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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%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

100.0%

<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

. 

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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10

15

20

25

30

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

*

*

*

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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