Recurrent Pregnancy LossACOG District II, April 30, 2016

John T. Queenan, Jr., MDProfessor

Reproductive EndocrinologyDepartment of Obstetrics and Gynecology

University of Rochester Medical CenterRochester, NY

Conflict of Interest

I don’t have financial interest or other relationships with the industry relative to the topics being discussed.

I will not discuss any drugs by their brand names

Lecture Objectives

After this lecture, participants should be able to: Describe the numerous causes of recurrent

pregnancy loss

Understand how to diagnose the anatomic, autoimmune, endocrine, infectious, and genetic factors associated with RPL

Formulate a diagnostic plan to identify treatable causes

Miscarriage

The most common complication of pregnancy (15-25%)

Definition: the spontaneous loss of a pregnancy before a fetus has reached viability.

Embryonic Loss after Implantation

Cycles Studied 623

Pregnancy Detected 152

Clinically Detected 102

Lost after clinical detection 4 (14%)

623 cycles in 197 ovulating women aged 25-35

Wilcox AJ et al NEJM 1988

Lost after hormonal detection 66 (43%)

Cycles Studied

623

Pregnancy Detected

152

Clinically Detected

102

Lost after clinical detection

4 (14%)

US Dept Health and Human ServicesSurvey of Married Women in the United States

5% have experienced two fetal losses

1-3% have experienced three or more losses

U.S Vital and Health Statistics Series 23, No. 11

Definitions of RSAb

Three, consecutive: used for epidemiologic studies

Clinical definitions:Three, any order2 (1st) or 1 (2nd) trimesterThree, [SAb, any anomaly, or stillborn], any order“Two or three or more” ACOG 2011“Two or more” ASRM 2012

Continuum of Causation

LATE IUGR Retardation CNS disorders Delayed growth

and development Stillbirth

EARLY Biochemical

pregnancy Missed Abortion Spontaneous

losses

from Genetics, Obstetrics & Gynecology. Simpson, Elias 3rd ed.

Etiologies

Anatomic Autoimmune Endocrine Infectious Genetic Idiopathic (~40%)

Anatomic Causes10-15% of patients presenting with RSAb

Cervical Incompetence

Uterine septum Adhesions Polyps Fibroids Müllerian Anomalies

Uterine AnomaliesDiagnosis may be aided by MRI, 3-D sono, laparoscopy

Cerclage: for h/o 2nd trimester loss or progressive cervical shortening

Uterine Septum

80-90% of anomaliesin RSAb pts.

SAb rate for the septate uterus is 65%

After resection, 80% term delivery, 5% preterm delivery, 15% SAb rate

Grimbizis GF et al Hum Reprod Update 7:161, 2001

Definite Causes of IUA (Äsherman’s) in 1856 CasesTRAUMA AFTER PREGNANCY

Curettage after abortionPostpartum curettageCesarean SectionEvacuation of molar pregnancy

%67 222

0.6

Schenker, Margalioth. Fertil Steril 1992

Definite Causes of IUA (Äsherman’s) in 1856 Cases

PREGNANCY w/o TRAUMAPostpartum, post abortal

TRAUMA w/o PREGNANCYMyomectomyD + CEndo. Biopsy/polypectomy

INFECTION Pelvic TB

%1.5

1.31.20.5

4.0

Schenker, Margalioth. Fertil Steril 1992

Äsherman’s syndromeCase Series only. No RCTs

After hysteroscopic resection in 187 subjects: 76% conceived. Of those, 80% went to term, 18% aborted, 2% ectopic

Valle and Sciarra Am J Obstet Gynecol 1988

85% viable pregnancy rate after resection and short-term IUD placement

Ismajovich et al J Reprod Med 1985

Polyps and fibroids within the cavity should be excised if causing symptoms or are the only RSAb factor found

Polyps

Fibroid

Intramural fibroids that do not distort the cavity can grow up to 5-7 cm before they affect implantation

Endocrine Causes

Rules of Thumb: Well-controlled DM is not associated with

increased risk of RSAb

Significant thyroid disease and Diabetes are associated with increased risk, but are almost always clinically evident before RSAb.

