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Recurrent Pregnancy Loss
MOSTAFA ABUZEID, M.D., F.A.C.O.G., F.R.C.O.G.
Director of Division Reproductive Endocrinology and Infertility, Michigan State University, College of Human Medicine, Flint Campus, Michigan
Practice and Medical Director, IVF Michigan Rochester Hills & Flint PC, Michigan
Professor of Obstetrics and Gynecology and Reproductive Biology, Michigan State University,
College of Human Medicine Flint Campus, Michigan
Objectives
Scope and magnitude of the problem
Etiology
Genetic factors
Anatomical Factors
Unexplained RPL
RPLDefinition
• Two or more failed clinical pregnancies
A clinical pregnancy that is documented by:
Ultrasonography or histopathological
examination”.
Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103–1111
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RPL Scope and magnitude of the problem
Incidence: Sporadic pregnancy loss: 10‐15% of all clinically recognized pregnancies
RPL: Affects 1% of all women in reproductive age
Timing of recurrent pregnancy loss: Most cases are either pre‐embryonic or embryonic
Fetal loss (>9 weeks) is less common
Loss beyond 14 weeks is infrequent
RPL Scope and magnitude of the problem
• The incidence of RPL increases with increasing maternal age to reach 1 in 4 by age 40
• This correlates with the occurrence of meiotic nondisjunction at the oocytes’ level reaching 50% by the age of 43
Abnormal embryos increase with maternal age
0.0%
10.0%
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30.0%
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60.0%
70.0%
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<35 35-36 37-38 39-40 41-42 43-44 >44
50.2%54.9%
58.5%
71.9%
85.1%86.5%
91.2%
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Ovarian reserve testing
Miscarriage rate increases with increased maternal
age, due to the increased incidence of aneuploidy
Patients with diminished ovarian reserve have higher
occurrence rate of aneuploidy and thus higher incidence
of RPL compared to the general population
Place of ovarian reserve test in the work up of RPL
RPL: Scope and magnitude of the problem
The Risk of Recurrent Early Pregnancy Loss in Young Women
Number of Prior Miscarriages
% Risk of Miscarriage in Next Pregnancy
Women who have had at least one liveborn infant:
0 12%
1 24%
2 26%
3 32%
4 26%
6 53%
Women who have not had at least one liveborn infant:
2 or more 40-45%
Clifford, et al. Hum Reprod 1997;12:387
RPL: Etiology
• Genetic factors• Anatomical factors• Endocrine Factors• Infectious Causes• Environmental Factors• Cervical Insufficiency • Thrombophilia• Immunologic problems • Unexplained RPL
Clinical Gynecologic Endocrinology and Infertility, 6th Ed. Speroff L., Glass RH and Kase NG (eds). Lippincott Williams & Wilkins,
1999. Chap 27, p 1044‐1052
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Endocrine Causes
Mild endocrine diseases are likely not causes for recurrent abortion
Significant thyroid disease, poorly controlled diabetes, or significant hyperprolactinemia can result in spontaneous abortion
Patients with PCOS who have elevated serum insulin levels have been found to have a higher incidence of spontaneous abortion
Microbiologic causes
Selected organisms such as Ureaplasma urealyticum,
Mycoplasma hominis, chlamydia, Listeria monocytogenes,
Toxoplasma gondii, rubella, cytomegalovirus and herpes virus were
identified in POC samples after spontaneous miscarriages
An association between inflammation in the endometrium and
RPL has been suspected, but has not been confirmed
Treatment of both partners with doxycycline has been suggested
ASRM and other societies do not recommend routine testing
and treatment
The Practice Committee of ASRM. Fertil Steril 2012; 98 (5): 1103‐1111Khalife D et al. Seminars in perinatology 43 (2019) 105-115
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Environmental ,lifestyle, and occupational factors
Cigarette smoking, cocaine use, alcohol (>4 drinks per week) and
caffeine consumption (>3 cups per day or 300 mg/day) have all
been associated with an increased risk of RPL via an
unfavorable effect on trophoblast invasion.
Multiple studies have concluded that obesity (BMI>30 kg/m2) is
associated with an increased risk of miscarriage.
Both ASRM and other societies suggest that weight loss should be
emphasized prior to conception in order to decrease
recurrent miscarriages.
Khalife D et al. Seminars in Perinatology 43 (2019) 105-115
Other environmental factors
Isotretinoin
Anesthetic gases
Tetrachloroethylene (used in dry cleaning)
Women working in pharmaceutical industry
Vitamin D testing
A recent study highlighted the significant
association between vitamin D deficiency and RPL
(RR 0.88 (95% CI 0.770.99).
