductive failure .

32. Antiphospholipid syndrome —
 Several autoimmune diseases have been linked to poor
obstetric outcome, but antiphospholipid syndrome (APS) is
the only immune condition in which pregnancy loss is a
diagnostic criterion for the disease.
 Primary Antiphospholipid Syndrome (PAPS) refers to the
association of adverse pregnancy outcome and presence of
antiphospholipid antibodies

33. Which antibodies ?
 A number of antibodies have been studied
 The antibodies with the greatest significance and
association with obstetric events are
 Lupus anticoagulant (LA)
 Anticardiolipin antibodies (ACL IgG and ACL IgM)
 Others such as β2glycoprotein-I, antiphosphatidylserine
antibodies, annexin, etc may not be obstetrically
significant

34. Statistical Distribution
• Prevalence of antiphospholipid antibodies in various
categories of women was studied
Women with 3 or
more early fetal
losses
Women with normal
pregnancy outcome
Women who have not
been pregnant
(includes women not
desiring pregnancy
and infertile women)
16% 7% 3%
Parke AL et al, Arch Rheumat 1991

35. Diagnosis of PAPS
 Based on clinical and laboratory criteria
 One obstetric / thrombotic criteria and one laboratory
criteria should be present to diagnose PAPS
 Other autoimmune disease has to be ruled out to make
the diagnosis of PAPS
Wilson A et al, International Consensus statement on APS

36. Obstetric Criteria
Three or more consecutive spontaneous abortion
before the 10th week of gestation
One or more unexplained fetal death at or beyond
the 10th week of gestation
Severe preeclampsia or placental insufficiency
(IUGR) necessitating birth before the 34th week of
gestation

37. Vascular Thrombosis Criteria
 Unexplained venous thrombosis
 Unexplained arterial thrombosis
 Small vessel thrombosis in any tissue or organ, without
significant evidence of inflammation of the vessel wall

38. Laboratory Criteria
 Anticardiolipin antibody IgG or IgM isotype in medium to
high titers by standardized ELISA assay
 Lupus anticoagulant present
 A positive test has to be repeated on at least one more
occasion six weeks apart to fulfill the laboratory criteria

39. Pitfalls in diagnosis of PAPS
 Usually an over diagnosed syndrome
 Not meeting clinical and the strict laboratory criteria
 Not repeating the laboratory test at 6 weeks
 Non standardized ELISA for ACL antibodies
 Inter laboratory variations for phospholipid dependent
coagulation tests used for screening for lupus anticoagulant

40. False results in PAPS
 Improperly collected and processed samples
 Temporal and trimester wise fluctuations
 VDRL positive patients who may or may not have syphilis
 General infections and inflammations
 Coagulopathies and anticoagulant medication users (including
aspirin, heparin)

41. Women with PAPS
without a history of
thrombotic events
(most women with
RPL)
Women with PAPS
with history of
thrombotic events
(past or present)
Prophylactic therapies
such as aspirin, heparin
in pregnancy and 6 to 8
weeks postpartum
Full anticoagulation
with heparin (or
warfarin) in pregnancy
and postpartum
Management

42. When to start treatment
 Aspirin is started when pregnancy is being attempted
or documented.
 Heparin is started as soon as cardiac activity is
documented on TVS.

43. What not to do for PAPS
 Steroid therapy should be avoided for PAPS because it
significantly increases morbidity (hypertension, diabetes,
preterm births) without any demonstrable benefit
 Immunoglobulin therapy is experimental and not for clinical
use at present

44. Endocrinal factors
Endocrine factors may account for 15 - 60 % of
RPL.
Luteal phase defects
Thyroid Dysfunction
DM
Hyperprolactinaemia
Polycystic ovaries

45. Diabetes mellitus —
 Although rare, poorly controlled diabetes mellitus is
associated with early (and late) pregnancy loss.
 The increased risk in poorly controlled diabetic women is
believed to be secondary to hyperglycemia, maternal
vascular disease, and possibly immunologic factors.
 There is no increased risk of miscarriage in women with
well-controlled diabetes mellitus.

46. Polycystic ovary syndrome —
 The miscarriage rate may be as high as 20 - 40 %, which is
higher than the baseline rate in the general obstetric
population (10 -20 %).
The mechanism for excess pregnancy loss in these patients is
unknown, but may be related to-
 elevated LH levels,
 high testosterone and androstenedione concentrations
(which may adversely affect the endometrium), or
 insulin resistance.