Hypothyroidism screening

ACOG says “no longer recommended”

A high prevalence (3-10%) in reproductive age women supports checking TSH

Increased miscarriage rate for patients with hypothyroidism + subclinical hypothyroidism

Correction to the euthyroid state is simple, and you should aim for TSH < 2.5 µU/ml

Speroff, Fritz. 8th ed

Hypothyroidism: confirmed

Levothyroxine requirements increase in 85% of pregnant patients

Onset as early as 5th week of gestation

Given the importance of the euthyroid state on fetal development, recommend increase levothyroxine dose 30% once pregnancy is confirmed

Alexander et al New England J Med 2004

Prolactin

64 patients with 2 or more losses and ↑Prolactin

85.7% live born rate when treated with dopamine agoinst

52.4% live born rate if untreated

Hirahara F et al Fertil Steril 1998

The role of P4 in RSAbTwo Meta-analyses of patients

prospectively randomized to Placebo vs. Progesterone failed to show any benefit of Progesterone in preventing SAb in patients with prior sporadic miscarriage.

Goldstein P et al. Br J Obstet Gynaecol 1989; 96:265-74Oates-Whitehead TM Cochrane Database Syst Rev 2003

The role of P4 in RSAbHowever, a subgroup analyses of

women with recurrent miscarriage suggests that progesterone use in the first trimester might be of benefit.

Goldstein P et al. Br J Obstet Gynaecol 1989; 96:265-74Oates-Whitehead TM Cochrane Database Syst Rev 2003

AUTOIMMUNE RSAbAntiphospholipid Syndrome

Laboratory: Positive if present on two occasions at least 12 wks apart

Lupus Anticoagulant Kaolin Clotting Time

Russell’s Viper Venom Test

AntiCardiolipin Antibody IgM or IgG (>99 %ile)

Beta2-Glycoprotein 1 Antibodies IgM or IgG (>99 %ile)

ACOG Practice Bulletin #118, 2011

Cochrane Database of Systematic Reviews

RSAb with APS (+LAC or +ACL):

Treatment with unfractionated heparin and baby ASA reduces pregnancy losses by 54% (Level 1 evidence)

No advantage: LMWH vs. unfractionated No advantage: low dose vs. high dose

unfractionated heparin

AUTOIMMUNE RSAb

Many patients (and many MDs) are tempted to use anticoagulation/Baby ASA for “presumed” autoimmune RSAb.

Borderline LAC and/or ACL titers Elevated titers once, not confirmed >12 wks

later Frustration with no other etiology found

ALFIE StudyAnticoagulants for Living Fetuses

4 yr study, 8 academic centers 364 women with 2 or more losses Negative RPL work-up Randomized to: ASA, LMW Heparin/ASA, or

placebo

“Trial halted early on the basis of futility.”

Kaansdorp S et al N Engl J Med March 24, 2010

Inherited

Factor V LeidenPGMAnti-Thrombin IIIProtein SProtein C MTHFR

Are prevalent in the general population

Were previously thought to cause RSAb

Autoimmune RSAbThrombophilias

Prevalence of Thrombophilias

Factor V Leiden – 3-8% Prothrombin G20210A mutation – 1-4% *Protein C deficiency - 0.15-0.8% *Protein S deficiency – 0.1% Antithrombin III deficiency – 1/5000 *Hyperhomocysteinemia (MTHFR mutation) –

11%Thrombophilias collectively present in up to 20% of Western population

* Results affected by pregnancy

AUTOIMMUNE RSAbInherited Thrombophilias

“Causal link cannot be made between inherited thrombophilias and adverse pregnancy outcomes.”

“Inherited thrombophilia testing in women who have experienced recurrent fetal loss is not recommended because it is unclear whether anticoagulation reduces recurrence.”

ACOG Practice Bulletin #113, 2010

Idiopathic RSAb (~40%)

After three consecutive losses, the chance for a liveborn in the next pregnancy is 70%

“No therapy” is often a valid approach TLC has proven benefits in some

studies

Cochrane Database of Systematic Reviews

Idiopathic RSAbNo effect from:

Vitamin supplementation (2005) Bedrest before 23 weeks (2005) Immunotherapy (2005) Anticoagulants (2005) Human chorionic gonadotropin (2005)

Cochrane Reviews 2005

Cochrane Database of Systematic Reviews

Idiopathic RSAbNo effect from:

Anticoagulants for women w/o APAb Any vitamins taken before 20 wks IVIG Paternal cell immunizations Third party donor leukocytes

Cochrane Reviews 2007

Internet as a portal (for misinformation)

“Automimmunity has no symptoms” “What your doctor isn’t telling you” “Miscarriages are occurring at implantation”

Steroids Acupuncture Plaquenil Antibiotics Intralipid Herbal remedies IVIG

CHRONIC ILLNESS

Any systemic disease which may compromise the host, the uterine vasculature in particular, may be a cause of RSAb.