It has been suggested that all women with RPL
have levels of 25‐hydroxy vitamin D tested and
normalized to >30 ng/ml pre‐conceptually to
minimize pregnancy loss
Khalife D et al. Seminars in Perinatology 43 (2019) 105-115
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RPL: Genetic Factors
Chromosomal abnormalities Autosomal Trisomy 50%
‐ Nondisjunctional or translocation
‐ Trisomy 16
‐ Trisomy 22, 21, 15, 14, 13 and 18
Monosomy (45X) 25%
Polyploidies 20%
Structual abnormalities 5%
Autosomal Monosomy very rare
Sex Chromosome Polysomy very rare
RPL: Genetic Factors
Embryo or Fetal chromosomal abnormalities:
‐ First‐trimester miscarriages 70%
‐ Second‐trimester 30%
‐ Stillbirths 3%
Newborn chromosomal abnormalities 0.5%
RPL: Genetic Factors Parental chromosomal abnormalities 3‐5%
Most common aberration
‐ Balanced translocation
Other abnormalities‐ Sex chromosome mosaicism‐ Chromosomic inversions‐ Ring chromosomes
Abnormalities of meiosis‐ sperm cell lines
Rare (1/2500)‐ Robertsonian Translocation (homologous chromosomes)
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RPL: Genetic Factors
Parental Balanced Translocation
3‐5% of couples with RPL
Reciprocal or Robertsonian
Segregation during meiosis Gamete with duplication
or deletion of chromosomes
Chance of pregnancy with Unbalanced Translocation 5‐10%
Couple with RPL should undergo Karyotyping
Role of Preimplantataion Genetic Diagnosis (PGD)
Role of amniocentesis or chorionic villus in ongoing
pregnancy
Robertsonian and reciprocal translocation
The key difference between Robertsonian and reciprocal translocation is that Robertsoniantranslocation refers to the exchange of genetic material between five acrocentric chromosome pairs (13, 14, 15, 21 and 22), which causes the reduction of usual chromosome number in a cell
While reciprocal translocation refers to the exchange of genetic material between non homologous chromosomes, which do not cause a change in chromosome number
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Robertsonian translocation
Indications for chromosomal analysis
Recurrent miscarriages
Malformed or mentally retarded child
A child with known chromosomal abnormalities
Evaluation of products of conception
Routine karyotype analysis
‐ High proportions of failure of cell culture
‐Maternal cell contamination of the specimen
Single nucleotide polymorphism (SNP) microarrays technique
‐ Amplification of DNA
‐ Eliminating the possibility of maternal contamination
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RPL: Anatomical Factors
Congenital
Acquired
RPL: Anatomic factorsCongenital
Patients with a uterine septum have the highest incidence
of RPL (44.3%) followed by bicornuate (36%) and arcuate
uteri (25.7%)
Hysteroscopic removal of septum should be considered as
it has been shown that live birth rates may improve up to
90.9%
Grimbizis GF et al.Clinical implications of uterine malformations and hysteroscopictreatment results. Hum ReprodUpdate. 2001;7(2):161–174
RPL: Congenital Uterine Anomalies
Septate Uterus:
One of the poorest reproductive outcomes
Spontaneous Abortion:*
‐ 25.5% incidence of early miscarriage (< 13 weeks)*
‐ 6.2% incidence of late miscarriage (14 to 22 weeks)*
Cervical incompetence related?
Premature birth:**
‐ Increased ~ 21%
‐ Fetal survival rates are estimated at 32%
Reproductive outcome is improved after hysteroscopic resection
* Raga et al: Hum Reprod 1997;12(10):2277 **Devi Wold et al: Semin Reprod Med. 2006;24(1):25
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Hysteroscopic correction of an incomplete uterine septum
Results
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Clinical preg rate perpatient
Delivery/ongoing rate perpatient
74.4%
65.4%67.3%
60.2%
(%)
Group 1
Group 2
ESHRE – 2012Istanbul, Turkey
Ashraf et al. Hum Reprod, July 2012, 27, Supplement 2, Page ii14‐ii16, O‐033Abuzeid et al. FVV in ObGyn 2014, 6 (4): 194‐202
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RPL: Anatomical Factors
American Fertility Society. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, müllerian anomalies and intrauterine adhesions. Fertil Steril. 1988;49:944‐55.
