1. family and parenting
2. motherhood
3. pregnancy

TU305
TRIED AND TRUE AND NEW: MANAGEMENT STRATEGIES FOR
RECURRENT FIRST TRIMESTER PREGNANCY LOSS
PAUL R. BREZINA, MD, MBA
APRIL 29, 2014
MCCORMICK PLACE LAKESIDE CENTER
CHICAGO, ILLINOIS
TABLE OF CONTENTS
FACULTY ........................................................................................................................... iii
COURSE OBJECTIVES ........................................................................................................ v
SCHEDULE ....................................................................................................................... vii
DISCLOSURE OF FACULTY AND INDUSTRY RELATIONSHIPS, ACCREDITATION, AND COGNATES .. ix
INTRODUCTION .................................................................................................................. xi
PAUL R. BREZINA, MD, MBA
CONTROVERSIES IN THE EVALUATION OF RECURRENT MISCARRIAGE ..................................... 1
WILLIAM H. KUTTEH, MD, PHD, HCLD
RECURRENT FIRST TRIMESTER PREGNANCY LOSS: THE ROLE OF PRODUCTS OF CONCEPTION18
PAUL R. BREZINA, MD, MBA
ANTIPHOSPHOLIPID ANTIBODY SYNDROME: RECURRENT EARLY PREGNANCY LOSS ............. 28
WILLIAM H. KUTTEH, MD, PHD, HCLD
RECURRENT EARLY PREGNANCY LOSS: CONGENITAL AND ACQUIRED UTERINE ANOMALIES . 43
WILLIAM H. KUTTEH, MD, PHD, HCLD
RECURRENT FIRST TRIMESTER PREGNANCY LOSS: ENDOCRINE FACTORS .......................... 61
PAUL R. BREZINA, MD, MBA
EDUCATIONAL OPPORTUNITIES ......................................................................................... 72
COURSE DIRECTOR
Paul R. Brezina, MD, MBA
Fertility Associates of Memphis
Memphis, Tennessee
FACULTY
William H. Kutteh, MD, PhD, HCLD
Vanderbilt University School of Medicine and Fertility Associates of
Memphis
Memphis, Tennessee
Course Objectives
After attending this course, the practitioner should be able to:

Discuss how advances in genetics have influenced our thinking of pregnancy
loss and recurrent pregnancy loss

Discuss new algorithms for initiating the RPL workup

Describe the known etiologies that have been associated with RPL and outline
the diagnostic tests that should be offered to couples with RPL

Explain the risks, benefits and expected outcomes of treatments for RPL
TRIED AND TRUE AND NEW: MANAGEMENT STRATEGIES FOR RECURRENT FIRST TRIMESTER
PREGNANCY LOSS
APRIL 29, 2014
CHICAGO, ILLINOIS
PAUL R. BREZINA, MD, MBA
SCHEDULE
TUESDAY, APRIL 29, 2014
PM
2:00
Welcome, Introduction of Faculty, Review of Learning Objectives,
Announcements
Dr. Brezina
2:05
2:35
3:05
Controversies in the Evaluation of Recurrent Miscarriage
Dr. Kutteh
Recurrent First Trimester Pregnancy Loss: The Role of Products
of Conception
Dr. Brezina
Antiphospholipid Antibody Syndrome: Recurrent Early
Pregnancy Loss
Dr. Kutteh
4:00
Break
4:15
4:45
Recurrent Early Pregnancy Loss: Congenital and Acquired
Uterine Anomalies
Dr. Kutteh
Recurrent First Trimester Pregnancy Loss: Endocrine FactorsDr. Brezina
5:00
Adjournment
DISCLOSURE OF FACULTY – INDUSTRY RELATIONSHIPS
In accordance with College policy, planning committee members have signed a conflict of
interest statement in which they have disclosed no financial interests or other relationships
with industry relative to topics they will discuss at this program. All faculty members have
signed a conflict of interest statement in which they have disclosed any financial interests
or other relationships with industry relative to topics they will discuss at this program. At
the beginning of the program, faculty members are expected to disclose any such
information to participants. Such disclosure allows you to better evaluate the objectivity of
the information presented in lectures. Please report on your evaluation any undisclosed
conflict of interest you perceive. Thank you!
College Committee on Continuing Medical Education
ACCME ACCREDITATION
The American College of Obstetricians and Gynecologists is accredited by the
Accreditation Council for Continuing Medical Education (ACCME) to provide continuing
medical education for physicians.
AMA PRA CATEGORY 1 CREDIT(S)™
OR
COLLEGE COGNATE CREDIT
AMA PRA CATEGORY 1 CREDIT(S)™
The American College of Obstetricians and Gynecologists designates this live activity
for a maximum of 27 AMA PRA Category Credit(s)TM Physicians should only claim
those credits commensurate with the extent of their participation in the activity.
College Cognate Credit(s)
The American College of Obstetricians and Gynecologists designates this live activity
for a maximum of 27 College Cognate Credit(s) toward the Program for Continuing
Professional Development for the Annual Clinical Meeting. The College has a
reciprocity agreement with the AMA that allows AMA PRA Category 1 CreditsTM to be
equivalent to College Cognate Credits.
Please refer to the Annual Clinical Meeting Final Program for an additional breakdown
of credits.
TU305
TRIED AND TRUE AND NEW:
MANAGEMENT STRATEGIES FOR
RECURRENT FIRST TRIMESTER
PREGNANCY LOSS
APRIL 29, 2014
PAUL R. BREZINA, MD, MBA
MCCORMICK PLACE LAKESIDE CENTER
CHICAGO, ILLINOIS
In accordance with ACOG policy, all planning
committee members and faculty have declared
any financial interests or other relationships
with industry relative to topics they will discuss.
This disclosure allows you to better evaluate the
scientific objectivity of the information
presented.
ACCME ACCREDITATION
AMA PRA CATEGORY 1 CREDIT(S)™
The American College of Obstetricians and Gynecologists designates this live
activity for a maximum of 27 AMA PRA Category Credit(s)TM Physicians
should only claim those credits commensurate with the extent of their
participation in the activity.
College Cognate Credit(s)
The American College of Obstetricians and Gynecologists designates this live
activity for a maximum of 27 College Cognate Credit(s) toward the Program
for Continuing Professional Development for the Annual Clinical Meeting.
The College has a reciprocity agreement with the AMA that allows AMA PRA
Category 1 CreditsTM to be equivalent to College Cognate Credits.
Please refer to the Annual Clinical Meeting Final Program for an additional
breakdown of credits.
Introduction of Speakers
• Paul R. Brezina, MD, MBA
– Fertility Associates of Memphis
– Memphis, Tennessee
• William H. Kutteh, MD PhD HCLD
– Vanderbilt University School of Medicine and
Fertility Associates of Memphis
– Memphis, Tennessee
• Paul R. Brezina, MD –This speaker has relevant financial
relationships with the following commercial interests: Speaker: AbbVie
Pharmaceuticals
• William H. Kutteh, MD, PhD, HCLD – This speaker has no
conflicts of interest to disclose relative to the contents of this presentation.
Role of Course Director
The course director is responsible for:
• Selecting speakers.
• Reviewing the lecture content.
• Analyzing course content for potential
conflicts of interest.
Conflict of Interest
• Circumstances reflect a conflict of
interest when an individual has an
opportunity to affect CME about
products or services of a commercial
interest with which he/she has a
financial interest.
www.accme.org
If a Conflict of Interest is Determined,
the Course Director will:
• Resolve the issues pertaining to the
conflict of interest prior to the educational
meeting.
• If a conflict of interest becomes apparent
during the meeting, the Course Director
will resolve this issue during the meeting.
Evaluations
A course evaluation can be submitted once the
course has ended. Completion of the online
evaluation is mandatory in order to receive CME
credit for each course attended.
To obtain an official certificate, click on the Print
Certificate button AFTER completing evaluations
for all courses attended.
Any questions, contact College staff at
[email protected].
CONTROVERSIES IN THE EVALUATION OF RECURRENT MISCARRIAGE
WILLIAM H. KUTTEH, MD, PHD, HCLD
SATURDAY, 2:05 P.M.
LEARNING OBJECTIVES
After this lecture, you should be able to:

Discuss the current trends in the diagnosis and treatment of RPL.