Examples include: heart disease, chronic hypertension, renal failure, collagen vascular disease, uncontrolled DM

Obesity (BMI>30 vs.19-25)

Odds Ratio C.I. P

First Trimester Loss 1.2 1.01-1.46 0.04

Recurrent Miscarriage 3.5 1.03-12.01 0.04

Lashen et al Hum Reprod 2004; 19:1644-46.

Environmental Exposures

Tobacco Alcohol Caffeine Lead Mercury PCBs Pesticides Radiation

Chromosomal Abnormalities in the aborted embryo/fetus

First trimester losses 50-60%

Second trimester losses 30%

Stillborn 3%

Teratology 12:11, 1975Perinatal Genetics 133; 1986Fertil Steril 33:107, 1980Birth Defects 29:53, 1993

Chromosomal Abnormalities in the aborted embryo

FISH; Comparative Genomic Hybridization (not culture dependent)

First trimester losses 75%

Human Reproduction 18:1724, 2003Eur J Hum Genet 9:539, 2001

Couples with Habitual Abortion

ABNORMAL PARENTAL KARYOTYPES:

Women: 6.2%Men: 2.6%Overall: 4.4%

Couples with Habitual Abortion

High frequency of karyotypicabnormalities in POC

Low frequency of karyotypicabnormality in either parent

Fetal chromosomal aberrations may arise spontaneously from random errors in meiosis and mitosis of either the sperm or the egg

These errors may be induced by exposure to noxious agents and could occur repetitively

Types of genetic Errors in SAb

Numerical 90% Aneuploidy Polyploidy

Structural 10% Mosaicisms Inversions Reciprocal and Robertsonian Translocations

Genetic Counseling

For structural chromosomal abnormality:Outcome will depend on which chromosome is

affected, the type and location of the rearrangement

Couple should be offered amnio, CVS, PGD, or donor gametes

Cytogenetic analysis of future POCs

Numerical: Aneuploidy Too many or one too few chromosomes (e.g.

trisomy, monsomy, tetraploidy etc.)

Not present in the parental karyotypes

Nondisjunction: accident of parental meiosis at the time of fertilization or early cell division in the zygote

Associated with advancing age of the female

At present, women more often will deliver over the age of 30 than under in Western Societies.

Platteau et al Fertil Steril 84:319, 2005

The majority of embryos derived from women over the age of 37 are chromosomally abnormal.

Munné S Fertil Steril 1995Marquez C RBM Online 2000Stephenson Hum Reprod 2002

Miscarriage rates by age at conceptionAge (years) Pregnancies (#) SAb Rate

20-24 350,395 9%25-29 414,149 11%30-34 235,049 15%35-39 93,940 25%40-44 25,132 51%

≥45 1,865 75%Nybo Andersen AM et al BMJ 2000; 320:1708-12.

Consensus

Fecundity decreases with advancing maternal age

Miscarriage increases with advancing maternal age

Reduced fecundity is associated markedly with chromosomal anomalies in the products of conception.

Preimplantation Genetic Diagnosis (PGD)

The opportunity to exclude (in-vitro derived) embryos with documented genetic abnormalities before the initiationof pregnancy

PGD vs. PGS

PGD: one or more parents are at risk of transmitting a genetic disease or abnormality to their offspring

PGS: genetic parents are presumably normal but their embryos are screened for aneuploidy (RSAb)

PGD vs. PGS: Indications

PGD: autosomal dominant, autosomal recessive, X-linked disorders, single gene defects, mutations (BRCA-1), HLA matching, structural chromosomal abnormalities

PGS: advanced maternal age, recurrent pregnancy loss, repeated IVF failure, severe male factor

BEST Trial: RCT of Single embryo transfer after CCS vs. Dual embryo transfer w/o CCS

ASRM Annual Mtg. 2013

Chart1

CCS-SETCCS-SETCCS-SET

DETDETDET

Ongoing PR

Sab rate

Twins

70

13

0

67

20

53

Sheet1

Ongoing PRSab rateTwins

CCS-SET70130

DET672053

To resize chart data range, drag lower right corner of range.