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3‐D Diagnosis Uterine Anomalies
Strassmann metroplasty
Recurrent Pregnancy Loss
3‐D Diagnosis Uterine Anomalies
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ASRM
Practice Committee of the American Society for Reproductive Medicine. Uterine Septum: a guideline 2016
ESHRE/ESGE classification of uterine anomalies
Figure 2 ESHRE/ESGE classification of uterine anomalies: schematic representation (Class U2: internal indentation .50% of the uterine wall thicknessand external contour straight or with indentation ,50%, Class U3: external indentation .50% of the uterine wall thickness, Class U3b: width ofthe fundal indentation at the midline .150% of the uterine wall thickness).
Grimbizis et. al. The ESHRE/ESGE consensus on the classification of female genital tract congenital anomalies. Hum Reprod.2013;28(8):2032‐2044.
International Federation of Gynecology and Obstetrics (FIGO) classification system for fibroid location. (Adapted from Munro MG, Critchley HO, BroderMS, Fraser IS; for the FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM‐COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age
ASRM. Myomas, myomectomy, and fertility. Fertil Steril2017 Int J Gynecol Obstet 2011;113:3‐13. Published by Elsevier Ireland Ltd. Reprinted by permissio nof Elsevier
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DOES HYSTEROSCOPIC RESECTION OF SUBMUCOSAL MYOMAS AFFECT MISCARRIAGE RATES?
There is insufficient evidence to conclude that hysteroscopicmyomectomy reduces the likelihood of early pregnancy loss in women with infertility and a submucous fibroid
(Grade C)
Grade C: There is insufficient evidence to support the recommendations, either for or against.
Practice Committee of the ASRM Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline, Fertil Sterill. 2017;108(3): 416-425
Acquired uterine abnormalities
Impact of Partial Ashermann’s syndrome on Miscarriage rate
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The Practice Committee of ASRM. Fertil Steril 2012; 98 (5): 1103‐1111
Inherited thrombophilias
Routine screening is for now not endorsed
ASRM and Other societies recommend that testing for
inherited thrombophilias in the setting of RPL only limited
to patients with:
‐ Personal or strong family history of venous
thromboembolism
‐ Additional risk factors for thrombophilias
The Practice Committee of ASRM. Fertil Steril 2012; 98 (5): 1103‐1111
Other immune abnormalities
Similarities in human leukocyte antigens(HLA) genotypes,
HY antigens
The presence of embryotoxic factors, and cellular immune
markers including:
‐ Cytokine testing
‐ Natural killer and T cell immunity assays.
None of these tests are routinely recommended by the
ASRM or other societies
Further research is needed before advising any treatment
The Practice Committee of ASRM. Fertil Steril 2012; 98 (5): 1103‐1111
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Women with recurrent miscarriages who are more likely to have an immunologic cause if they have the followings except:
1. Have a history of previous spontaneous miscarriages
2. Are over 35 year old
3. Have aborted conceptus with a normal karyotype
4. Usually have at least one loss after the first trimester
5. Have no recent full term pregnancies
PGS and Unexplained RPL
Role of PGS in treatment of unexplained RPL One recent study reported a 41.1% incidence of
abnormal embryonic karyotype in patients who had a
negative work‐up for RPL, suggesting the true
incidence of unexplained RPL to be approximately 24.5%*
In addition, a recent study by Hodes‐Wertz et. al.,
suggested that unexplained RPL is mostly caused by
chromosomal abnormalities, with only a residual 6.9%
miscarriage rate are due to unexplained factors**
* Sugiura‐Ogasawara M et al. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage. Hum Reprod. 2012;27:2297‐2303.**Hodes‐Wertz B et al. Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos. Fertil Steril. 2012;98(3):675‐580.
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Role of PGS in treatment of unexplained RPLIn patients with idiopathic RPL, the work by Murugappan et. al., suggested that expectant management of RPL is as successful as IVF‐ET with PGS, and had a lower median time to pregnancy.