Describe the different society definitions of “pregnancy” and “RPL”.

Discuss the role of genetic testing in developing a strategy for the evaluation of
RPL

Discuss the effect of maternal age and number of prior losses on predicting
future live births
This speaker has no conflicts of interest to disclose relative to the contents of this
presentation.
CONTROVERSIES IN THE
EVALUATION OF RECURRENT
MISCARRIAGE
William H. Kutteh, M.D., Ph.D., H.C.L.D.
Professor of Obstetrics and Gynecology
Vanderbilt University Medical Center
DISCLOSURES
• None
LEARNING OBJECTIVES
At the conclusion of this presentation, participants
should be able to:
1. Discuss the current trends in the diagnosis and
treatment of RPL.
2. Describe the different society definitions of
“pregnancy” and “RPL”.
3. Discuss the role of genetic testing in developing a
strategy for the evaluation of RPL
4. Discuss the effect of maternal age and number of
prior losses on predicting future live births
CONTROVERSIES in RPL
• How many losses diagnose RPL?
• What counts as a pregnancy loss?
• What does a complete workup include?
• Should we get karyotypes on parents?
• What about thrombophilias?
• Should we get karyotypes on POC?
• What is the prognosis for a live birth?
Natural miscarriage history
Risk of 1 Risk of 2 Risk of 3
loss
Losses Losses
Reference
Alberman, 1988
(study of female MD)
10.4%
Wilcox et al., 1988
(preclinical + clinical)
63/198
31.3%
2.3%
0.34%
766/59,035
Kutteh, 1995*
(unselected women)
1.3%
*Considered a minimum estimate as many lost to follow up.
Population 1/3 hispanic, 1/3 White, 1/3 African-American
Kutteh, WH. Williams Obstetrics. Supp 15:1-4, 1995
Theoretical Incidence of RPL
Based on Number of Miscarriages Used to
Define
# Miscarriages to Define RPL
Incidence of RPL
Two
1/45
Three
1/300
Four
1/2000
Five
1/13,000
Six
1/90,000
Seven
1/600,000
Eight
1/4,000,000
Incidence based on mean sporadic miscarriage rate of 15% (=μ).
Incidence=μnumber of miscarriages (μ = sporadic miscarriage rate of 15%).
Saravelos SH, Regan LR. Obstet Gynecol Clinics N Am. 2014.
Spontaneous Pregnancy Loss:
Role of Maternal Age
American Society for Reproductive Medicine: Patient’s
Fact Sheet: Recurrent Pregnancy Loss. 2005.
Hassold
7 T et al 1980 Ann Hum Genet 44:151-178
Theoretical Incidence of RPL
Based on Maternal Age
Maternal Age
Incidence of RPL
20
1/85
25
1/70
30
1/45
35
1/16
40
1/4
45
1/2
Incidence based on mean sporadic miscarriage rate according to age.
Incidence=μ2 (μ = sporadic miscarriage rate for age).
Saravelos SH, Regan LR. Obstet Gynecol Clinics N Am. 2014.
Maternal Age is Related to
Aneuploidy in oocytes
Aneuploidy Risk
10%
30%
50%
100%
Maternal Age
<35 years
40 years
43 years
> 45 years
Pellester F, Andreo B,Arnal F, Humeau C, Demaille J
Maternal aging and chromosomal anormalities:new data drawn
from in vitro unfertilized human oocytes, Hum Genet 112 : 195,
2003
How many losses? Traditional
• Three or more
spontaneous,
consecutive pregnancy
losses (fathered by the
same partner)
Williams OB 21st Edition “most generally accepted
definition”
How many losses? - ACOG
• “RPL is typically defined as two or
three or more consecutive
pregnancy losses”
• “Patients with two or more
consecutive, spontaneous losses
are candidates for an evaluation to
determine the etiology”
ACOG Practice Bulletin No. 24, February 2001 (withdrawn)
How many losses? - ASRM
• “RPL is a disease distinct from
infertility defined by two or
more failed consecutive failed
pregnancies”
• “Clinical evaluation may
proceed following two first
trimester pregnancy losses”
ASRM Committee Opinion Fertil Steril. 99:63, 2012
ASRM Practice Committee Fertil Steril 98:1103-1101, 2012
How many losses? Insurance
• After two consecutive
losses, most insurance
companies will pay for a
complete evaluation of
recurrent pregnancy
loss
Kutteh experience over last 20 years of clinical practic
Does the Number of losses affect the frequency
of abnormal findings in women with RPL?
Frequency of abnormal tests in 1020 women with RPL
EVIDENCE-BASED TESTS
INVESTIGATIVE TESTS
Karyotpe parents
Prolactin
Evaluate uterine anatomy
Antiphosphatidyl serine
Lupus anticoagulant
Midluteal progesterone
Anticardiolipin antibodies
Mycoplasma/ureaplasma
Thyroid stimulating hormone
Factor II (prothrombin) DNA
Factor V Leiden DNA
MTHFR/Homocysteine
Christiansen et al. Semin Reprod Med 24;5-16,2006.
Jauniaux etal. Hum Reprod 21:2216-2222, 2006.
Jaslow & Kutteh. Fertil Steril 93:1234-43, 2010
Theoretical Incidence of RPL occurring by
Chance for Women with one, two and three
miscarriages
AGES (years)
1 miscarriage
By chance
2 miscarriages
By chance
3 miscarriages
By chance
20-24
11%
1.21%
0.13%
25-29
12%
1.44%
0.17%
30-34
15%
2.25%
0.34%
35-39
25%
6.25%
1.56%
Saravelos SH and LiTC. Human Reprod. 27:1882-1886, 2012
Possible RPL Etiologies based on Number of
Losses
Frequency of abnormal tests in 1020 women with RPL
2
3
4 or
# of prior
more P value
losses
(n=447) (n=343) (n=230)
Evidence-based
test results
41%
40%
42%
NS
Investigative test
results
20%
22%
21%
NS
Total abnormal
test results
61%
62%
63%
NS
Jaslow & Kutteh. Fertil Steril 93:1234-43, 2010.
Spectrum of Pregnancy Loss
•
•
•
•
•
•
Pregnancy of Unknown
Location (PUL)
Early embryonic (< 6 wks)
Embryonic (> 6 to 9 wks)
Fetal loss (> 9 to 20 wks)
Miscarriage (< 20 wks)
Stillbirth (> 20 wks)
Silver et al. Obstet Gynecol 118: 1402-1408, 2011.
What counts as a Loss? Traditional
• Miscarriage is the
loss of a pregnancy
before 20 weeks of
gestation or less
than 500g
Williams OB 21st Edition “most generally accepted definition”
What counts as a loss? - ACOG
• “Loss of a recognized
pregnancy in the first or early
second trimester <15 wks)”
• “Most are evident by the 12th
week and the demise
precedes clinical features of
pregnancy loss by one or
more weeks”
ACOG Practice Bulletin No. 24, February 2001 (withdrawn)
What counts as a loss? - ASRM
• “Pregnancy is defined as
a clinical pregnancy
documented by
ultrasonography or
histopathologic
examination”
ASRM Committee Opinion Fertil Steril. 99:63, 2012
ASRM Practice Committee Fertil Steril 98:1103-1101, 2012
What counts as a loss? Patient
• A positive pregnancy
test from home (or
their doctors office)
that does not result
in a baby
Kutteh experience over last 20 years of clinical
practice
What counts as a loss? - My
Opinion
• A pregnancy that is documented by
an appropriately rising quantitative
hCG that fails
• Using this definition there is
< 7% chance of being an ectopic
Kutteh experience over last 20 years of practice
Barnhart KT. Obstet Gynecol 104:50-55, 2004
What is a complete workup? - ACOG
• Karyotypes on both partners
• Uterine cavity evaluation
• Glucose level
• LAC, aCL, β2-glycoprotein
(No inherited thrombophilias)
ACOG Bulletin No. 24, Feb 2001 (withdrawn)
ACOG Bulletin No. 124, September 2011
What is a complete workup? - ASRM
• Karyotypes on both partners
• Uterine cavity evaluation
• Prog, PCOS, HgbA1c
• LAC, aCL, antiβ2 GP1
(No inherited thrombophilias)
ASRM Committee Opinion Fertil Steril. 99:63, 2012
ASRM Practice Committee Fertil Steril 98:1103-1101, 2012
What is a complete workup?- RCOG
• Pelvic Ultrasound
• Refer to RM clinic
• Other Tests to consider:
- Karyotypes,
- Antiphospholipid antibodies
- thyroid disease
- thrombophilias
- microbiologic factors
Royal College of Ob/Gyn Green Top Guideline No. 17. April 2011
What is evidence-based?- Genetics
Frequency of abnormal tests in 1020 women with RPL
Control
0.4%
7.5%
0.5%
6.7%
3.9%
6.8%
# of prior
losses
Parental
genetics
Anatomy
Lupus
anticoagulant
Anticardiolipin
TSH
Factor V
2
3
>4
P
n=447 n=343 n=230 value
2.8%
5.4%
5.2%
NS
18.7% 18.2% 16.7%
NS
5.0%
1.9%
NS
15.6% 13.1% 17.1%
8.1% 6.5% 6.2%
4.2% 8.1% 10.3%
NS
NS
NS
2.9%
Jaslow & Kutteh. Fertil Steril 93:1234-43, 2010.