Reasonable Approach to RSAb

Anatomic Factors HSG

Vaginal ultrasound

Saline infusion

MRI

Correct: significant polyps, septa, adhesions, fibroids, incompetent cervix

Chronic Illness treat the underlying

disease Immunologic Factor

Baby ASA/Heparin

Influence of Age Role of IVF/PGD

Reasonable Approach to RSAb

Genetic Factors Pedigree

Parental chromosomes

Karyotype future losses

Counseling

Donor gametes prn

Environmental Factors Thorough screen No lab tests

Endocrine Factors 90% success rate

Misc. Factors Counseling and

support should be offered

Practice BulletinsAntiphospholipid Syndrome. ACOG Practice Bulletin. #118, January 2011

Inherited Thrombophilias in Pregnancy. ACOG Practice Bulletin #113. July 2010.

Recurrent Pregnancy Loss. ASRM Practice Committee Report. Fertil Steril 98:1103, 2012

Preimplantation Genetic TestingPractice Committee of SART and Practice Committee of

ASRM. Fertil Steril 2007; 88:1497-1504.

ReferencesRai R et al. Recurrent Miscarriage. Lancet 2006; 368:601-611.

Jauniaux E et al. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Human Reproduction2006; 21:2216-2222.

Christiansen OB et al. Evidence-based investigations and treatments of recurrent pregnancy loss. Fertil Steril 2005; 83:821-839.

Lashen H et al. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study. Human Reproduction 2004; 19:1644-46.

Fritz M., Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th ed., pgs 1191-1220

ReferencesSurrey E et al. Impact of Intramural Leiomyomata in patients with normal

endometrial cavity on IVF cycle outcome. Fertil Steril 75:405, 2001

Negro R et al., Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. JCEM 95:44-8, 2010

Scott JR, Immunotherapy for Recurrent Miscarriages. Cochrane Reviews, BMJ, Issue 1: 2002

Rey E, Kahn SR, David M, Shrier R. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 361:901-8, 2003.

Kaandorp S et al. Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage. N Engl J Med 10.1056, 2010

Recurrent Pregnancy Loss�ACOG District II, April 30, 2016�Conflict of InterestLecture ObjectivesMiscarriageEmbryonic Loss after ImplantationSlide Number 6Definitions of RSAbContinuum of CausationEtiologiesAnatomic Causes�10-15% of patients presenting with RSAbUterine Anomalies�Diagnosis may be aided by MRI, 3-D sono, laparoscopyUterine SeptumDefinite Causes of IUA (Äsherman’s) in 1856 CasesDefinite Causes of IUA (Äsherman’s) in 1856 CasesÄsherman’s syndromePolyps and fibroids within the cavity should be excised if causing symptoms or are the only RSAb factor foundEndocrine CausesHypothyroidism screeningHypothyroidism: confirmedProlactinThe role of P4 in RSAbThe role of P4 in RSAbAUTOIMMUNE RSAb�Antiphospholipid SyndromeCochrane Database �of Systematic ReviewsAUTOIMMUNE RSAbALFIE Study �Anticoagulants for Living FetusesAutoimmune RSAb�ThrombophiliasPrevalence of ThrombophiliasAUTOIMMUNE RSAbIdiopathic RSAb (~40%)Cochrane Database �of Systematic ReviewsCochrane Database �of Systematic ReviewsInternet as a portal (for misinformation)CHRONIC ILLNESSObesity (BMI>30 vs.19-25)Environmental ExposuresChromosomal Abnormalities in the aborted embryo/fetusChromosomal Abnormalities in the aborted embryo Couples with Habitual Abortion Couples with Habitual AbortionSlide Number 41Types of genetic Errors in SAbGenetic CounselingNumerical: AneuploidySlide Number 45Miscarriage rates by age at conceptionConsensusPreimplantation Genetic �Diagnosis (PGD)PGD vs. PGSPGD vs. PGS: IndicationsSlide Number 51 Reasonable Approach to RSAb Reasonable Approach to RSAbPractice BulletinsReferencesReferences