47. Thyroid antibodies and disease —
 Some studies have reported an increased rate of fetal
loss in women with high serum thyroid antibody
concentrations (thyroid peroxidase or thyroglobulin),
including those who are euthyroid.

48. Hyperprolactinemia —
 Normal circulating levels of prolactin may play an important
role in maintaining early pregnancy.
 Prolactin levels during early pregnancy were significantly
greater in women who miscarried.

49. Luteal phase defect —
 Progesterone is required for successful implantation and
maintenance of pregnancy; therefore, disorders related to
impaired progesterone production or action are likely to
affect pregnancy success.
 A defect in corpus luteum function (ie, luteal phase defect)
has been hypothesized to be a potential cause of impaired
progesterone production and resultant infertility or
pregnancy failure.
Practice Committee of the American Society for Reproductive Medicine. Current clinical irrelevance of
luteal phase deficiency: a committee opinion. Fertil Steril 2015; 103:e27.
Regan L, Rai R. Epidemiology and the medical causes of miscarriage. Baillieres Best Pract Res Clin Obstet
Gynaecol 2000; 14:839.

50. Genetic factors —
 Genetic factors are a major cause of clinically recognized
miscarriages

51. RM
 parental chromosomal abnormalities occur in either partner
in 5-7% of couples with RM, while the rate in the normal
population is approximately 0.2%
 Balanced translocations in either parent, including reciprocal
and Robertsonian translocations, are the most common
abnormalities, detected in about 4% of couples with RM.
 The other chromosomal abnormalities include inversions and
sex chromosome abnormalities

52. Translocation
Translocation is exchange of chromosomal segments
between two, non-homologous chromosomes.

53. Translocations
Two major types
Robertsonian translocation -two non-
homologous acrocentric
chromosomes break at the centromere and
the long arms fuse. The short arms are
often lost.
Reciprocal translocation- two non-
homologous chromosomes exchange
information
Source- Emery’s book of
principles of Medical Genetics

54. • A 2 breakpoint event
involving one chr, segment
between the break gets
inverted, and reinserted
• Two types-
Pericentric (0.12-0.7%)
Paracentric(0.1-0.5%)
Source- Emery’s book of
principles of Medical
Genetics

55.  Karyotype of the abortus ( fetal/placental
tissue)
 Peripheral blood Karyotyping of the parents in
all couples with RM

56. Thrombophilia and fibrinolytic
factors —
 Thrombosis of spiral arteries and the intervillous space on the
maternal side of the placenta can impair adequate placental perfusion.
 The resulting abnormalities of the uteroplacental circulation may
cause late fetal loss, intrauterine growth restriction, placental
abruption, or preeclampsia.
 A relationship to early pregnancy loss is less clear and may be
restricted to specific thrombophilic defects that have not been
completely defined, or the presence of multiple defects.
 There is a large and contradictory literature on the association
between maternal inherited thrombophilia and RPL occurring in the
first trimester

57. Infection —
Some infections, such as
 Listeria monocytogenes,
 Toxoplasma gondii,
 cytomegalovirus, and
 primary genital herpes, are known to cause sporadic
pregnancy loss, but no infectious agent has been proven to
cause RPL .

58. Decreased ovarian reserve —
 Women with unexplained RPL have a higher incidence of
elevated day 3 FSH and E2 levels than women with a
known cause of RPL .
 As the day 3 serum FSH level increases, the quality and
quantity of oocytes decrease.

59. Environmental chemicals and stress —
 Although a frequent concern of patients, there is no high-
quality evidence showing a relationship between RPL and
occupational factors, stress, or low level exposure to most
environmental chemicals .
 Chemicals that have been associated with sporadic
spontaneous pregnancy loss include anesthetic gases (nitrous
oxide), arsenic, aniline dyes, benzene, ethylene oxide,
formaldehyde, pesticides, lead, mercury, and cadmium .