Parental Genetic Abnormalities
(found in 3-5% of couples with RPL)
• Reciprocal translocation 59%
• Robertsonian translocation
27%
• Inversions 9%
• Sex chromosome aneuploidy
4%
• Supernumerary chromosome
1%
Balanced translocation
Prognosis based on parental karyotypes
The karyotype results from the parents provides
prognostic information for subsequent pregnancies
Parents Karyotype
Reciprocal
Robertsonian
Subsequent Miscarriage
50-70%
30-50%
(Exception is translocation to same chromosome)
Inversions
Normal
30%
30%
Brigham, Hum Reprod. 1999 Nov;14(11):2868-71
Engels, Am J Med Genet A. 2008 Oct 15;146A(20):2611-6
Neri, Am J Med Genet. 1983 Dec;16(4):535-61
Stephenson, Hum Reprod. 2006 Apr;21(4):1076-82. Epub 2006 Jan 5
Sugiura-Ogasawara, Fertil Steril. 2004 Feb;81(2):367-73.
Carp, Fertil Steril. 2006 Feb;85(2):446-50
28
What about Thrombophilias?
Hypercoagulable State Pregnancy
Changes
•
Decrease in Protein S, fibrinolysis
•
Increased Activated Protein C Resistance
•
Increased levels of factors II,VII,VIII,X,XII
•
Net change: Increased clot formation,
extension and stability=prothrombotic state
Arkel and Ku. Clin Appl Thromb Haemost 4: 259-268, 2001
ACCP Evidence-Based
Guidelines
Thrombophilia, Therapy, & Pregnancy
“Available data suggest that both acquired and
inherited thrombophilias are associated with an
increased risk of early (recurrent) fetal loss. In
particular, associations were observed with
anticardiolipin antibody and lupus anticoagulant,
homozygosity and heterozygosity for factor V
Leiden mutation and heterozygosity for the
prothrombin G20210A variant.”
Bates et al. Chest 133: 844S-886S, 2008
ACOG Bulletin 124, Sept 2011
Inherited Thrombophilias in Pregnancy
“Whereas meta-analysis and a retrospective
cohort study have revealed an association
between inherited thrombophilias and firsttrimester pregnancy loss, prospective
cohort studies have found no association
between inherited thrombophilias and fetal
loss.”
Lockwood C and Wendell G. Obstet Gynecol 118:730-740,2011.
What is evidence-based?- Anatomy
Frequency of abnormal tests in 1020 women with RPL
Control
0.4%
7.5%
0.5%
6.7%
3.9%
6.8%
# of prior
losses
Parental
genetics
Anatomy
Lupus
anticoagulant
Anticardiolipin
TSH
Factor V
2
3
>4
n=447 n=343 n=230
2.8%
5.4% 5.2%
P
value
18.7% 18.2% 16.7%
NS
5.0%
1.9%
NS
15.6% 13.1% 17.1%
8.1% 6.5% 6.2%
4.2% 8.1% 10.3%
NS
NS
NS
2.9%
NS
Jaslow & Kutteh. Fertil Steril 93:1234-43, 2010.
Congenital Uterine Anomalies
3-D Sonohysterograpy for the Evaluation of the Uterine Cavity
Comparison of Uterine Anomalies
Primary RM compared with Secondary RM
All uterine anomalies
Primary RM
(n = 479)
Secondary RM
(n = 425)
P
22.8 (109)
15.8 (67)
0.009
0.011
8.8 (42)
4.5 (19)
Bicornuate uterus
1.0
(5)
0.5
(2)
Didelphic uterus
0.2
(1)
0.2
(1)
Septate uterus
6.3 (30)
3.1 (13)
T-shaped uterus
0.4
(2)
0.2
(1)
Unicornuate uterus
0.8
(4)
0.5
(2)
ns
14.6 (70)
11.8 (50)
ns
Adhesions
4.0 (19)
4.2 (18)
ns
Fibroid(s)
7.3 (35)
5.4 (23)
ns
Polyp(s)
4.0 (19)
2.4 (10)
ns
Congenital anomalies
Acquired anomalies
ns
ns
0.028
ns
Values are % occurrence (n). Jaslow and Kutteh. 99:1916-22, 2013.
Comparison of Uterine Anomalies
2 losses compared with 3 or more losses
2 losses
(n = 397)
> 3 losses
(n = 507)
P
18.9 (75)
19.9 (101)
ns
6.5 (26)
6.9 (35)
ns
Bicornuate uterus
1.0
(5)
0.5
(2)
ns
Didelphic uterus
0.2
(1)
0.2
(1)
ns
Septate uterus
5.0 (20)
All uterine anomalies
Congenital anomalies
T-shaped uterus
0
0.6
(3)
1.2
ns
ns
(6)
ns
12.6 (50)
13.8 (70)
ns
Adhesions
3.5 (14)
4.5 (23)
ns
Fibroid(s)
5.8 (23)
6.9 (35)
ns
Polyp(s)
3.5 (14)
3.0 (15)
ns
Unicornuate uterus
Acquired anomalies
0
4.5 (23)
Values are % occurrence (n). Jaslow and Kutteh. 99:1916-22, 2013.
What is evidence-based? - Autoimmune
Frequency of abnormal tests in 1020 women with RPL
Control
# of prior
losses
0.4%
Parental
genetics
7.5%
0.5%
2
n=44
7
2.8%
3
P
>4
n=34
n=230 value
3
5.4%
5.2%
NS
Anatomy
18.7% 18.2% 16.7%
NS
Lupus
anticoagulant
5.0%
NS
2.9%
1.9%
NS
6.7% Anticardiolipin 15.6% 13.1% 17.1%
3.9% TSH
8.1% 6.5% 6.2%
NS
Factor&VKutteh. Fertil
4.2%
10.3%
6.8% Jaslow
Steril8.1%
93:1234-43,
2010. NS
Pathophysiology of aPL
IT’S NOT JUST ANTICOAGULATION
!
• Inhibit hCG release from placental explants
• Block of in vitro trophoblast migration
&invasion
• Inhibit formation of giant, multinucleated cell
• Inhibit of trophoblast cell adhesion molecules
(alpha 1 and 5 integrins, E and VE cadherins)
• Activate complement on the trophoblast
surface inducing an inflammatory response
Girardi,Redecha,Salmon. Nature Med 10:1222-1226,
2005
Age
Sporadic (Control) vs. Recurrent
miscarriage
Risk of cytogenetic abnormality in miscarriage
* P<0.05
Maternal Age in years
Stephenson et al., Hum Reprod. 2002 Feb;17(2):446-51
Karyotype of POC provides
prognosis for subsequent
pregnancy
•If the POC of the first
miscarriage are normal,
the second miscarriage will
be aneuploid in 35%
70
Aneuploidy in 2nd Miscarriage
60
50
40
30
•If the POC of the first
miscarriage are aneuploid,
the second miscarriage will
be aneuploid in 65%
20
10
0
Euploid
Miscarriage
Aneuploid
Miscarriage
Ogasawara, Fertil Steril. 2000 Feb;73(2):300-4
Carp, Fertil Steril. 2001 Apr;75(4):678-82
Hassold TJ Am J Hum Genet 1980; 32: 723-730
Aneuploidy in Products of
Conception
Possibility exists that
aneuploidies on these
chromosomes
survived longer and
thus allowed a
karyotype to be
obtained from POC
•
•
Chromosome
Number
% of All
Trisomies
16
22
21
15
13
18
14
7
2
8
9
4
20
10
12
6
3
17
11
5
19
1
24.7 %
13.9 %
12.3 %
8.3 %
6.8 %
4.8 %
4.4 %
3.4 %
3.2 %
3.0 %
2.9 %
2.8 %
2.7 %
1.5 %
1.2 %
1.0 %
0.9 %
0.9 %
0.5 %
0.4 %
0.2 %
0%
59.2%
8% of all SAB
are 45, X
6.6%
Monni G, Ibba RM, Zoppi MA. Prenatal Genetic Diagnosis through Chorionic Villus Sampling. In: Milunsky A, Milunsky JM, eds. Genetic Disorders and the Fetus. 6th ed. Oxford, UK: WileyBlackwell. 2010.
Kearns WG, er.al Preimplantation genetic diagnosis and screening. Semin Reprod Med. 2005 Nov;23(4):336-47. Review.
Results: % Aneuploidy by Chromosome
in RPL
(After PGS on 1702 embryos from RPL patients)
1702 SNP microarrays
obtained
1404 (82%) Cleavage
Stage
298 (18%) Blastocyst
Stage
759 (45%) Euploid
Embryos
943 (55%) Aneuploid
Embryo
Ch21
4.8%
Ch22
4.7%
X/Y
3.1%
Ch1
4.9%
Ch2
5.2%
Ch3
3.9%
Ch20
4.5%
Ch4
3.7%
Ch19
3.5%
Ch5
4.1%
Ch18
4.2%
Ch6
3.9%
Ch17
4.8%
Significant levels of
aneuploidy
occurs in all chromosomes
during early human
Embryogenesis
Ch7
4.0%
Ch8
4.6%
Ch16
5.8%
Ch9
4.9%
Ch15
4.6%
Ch14
4.1%
Ch13
4.2%
Ch12
4.0%
Ch11
4.4%
Ch10
4.0%
Range of aneuploidy was
Brezina,
Kearns, Kutteh. J Assist Reprod Genetics. In Press,
From 3.1%
to 5.8%
2013.
Initial Evaluation for Early RPL
Miscarriage #1
(No action unless clinically indicated
2nd Miscarriages
Aneuploid karyotype
Obtain Miscarriage
Karyotype
No further evaluation
Euploid karyotype
RPL Workup
Brezina and Kutteh. Clin Reprod Med Surg. In press 2013.
Modified from Bernardi et al. Fertil Steril 98:156-161,2012
Unbalanced
chromosomal
translocation or
inversion
Perform parental
karyotypes and offer
preimplantation
genetic diagnosis for
future pregnancy
attempts
What about True Unexplained RPL?
•
•
•
•
•
•
Current evaluation completed
Test results all return as normal
Chromosomes on POC are normal
Subsequent live birth is 40% to 80%
Depends on maternal age
Depends on number of prior losses
45
Chance of Live Birth based on # Prior
Losses
Current Diagnostic and Treatment Strategies
(n-665)
Lund et al. Obstet Gynecol 119: 37-43, 2012
Chance of Live Birth based on Maternal Age
Current Diagnostic and Treatment Strategies
(n=665)
Lund et al. Obstet Gynecol 119: 37-43, 2012
RECURRENT FIRST TRIMESTER PREGNANCY LOSS: THE ROLE OF PRODUCTS OF CONCEPTION
PAUL R. BREZINA, MD, MBA
SATURDAY, 2:35 P.M.
LEARNING OBJECTIVES
After this lecture, you should be able to:

Describe the impact of aneuploidy on pregnancy loss

Discuss how genetic testing of products of conception taken from miscarriages
may help in future diagnosis and treatment
This speaker has relevant financial relationships with the following commercial interests:
Speaker: AbbVie Pharmaceuticals
Recurrent First Trimester Pregnancy Loss:
The Role of Products of Conception
PAU L R . B R E Z I N A, M D , M B A
D I R E C T O R : P R E I M P L A N TAT I O N G E N E T I C S
F E R T I L I T Y A S S O C I AT E S O F M E M P H I S
MEMPHIS, TN
Clinical Assistant Professor of Obstetrics and Gynecology
Vanderbilt University Medical Center
Disclosures
 Nothing to disclose
 No conflict of interest
Learning Objectives
At the conclusion of this presentation, the
physician should be able to:
1. Describe the impact of aneuploidy on pregnancy
loss
2. Discuss how genetic testing of products of
conception taken from miscarriages may help in
future diagnosis and treatment
31-year-old Caucasian, G2 P0100
 CC: “I am 8 weeks pregnant and have vaginal bleeding”
 HPI: Last pregnancy SAB at 7 weeks. Had ultrasound
showing IUP with good FCA last week.
 PMH: Noncontributory
 POB HX: 1 SAB at 7 weeks with D+C

(no karyotype obtained)
 PGYN Hx: menarche age 13, regular cycles q28 days
with no hx of abn pap/stds
 PSurg Hx: D+C *1
 Meds: prenatal vitamins
 All: NKDA
 Soc: No ETOH, Drugs, Tob
31-year-old Caucasian, G2 P0100
 Work up
 CBC, CMP all Normal
 Ultrasound
Single IUP
No FCA
 CRL 0.6 cm
 Minimal clot in endometrium


31-year-old Caucasian, G2 P0100
 What can we offer this patient?
 Not yet 3 losses
What should we do?
Background
 Spontaneous abortion occurs in approximately 15%
of clinically diagnosed pregnancies
 Recurrent pregnancy loss (RPL) occurs in about 1-
2% of this same population (Kutteh 2007)