Murugappan G et al. (2016). Intent to treat analysis of in vitro fertilization and preimplantation genetic screening versus expectant management in patients with recurrent pregnancy loss. Hum Reprod. 2016;31:1668‐74
The Role of Diagnostic Hysteroscopy in Diagnosis of Incomplete Uterine Septum in Patients with Recurrent Pregnancy Loss in the Era of Transvaginal 3D Ultrasound Scan
Abuzeid O et al. Gynecol Surgery 2019;16:14
Figure 5: Comparison between the mean IILFM measured in mm on hysteroscopy and on TV 3D US in patients with PSUAA, with PSUOA and in the overall population
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15
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25
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Overall Population Incomplete Uterine Septum Arcuate Uterine Anomaly
15.3 + 5.1 18,5+6.5
14.1+3.8
4.9+4.4 6,3+6.3 4.3+3.4
Internal Indentation Length at the fundal midline in mm on Hysteroscopy Internal Indentation Length at the fundal midline in mm on TV 3D US
mm
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*
*
Abuzeid O et al. Gynecol Surgery 2019;16:14
The Role of Diagnostic Hysteroscopy in Diagnosis of Incomplete Uterine Septum in Patients with Recurrent Pregnancy Loss in the Era of Transvaginal 3D Ultrasound Scan
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Conclusions:
The data suggest that mean IILFM in patients with unexplained RPL and PSU can be underestimated on TV 3D US
Therefore, the diagnostic accuracy of TV 3D US in such patients may need further evaluation
All patients with unexplained RPL should undergo a diagnostic hysteroscopy to rule out PSU irrespective of the finding on TV 3D US
Summary of Laboratory Evaluation and Management for Repeated Early Pregnancy Losses
Category Evaluation Treatment
Normal Statistics Numbers review, No lab tests Education and support
Genetic Factors Karyotypes of both parents CounselingDonor gametes where appropriate
Environmental Factors No lab tests Counseling
Endocrine Factors TSH, prolactin, luteal phase assessment
Empiric clomiphene
Anatomic Causes Vaginal ultrasound with saline instillation, confirmed by MRI
Surgery
Clinical Gynecologic Endocrinology and Infertility, 6th Ed. Speroff L., Glass RH and Kase NG (eds) . Lippincott Williams & Wilkins, 1999. Chap 27, p 1044
Summary of Laboratory Evaluation and Management for Repeated Early Pregnancy Losses (continued)
Category Evaluation Treatment
Infectious Causes Cultures if clinically indicated Empiric doxycycline or erythromycin
Thrombophilia Screen for inherited predisposition for thrombosis
Low molecular weight heparin anticoagulation
Immunologic Activated partial thromboplastin time, kaolin clotting time, anticardiolipin antibody, lupus anticoagulant
Low-dose aspirin and heparin
Clinical Gynecologic Endocrinology and Infertility, 6th Ed. Speroff L., Glass RH and Kase NG (eds) . Lippincott Williams & Wilkins, 1999. Chap 27, p 1044
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RPL: Treatment Modalities
Prognosis for Viable Birth*
STATUS INTERVENTION PER CENT
Genetic factors Timed intercourse and supportive care 20 – 90
Anatomic factors Surgery and supportive care 60 – 90
Endocrine factorsLuteal phase deficiency
Progesterone and/or ovulation induction with or without pituitary desensitization Supportive care
80 – 90
Hypothyroidism Thyroid replacement and support care 80 – 90
Infections Appropriate antibiotic and supportive care
70 – 90
Antiphospholipid syndrome Aspirin, heparin, and supportive care 70 – 90
Th1 cellular immunity Progesterone immunosuppression and supportive care
60 – 90
Unknown factors Timed intercourse with supportive care 60 – 90
*Derived from more than 1000 cases at Brigham and Women’s Hospital
Hill JA. Recurrent pregnancy loss, In: Creasy and Resnick (eds). Maternal‐Fetal Medicine, 4th edition. SB, Saundes Co., NY, 1998.
Summary
The majority of miscarriages are sporadic and are
thought to result from genetic causes that are
greatly influenced by maternal age
Recurrent pregnancy loss is defined by two or
more failed clinical pregnancies
Up to 50% of cases of RPL will not have a clearly
defined etiology
The Practice Committee of ASRM. Fertil Steril 2012;98(5):1103‐1111.
Conclusions
Evaluation of RPL can proceed after two consecutive clinical
pregnancy losses
Assessment of RPL focuses on screening for genetic factors and
antiphospholipid syndrome, assessment of uterine anatomy,
hormonal and metabolic factors, and lifestyle variables
These may include:
‐ Peripheral karyotypic analysis of the parents
‐ Screening for lupus anticoagulant, anticardiolipin antibodies,
and anti‐B2 glycoprotein I
‐ Sonohysterogram, hysterosalpingogram, and/or hysteroscpy
‐ Screening for thyroid or prolactin abnormalities
The Practice Committee of ASRM. Fertil Steril 2012;98(5):1103‐1111.
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