60. OTHER CAUSES-

61. Personal habits —
 The association between RPL and obesity, smoking, alcohol
use, and caffeine consumption is unclear .
 These factors may act in a dose-dependent fashion or
synergistically to increase the rate of sporadic pregnancy
loss

62.  Pattern and trimester of pregnancy losses and whether a
live embryo or fetus was present
 Exposure to environmental, toxins or drugs
 Known gynecological or obstetrical infections
 Features associated with APS
 Chronic illness-Diabetes mellitus, hypertension, thyroid
 Family history of RPL or syndrome associated with
embryonic or fetal loss
 Previous diagnostic tests and treatments
Evaluation-History

63. Physical
 General physical exam
 Systemic Exam
 Pelvic exam
 TVS
Evaluation

64. • Etiology Investigation
• Genetic/Chromosomal---------------Karyotype both partners
• Anatomical------------------------------HSG or Sonohysterography or USG
• Endocrine-------------------------------TSH , Luteal phase duration, Blood sugar
• Immunological--------------------------Anticardiolipin Antibody , Lupus
anticoagulant , Anti-β2- glycoprotein 1 antibody
• Thrombophilias-------------------------Antithrombin III, Protein C, Protein S,
prothrombin gene,
factor V leiden, prothrombin gene mutation,
Activated protein C resistance
• Infectious-------------------------------- Endocervical swab to detect infection
INVESTIGATIONS

65.  ANA
 Maternal anti-paternal leukocyte antibodies
 Mixed lymphocyte maternal-paternal cell
cultures
 HLA genotyping
 Immunophenotype panels (CD56, CD16)
Evaluation-Tests NOT useful

66. Is there a male factor as well ?
 sperm integrity is required for sperm–egg interactions,
fertilization, and early embryonic development and sperm
quality is associated with the embryo’s ability to reach
the blastocyst stage and progress to implantation
 Microdeletions of the long arm of the human Y
chromosome are associated with variable spermatogenic
failure
 Y chromosome microdeletions are found in approximately
7% of men with very low sperm counts (Ferlin et al.,
2007).

67. Is there a male factor as well ?
 These men also often show a higher incidence of sperm
chromosomal abnormalities (Foresta et al., 2005).
 An elevated rate of sperm chromosome abnormalities has
also been found in some men of RM couples (Rubio et al.,
1999; Egozcue et al., 2000).
 A recent study reports that the incidence of sperm
chromosome abnormalities is 16.5% in male partners of
women with RM, while the incidence is under 5% in controls

68. Sperm fragmentation test
 Mutations and polymorphisms in several genes are suggested
to contribute to RM
 There are a number of assays which are used to analyse
DNA damage.
 Some tests measure DNA damage directly, such as TdT-
mediated-dUTP nick-end labelling (TUNEL) and COMET at a
neutral pH.
 Other tests are indirect, such as the sperm chromatin
structure assay (SCSA), acridine orange test, sperm
chromatin dispersion (SCD test) at acid and COMET at
alkaline pH.

69. SUMMARY AND RECOMMENDATIONS
 Recurrent pregnancy loss (RPL) refers to the occurrence of three or
more consecutive losses of clinically recognized pregnancies prior to
the 20th week of gestation (ectopic, molar, and biochemical
pregnancies are not included). It may be primary or secondary.
 0.4 to 1 percent of women have three consecutive pregnancy losses.
 3 - 5 % of couples with RPL have a major chromosomal rearrangement
(versus 0.7 percent of the general population); usually a balanced
translocation. Recurrent aneuploidy also appears to play a role in RPL.
Chromosomal abnormalities are the most common cause of sporadic
early pregnancy loss, accounting for at least 50 percent of such losses.

70. SUMMARY AND RECOMMENDATIONS
 Uterine abnormalities, both acquired (eg, submucosal
leiomyoma, intrauterine adhesions) and congenital (eg,
septum), have been reported to be responsible for 10 - 50 %
of RPL in small observational studies.
 Pregnancy loss is one of the diagnostic criteria for
antiphospholipid syndrome.
 Endocrine factors (eg, poorly controlled diabetes mellitus,
elevated thyroid peroxidase or thyroglobulin antibodies,
polycystic ovary syndrome, hyperprolactinemia) may account
for some cases of RPL.

71. SUMMARY AND RECOMMENDATIONS
There is no high-quality evidence showing a
relationship between RPL and occupational factors,
stress, or low level exposure to most environmental
chemicals.
RPL typically occurs at a similar gestational age in
consecutive pregnancies. The recurrence risk
increases as gestational age at the time of loss
increases.

72. Unexplained RPL
50% of RPL remain unexplained
Prognosis is still good
>50 % live birth even without intervention

73. ROLE OF
TENDER
LOVING
CARE

75. My World of
sharing happiness!
shrikhandedrlaxmi@gmail.com
Dr. Laxmi Shrikhande
Shrikhande Fertility Clinic
Ph-8805577600 / 8805677600

76. Questions

77. The Art of Living
Anything that
helps you to
become
unconditionally
happy and loving
is what is called
spirituality.
H. H. Sri Sri Ravishakar