Kutteh WH. Recurrent pregnancy loss, in Precis, an update in Obstetrics and Gynecology. Washington, American College of Obstetrics and Gynecology, 2007.
Background
 A definite cause of pregnancy loss can be
established in over half of couples after a thorough
evaluation (Stephenson 1996, Jaslow 2010)
 Successful outcomes will occur in over two-thirds of
all couples (Jaslow 2010, Lund 2012)



Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril. 1996;66:24-9.
Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril. 2010;93(4):1234-43.
Lund M, Kamper-Jørgensen M, Nielsen HS, Lidegaard Ø, Andersen AM, Christiansen. Prognosis for live birth in women with recurrent miscarriage: what is the best measure of
success? Obstet Gynecol. 2012;119:37-43.
Defining RPL
 The traditional definition of recurrent pregnancy loss (RPL)
included those couples with three or more spontaneous,
consecutive pregnancy losses. Ectopic and molar
pregnancies are not included. (ACOG 2001, ASRM 2012)
 The ASRM has defined RPL as “a distinct disorder defined by
2 or more failed clinical pregnancies” (ASRM 2012)
 For purposes of determining if an evaluation for RPL is
appropriate, pregnancy “is defined as a clinical pregnancy
documented by ultrasonography or histopathological
examination” (ASRM 2012)


The Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012 Jul 24.
[Epub ahead of print]
American College of Obstetricians and Gynecologists. ACOG practice bulletin. Management of recurrent pregnancy loss. Number 24, February 2001. (Replaces Technical
Bulletin Number 212, September 1995). American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 2002 Aug;78(2):179-90.
Classically when to initiate a RPL workup
 Several studies have recently indicated that the risk
of recurrent miscarriage after two successive losses
is similar to the risk of miscarriage in women after
three successive losses (ASRM 2012, Brezina 2012,
Stirrat 1990)
 It is reasonable to start an evaluation after two or
more consecutive spontaneous miscarriages (ASRM
2006)




The Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012 Jul 24.
[Epub ahead of print]
Stirrat GM. Recurrent miscarriage. Lancet. 1990;336:673-5 .
Practice Committee of the American Society for Reproductive Medicine. Aging and infertility in women. Fertil Steril. 2006 Nov;86(5 Suppl 1):S248-52.
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New
York, NY: Springer. (in press)
Causes of RPL
 Chief causes of RPL
 Embryonic chromosomal abnormalities
 Maternal anatomic abnormalities
 Endocrinologic abnormalities
 Autoimmune factors
 Lifestyle/Environment
 Others


Hypercoaguable state
Infection
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A
Practical Guide. 2nd ed. New York, NY: Springer. (in press)
Normal Chromosomal Division
Haploid
Sperm
Haploid
Oocyte
Diploid
Embryo
Polar Body
(Discarded)
Aneuploidy: Meiotic Nondisjunction
 The vast majority of embryonic aneuploidy is
thought to be a result of maternal meiotic
nondisjunction during oocyte development
(Brezina 2012, Sugiura-Ogasawara 2012, Hassold
1980, Werner 2012, Nayak 2011, Coulam 1997)
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New York,
NY: Springer. (in press)
Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Kitaori T, Mizutani E. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage. Hum Reprod.
2012;27:2297-303.
Hassold T, Chen N, Funkhouser J, Jooss T, Manuel B, Matsuura J, Matsuyama A, Wilson C, Yamane JA, Jacobs PA. A cytogenetic study of 1000 spontaneous abortions. Ann Hum
Genet. 1980;44(Pt 2):151-78.
Werner M, Reh A, Grifo J, Perle MA. Characteristics of chromosomal abnormalities diagnosed after spontaneous abortions in an infertile population. J Assist Reprod Genet.
2012;29:817-20.
Nayak S, Pavone ME, Milad M, Kazer R. Aneuploidy rates in failed pregnancies following assisted reproductive technology. J Women's Health (Larchmt). 2011;20:1239-43.
Coulam CB, Goodman C, Dorfmann A. Comparison of ultrasonographic findings in spontaneous abortions with normal and abnormal karyotypes. Hum Reprod. 1997;12:823-6.
Aneuploidy: Meiotic Nondisjunction
Haploid
Sperm
Diploid
Oocyte
Trisomic
Embryo
Monosomic
Embryo
Monoploid
Oocyte
Haploid Sperm
Aneuploidy and pregnancy loss
 The overall frequency of chromosome abnormalities in
spontaneous abortions is 50-70%. (Sugiura-Ogasawara 2012,
Hassold 1980, Werner 2012, Nayak 2011, Coulam 1997)
 Of these abnormalities, most are numerical: 52% are trisomies,
29% are monosomy 45,X, 16% are triploidies, 6% are
tetraploidies, and 4% are structural rearrangements (Boue 1985)







Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Kitaori T, Mizutani E. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage. Hum Reprod. 2012;27:2297-303.
Hassold T, Chen N, Funkhouser J, Jooss T, Manuel B, Matsuura J, Matsuyama A, Wilson C, Yamane JA, Jacobs PA. A cytogenetic study of 1000 spontaneous abortions. Ann Hum Genet. 1980;44(Pt
2):151-78.
Werner M, Reh A, Grifo J, Perle MA. Characteristics of chromosomal abnormalities diagnosed after spontaneous abortions in an infertile population. J Assist Reprod Genet. 2012;29:817-20.
Nayak S, Pavone ME, Milad M, Kazer R. Aneuploidy rates in failed pregnancies following assisted reproductive technology. J Women's Health (Larchmt). 2011;20:1239-43.
Coulam CB, Goodman C, Dorfmann A. Comparison of ultrasonographic findings in spontaneous abortions with normal and abnormal karyotypes. Hum Reprod. 1997;12:823-6.
Boué A, Boué J, Gropp A. Cytogenetics of pregnancy wastage. Annu Rev Genet. 1985;14:1-57.
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New York, NY: Springer. (in
press)
Aneuploidy and RPL
 Evidence suggests that some couples are at risk for
conceptions complicated by recurrent aneuploidy (Brezina
2012)
 Empirically, the birth of a trisomic infant places a woman at
an approximately 1% increased risk for a subsequent
trisomic conceptus (Stene 1984)
 Some data suggest that the rate of aneuploidy in embryos
in RPL is higher than 65% (Robbercht 2012, Philipp 2012).




Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New
York, NY: Springer. (in press)
Stene J, Stene E, Mikkelsen M. Risk for chromosome abnormality at amniocentesis following a child with a non-inherited chromosome aberration. Prenatal Diagnosis 1984; 4:8195.
Robberecht C, Pexsters A, Deprest J, Fryns JP, D'Hooghe T, Vermeesch JR. Cytogenetic and morphological analysis of early products of conception following hysteroembryoscopy from couples with recurrent pregnancy loss. Prenat Diagn. 2012;4:1-10.
Philipp T, Philipp K, Reiner A, Beer F, Kalousek DK. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental
defects of early failed pregnancies. Hum Reprod. 2003;18:1724-32.
Parental chromosomal disorders
 Parental chromosome anomalies occur in 3-5% of
couples with RPL (Brezina 2012, Hirshfeld-Cytron 2011)

But only 0.7% in the general population.
 Translocations
 Inversions
 Ring chromosomes (rare)
 Balanced translocations are the most common
chromosomal abnormalities contributing to recurrent
pregnancy loss (Hirshfeld-Cytron 2011)
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New York,
NY: Springer. (in press)
Hirshfeld-Cytron J, Sugiura-Ogasawara M, Stephenson MD. Management of recurrent pregnancy loss associated with a parental carrier of a reciprocal translocation: a systematic
review. Semin Reprod Med. 2011;29:470-81.
Balanced Parental Translocations
Parent A
Normal
Parent B
Balanced
Translocation
Offspring
Unbalanced
Translocation
Coexisting Embryonic Aneuploidy
with Balanced Translocations
 In addition to genetic errors resulting from the
parental balanced translocation, recent data from
preimplantation genetic testing has shown that
embryos resulting from parents harboring a balanced
reciprocal translocation also have rates of unrelated
chromosomal aneuploidy at rates exceeding 35%
(Du 2011)
Du L, Brezina PR, Benner AT, Swelstad BB, Gunn M, Kearns WG. The rate of de novo and inherited aneuploidy as determined by 23-chromosome single nucleotide polymorphism
microarray (SNP) in embryos generated from parents with known chromosomal translocations. Fertil Steril. 2011; 96:S221.
Testing Products of Conception
 Traditionally done with cell culture and karyotype
obtained through G-banding


Often not possible with very small sample amounts
Could not distinguish if a 46XX sample was maternal or fetal in
origin
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New York,
NY: Springer. (in press)
Hirshfeld-Cytron J, Sugiura-Ogasawara M, Stephenson MD. Management of recurrent pregnancy loss associated with a parental carrier of a reciprocal translocation: a systematic
review. Semin Reprod Med. 2011;29:470-81.
http://geneticslab.wikispaces.com/Chromosomes Accessed 1/28/13
Testing Products of Conception
 23 chromosome pair microarrays
 Capable of evaluating all 23 chromosomes
 Can be performed with very small samples


DNA amplification is part of process
Can be performed on very early pregnancies

Can determine if 46XX is maternal or fetal in origin

Can NOT detect BALANCED translocations in fetal
tissue


Provided maternal blood is concurrently evaluated
Can detect unbalanced translocations
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New York,
NY: Springer. (in press)
Hirshfeld-Cytron J, Sugiura-Ogasawara M, Stephenson MD. Management of recurrent pregnancy loss associated with a parental carrier of a reciprocal translocation: a systematic
review. Semin Reprod Med. 2011;29:470-81.
Brezina PR, Brezina DS, Kearns WG. Preimplantation genetic testing. BMJ. 2012;345:e5908.
Testing Products of Conception
 Genetic testing of products of conception at the time
of D+C is currently underutilized in the setting of first
trimester miscarriage
 Aneuploidy in first trimester miscarriages is
extremely common
 Determination of aneuploidy in a miscarriage may
obviate the need a further invasive and expensive
RPL workup
 Proposal of new emphasis on testing of POC
Proposal of new emphasis on testing of POC
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A
Practical Guide. 2nd ed. New York, NY: Springer. (in press)
31-year-old Caucasian, G2 P0100
 D+C with POC testing
 If
aneuploid and fetal in origin
No further testing
 If translocation present
Run parental karyotypes
 If euploid
Offer RPL workup
Workup for early RPL
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A
Practical Guide. 2nd ed. New York, NY: Springer. (in press)
ANTIPHOSPHOLIPID ANTIBODY SYNDROME: RECURRENT EARLY PREGNANCY LOSS
WILLIAM H. KUTTEH, MD, PHD, HCLD
SATURDAY, 3:05 P.M.
LEARNING OBJECTIVES
After this lecture, you should be able to:

Define the antiphospholipid syndrome

Discuss the proposed mechanisms of action

Describe ACOG’s testing guidelines

Compare unfractionated and low molecular weight heparins
This speaker has no conflicts of interest to disclose relative to the contents of this
presentation.
ANTIPHOSPHOLIPID ANTIBODY
SYNDROME
Recurrent Early Pregnancy Loss
William H. Kutteh, M.D., Ph.D., H.C.L.D.
Professor of Obstetrics and Gynecology
Vanderbilt University Medical Center
DISCLOSURES
• None
LEARNING OBJECTIVES
Antiphospholipid Antibody Syndrome
At the end of this presentation, the
participant should be able to:
• Define the antiphospholipid syndrome
• Discuss the proposed mechanisms of
action
• Describe ACOG’s testing guidelines
• Compare unfractionated and low
molecular weight heparins
Antiphospholipid Antibodies
• IgG or IgM or IgA isotypes
• Bind to phospholipids
• Includes lupus anticoagulant
• Harmful actions on trophoblast
Pathophysiology of aPL
IT’S NOT JUST ANTICOAGULATION!
• Inhibit hCG release from placental explants
• Block of in vitro trophoblast migration
&invasion
• Inhibit formation of giant, multinucleated cell
• Inhibit of trophoblast cell adhesion molecules
(alpha 1 and 5 integrins, E and VE cadherins)
• Activate complement on the trophoblast
surface inducing an inflammatory response
Girardi,Redecha,Salmon. Nature Med 10:1222-1226, 2005
REASONS TO TEST LAC AND aPL
• Intrauterine growth retardation
• Autoimmune disease
• False-positive serologic test for syphilis
• Prolonged coagulation studies
• Positive autoantibody tests
Prevalence of Positive ACA
Population
Number
ACA+%
Normal OB
RPL
SLE
7,278
2,226
1,579
5%
20%
37%
Kutteh. J. Reprod. Immunol. 35:151-171, 1997
Lupus Anticoagulant
• It is an IgG and/or IgM antibody
• Prolonged in vitro coagulation test
• Mixing study is unchanged
• Confirmed phospholipid dependence
• A misnomer
Screening Tests for LAC
•
•
•
aPTT – activated partial thromboplastin
time
KCT – Kaolin clotting test
dRVVT – dilute Russell’s Viper Venom
test
Martin Blood Coag. Fibrin. 7:31, 1996
Coagulation Pathway
Extrinsic
PTT-Intrinsic
XII
PT
Tissue factor
+
VII
XIa
VIIa
IXa
VIIIa
Common
dRVVT
IX
X
Xa
Prothrombin
XI
V
Thrombin
Fibrinogen
Fibrin
Research Diagnostic Criteria for APS
Clinical Criteria
Laboratory Criteria
Recurrent loss <10 wk Lupus anticoagulant
IgG antiCL (> 99%)
Fetal death > 10 wk
Venous Thrombosis
IgM antiCL (> 99%)
Arterial Thrombosis
IgG anti β2- glycoprotein
IgM anti β2- glycoprotein
Miyakis et al. J Thromb Haemost 4:295 – 306, 2006
ACOG Guidelines for Testing
“The three antiphospholipid antibodies
that contribute to the diagnosis of
antiphospholipid syndrome are:
1) lupus anticoagulant
2) anticardiolipin
3) anti-beta-2-glycoprotein 1”
Branch et al., ACOG Bulletin 132 Obstet Gynecol. 120:1514-1521,2012.
What about other aPL Antibodies?
• Phosphatidylinositol
• Phosphatidylglycerol
• Phosphatidylserine
• Diphosphatidylglycerol
• Phosphatidylethanolamine
• Phosphatidylcholine
• Phosphatidic acid
What about other APA antibodies?
Frequency of abnormal APA in 1020 women with RPL
# of prior
losses
2
(n=447)
Anticardiolipin
(> 99% positive)
15.6%
3
(n=343)
4 or more
P value
(n=230)
13.1%
17.1%
0.42
Lupus
Anticoagulant
5.0%
2.9%
1.9%
0.10
Antiphosphatidyl
Serine
(> 99% positive)
4.6%
5.6%
7.8%
0.29
Jaslow & Kutteh. Fertil Steril 93:1234-43, 2010.
Treatment options for
Antiphospholipid Syndrome
•
•
•
•
•
•
None
Low-dose Aspirin (81 to 100 mg)
Prednisone + Aspirin
Unfractionated Heparin + Aspirin
Low molecular weight heparin + Aspirin
Intravenous gammaglobulin
Outcome of observation of
pregnant women with APS
Only 20% of women with high
titer antiphospholipid antibodies
and prior fetal deaths delivered
infants without treatment.
Lockshin, Am J OB/GYN 160:439, 1989
Safety of Low-dose Aspirin
• 7500 pregnant women: aspirin 81mg vs. placebo
• No increase in perinatal morbidity (2.4% vs. 2.6%)
No increase in patent ductus arteriosis
No increase in bleeding abnormalities
• No increase in maternal morbidity (1.7% vs. 1.3%)
No increase in abruptio placenta
No increase in bleeding problems
Hauth et al. Obstet Gynecol. 85:1055,1995.
Prednisone does more harm
202 women with > 2 losses
• Prednisone/Aspirin vs. placebo
• Babies: More PTL, PTD, SGA
• Moms: More HTN, Gest DM
•
Laskin et al., NEJM 337:148-153, 1997.
Prednisone Treatment Outcome
Pred/ASA
42
n
25 (60%)
Liveborn
PTD/PTL 26 (62%)
5 (12%)
HTN
6 (15%)
Gest Diab
Placebo
P-value
46
25 (52%)
6 (12%)
2 (5%)
2 (5%)
Laskin, NEJM 337:148-153, 1997.
0.81
0.001
0.05
0.02
Heparin + Aspirin for APS
• Unfractionated
• Low-molecular weight
Is UF heparin better than LMWH?
Characteristics of Heparins
Characteristic
Source
Structure
Size in Daltons
Mechanism of Action
Crosses placenta
Unfractionated
Low molecular Weight
Porcine mucosa
Porcine mucosa
Glycosaminoglycan
Glycosaminoglycan
~ 15,000
~ 5,000
Thrombin-AT→↓Xa
AT→↓Xa
No
No
Administration frequency
Twice daily
Once daily
Half life, subcutaneously
~ 2 hours
~ 3 to 6 hours
Protamine sulfate reversal
Cost per week of prophylaxis
100%
~ 50%
$72 (US)
$332 (US) $173 generic
Risks Associated with Prophylactic Heparins
Characteristic
Unfractionated
Low molecular Weight
< 1%
< 1%
< < 1%
< 1%
Rare
Rare
Bleed with abdominal
surgery
3%
4%
Bleed with DVT treatment
3%
4%
Hemorrhage, severe
Thrombocytopenia (HIT)
Osteoporosis
Ecchymosis, severe
0
0
Anemia
< 1%
< 1%
Epidural hematoma
Low
Increased
Sanofi-Aventis product insert for FDA approval of enoxaparin sodium
Heparin/Aspirin vs. Aspirin alone
for treatment of APA - RPL
•
•
•
•
•
Screened > 600 women with RPL
Enrolled 50 women with RPL
≥ 3 pregnancy losses (average 3.9)
5-year study period
Prospective, single center, random
Kutteh AJOG 174:1584-9, 1996
Entry Criteria
All women had the following:
• > 3 recurrent,consecutive losses
• positive APL > 6 weeks apart
• IgG > 27 GPL (Harris standards)
• IgM > 23 MPL (Harris standards)
• Negative other evaluation
• Agreed to study protocol
Exclusion Criteria
Positive or abnormal evaluation:
• Karyotypes on either partner
• Uterine cavity by HSG or SHG
• TSH, Prolactin, midluteal Progesterone
• LAC or SLE
• cultures of mycoplasma or ureaplasma
• refused randomization
• aspirin allergy, medical condition
Preconception Treatment
•
•
•
Prenatal vitamins daily
Aspirin 81mg daily
Heparin injection teaching
Kutteh AJOG 174:1584-9, 1996
Pregnancy Treatment
Prenatal vitamins daily
• Aspirin 81 mg/d to 36 weeks
• Heparin BID adjusted dose
• Calcium 600mg BID
•
Kutteh AJOG 174:1584-9, 1996
Results - ASA vs. Heparin + Aspirin
Aspirin
Hep + Asp
Patients
25
25
Livebirths (%)
*11 (44%)
*20 (80%)
EGA (wk)
37.8 ± 2.1
36.7 ± 3.4
Weight (g)
3064
2922
SVD (%)
9 (82%)
15 (75%)
*p=0.02
Kutteh AJOG 174:1584, 1996
low-dose heparin equal to high dose
heparin for treatment of APS
HD Hep
LD Hep
Patients
25
25
Live births
20 (80%)
19 (76%)
EGA
36.7 ± 3.4
37.7 ± 1.6
Weight (g)
2922
3192
SVD (%)
15 (75%)
12 (68%)
Kutteh AJRI 35:402, 1996
“Early RPL with APS treatment justifies
the addition of heparin to aspirin”
Hep/ASA
ASA
p-value
Kutteh,1996
20/25 (80%)
Rai, 1997
32/45 (71%)
19/45 (42%)
0.01
Goel,2006
28/33(85%)
24/39 (62%)
0.05
54/109(50%)
0.02
Total
80/103(78%)
11/25(44%)
0.02
Ziakas et al. Obstet Gynecol 115:1256-62,2010
“Data on substitution of UF Heparin to
LMWH remain inconclusive”
LMWH
Farquarson, 2002 42/51 (82%)
Aspirin
p value 95% CI
35/47 (74%) 0.63 0.24 -1.65
Laskin, 2009
38/45 (84%)
35/43 (81%) 0.81 0.26 - 2.45
Total
80/96 (83%)
70/90 (78%) 0.70 0.34 – 1.45
Neither individual or combined data are significant so the data are not
interpretable. No conclusion can be made.
Ziakas et al. Obstet Gynecol 115:1256-62,2010
TREATMENT OPTIONS: APA - RPL
Treatment
# Treated
None
33/166
Aspirin (80mg/d) 118/257
Prednisone + Asp 94/215
IV IG
91/141
UF Hep + Asp
450/591
LMW Hep + Asp
72/92
Liveborn
20%
46%
44%
64%
76%
78%
ACCP Guidelines for Treatment
“For women with recurrent early pregnancy
loss ..and antiphospholipid antibodies..and
no history of venous or arterial thrombosis,
we recommend antepartum administration
of prophylactic or intermediate-dose UFH
or prophylactic LMWH with aspirin
(Grade IB).”
Bates et al. Chest 133: 844S-886S, 2008
ACOG Guidelines for Treatment
“For women with antiphospholipid
syndrome who have not had a thrombotic
event, expert consensus suggests that
clinical surveillance or prophylactic
heparin use antepartum in addition to 6
weeks of postpartum anticoagulation may
be warranted” (Level C)
Branch et al., ACOG Bulletin 132 Obstet Gynecol. 120:1514-1521,2012.
ACOG Guidelines for Treatment
“For women with antiphospholipid syndrome
who have had a thrombotic event, most
experts recommend prophylactic
anticoagulation with heparin throughout
pregnancy and 6 weeks postpartum”
(Level C)
Branch et al., ACOG Bulletin 132 Obstet Gynecol. 120:1514-1521,2012.
Postpartum Treatment
•
•
•
•
Prenatal vitamins daily
Aspirin 81mg day
Heparin BID for 3 weeks
Calcium 600mg BID
Kutteh AJOG 174:1584-9, 1996
ACCP Guidelines Postpartum
“Women with APLAs (lupus anticoagulants
or anticardiolipin antibodies) and no
previous venous thrombosis should
probably still be considered to have an
increased risk of VTE and should be
managed postpartum with anticoagulants
(prophylactic UFH or LMWH).”
Bates et al. 133: 844S-886S, 2008.
Long-term Treatment
•
•
•
•
•
Prenatal vitamins daily
Aspirin 81mg day
Avoid estrogen containing OCP
Counsel about increased risks
Lifestyle changes (tobacco,
weight)
Kutteh AJOG 174:1584-9, 1996
ACOG Guidelines Postpartum
“Pregnancy and the use of estrogencontaining oral contraceptives appear to
increase the risk of thrombosis. Experts
agree that women with APS should not
use estrogen-containing OCPs but that
progestin-only forms of contraception are
appropriate” (Level C)
Branch et al., ACOG Bulletin 132 Obstet Gynecol. 120:1514-1521,2012.
RECURRENT EARLY PREGNANCY LOSS: CONGENITAL AND ACQUIRED UTERINE ANOMALIES
WILLIAM H. KUTTEH, MD, PHD, HCLD
SATURDAY, 4:15 P.M.
LEARNING OBJECTIVES
After this lecture, you should be able to:

Discuss imaging methods to detect uterine abnormalities

Describe the most common congenital and acquired uterine anomalies

Explain surgical methods to correct uterine abnormalities
This speaker has no conflicts of interest to disclose relative to the contents of this
presentation.
RECURRENT EARLY
PREGNANCY LOSS
Congenital and Acquired Uterine Anomalies
William H. Kutteh, M.D., Ph.D., H.C.L.D.
Clinical Professor Of Obstetrics and Gynecology
Vanderbilt University Medical Center
DISCLOSURES
• None
LEARNING OBJECTIVES
Uterine Anomalies and RPL
At the end of this presentation, the
participant should be able to:
• Discuss imaging methods to detect
uterine abnormalities
• Describe the most common congenital
and acquired uterine anomalies
• Explain surgical methods to correct
uterine abnormalities
Development of Reproductive Structures
(6 to 10 gestational weeks)
Mullerian ducts (paramesonephric)
– fallopian tubes, uterus and upper 1/3 vagina
– develops if no AMH present
– fuses to the urogenital sinus
Wolffian ducts (mesonephric)
– semeniferous tubules, epididymus, vas
deferens – need testosterone to develop
Genesis of Mullerian Tract Anomalies
Mullerian tract anomalies result from:
•
•
•
•
Failure of ductal elongation
Failure of fusion
Failure of canalization
Failure of septal resorption
Causes are unknown
Associated renal anomalies
ASRM Classification of Mullerian Anomalies
American Fertility Society. Fertil Steril. 49:944-55,1988.
Classification and Frequency of
Congenital Uterine Anomalies
•
•
•
•
•
•
•
Class I Mullerian agenesis – 5%
Class II Unicornuate Uterus – 20%
Class III Didelphus Uterus – 7%
Class IV Bicornuate Uterus – 10%
Class V Septate Uterus – 55%
Class VI Arcuate Uterus –
Class VII DES exposure – 3%
American Fertility Society. Fertil Steril. 49:944-55,1988.
Uterine Imaging by 3-D Sonohysterograms
Types of Uterine Anomalies
Congenital – mullerian disorders
Acquired – uterine trauma
anatomical lesions
Some cause pregnancy loss, preterm
birth, and malpresentaion
Methods of Uterine Assessment
•
•
•
•
•
OPTIMAL
3-D Saline infusion sonohysterogram
(SHG)
MRI Pelvis
Laparoscopy and hysteroscopy
SUBOPTIMAL
Hysterosalpingogram (HSG)
2-D ultrasound
Chan et al. Human Reprod Update 17:761-71,2011
Study comparing SHG to HSG
•
•
•
•
•
•
•
Scheduled for HSG in radiology dept.
Scheduled for SHG at reproductive clinic
Ibuprofen 400mg 1 hour prior to procedure
Performed within the same cycle
Investigators blinded to other results
Patient completed tolerability survey
Physician completed findings
Bareddy, Ke, Kutteh. Fertil Steril. Oct 2004.
SHG vs. HSG Tolerability in women
with the diagnosis of RPL
Bareddy, Ke, Kutteh. Fertil Steril. Oct 2004.
3-D SHG superior to HSG in RPL
• SHG is more tolerable
Less cramping and pain
Less discomfort with new setting
Less time in and out
• SHG detected more uterine pathology
• Revenue stays in your office!
Bareddy, Ke, Kutteh. Fertil Steril. Oct 2004.
Septum or Bicornuate?– HSG suboptimal
Septum on MRI - Optimal
Uterine Septum on 3-D SHG - Optimal
Meta-Analysis of Congenital Uterine Anomalies
POPULATION
Unselected
Infertility
# SUBJECTS
(# studies)
PREVALENCE
(95% CI)
5,163 (9)
5.5 (3.5-8.5)
10,303 (19)
8.0 (5.3-12.0)
Recurrent
miscarriage
2,082 (6)
13.3 (8.9-20) *
Infertility +RM
7,053 ((9)
24.5 (18.3-32.8) *
Chan et al. Human Reprod Update 17:761-71,2011
Prevalence of uterine anomalies among 904 RPL patients
% occurrence (n)
Total frequency of anomalies
Congenital anomalies
Bicornuate uterus
Didelphic uterus
Septate uterus
T-shaped uterus
Unicornuate uterus
Acquired anomalies
Adhesions
Fibroid(s)
Polyp(s)
19.5 (176)
6.7 (61)
0.9 (8)
0.2 (2)
4.6 (42)
0.3 (3)
0.7 (6)
13.3 (120)
4.1 (37)
6.4 (58)
3.2 (29)
Jaslow and Kutteh. Fertil Steril. 99:1916-1922, 2013.
Septate Uterus
•
•
•
•
•
•
Caused by failure of septal resorption
Most common congenital uterine anomaly
May project from fundus to upper 1/3 of vagina
Spontaneous loss rate between 30% and 65%
Composed of fibromuscular tissue
Mechanism may be due to avascular tissue,
poor endometrial development, or distorted
uterine cavity
• General consensus is to correct
hysteroscopically
ASRM Committee Opinion. Fertil Steril 5:1103-11, 2012
Study
Anomalies/ Patients
%
95% CI
Weiss et al. (2005)
13/165
7.9
(4.2-12.5)
Stephenson (1996)
8/197
4.1
(1.7-7.3)
Bohlmann et al. (2010)
15/206
7.3
(4.1-11.3)
Ghi et al. (2009)
36/284 12.7
(9.0-16.8)
Salim et al. (2003)
27/509
5.3
(3.5-7.4)
Jaslow et al. (2013)
42/904
4.6
(3.4-6.1)
141/2265
6.0
(5.0-7.0)
All Studies
Jaslow and Kutteh. Fertil Steril 99:1916-22, 2013.
Septate Uterus
0
5
10
15
20
Percent of RM patients with a septate uterus (+ 95% CI)
Wide Fundus often seen with Septate Uterus
Hysteroscopic view of Uterine Septum
Resectoscope Loop in position using Electrocautery
Cutting through avascular septum
Identification of Left Ostia
Identification of Right Ostia
Uterine Cavity Normalized after Resection
Two-fold Increase in Uterine Septa
Primary RM compared with Secondary RM
All uterine anomalies
Congenital anomalies
Primary RM
(n = 479)
Secondary RM
(n = 425)
P
22.8 (109)
15.8 (67)
0.009
0.011
8.8 (42)
4.5 (19)
Bicornuate uterus
1.0
(5)
0.5
(2)
Didelphic uterus
0.2
(1)
0.2
(1)
Septate uterus
6.3 (30)
3.1 (13)
T-shaped uterus
0.4
(2)
0.2
(1)
Unicornuate uterus
0.8
(4)
0.5
(2)
ns
14.6 (70)
11.8 (50)
ns
Adhesions
4.0 (19)
4.2 (18)
ns
Fibroid(s)
7.3 (35)
5.4 (23)
ns
Polyp(s)
4.0 (19)
2.4 (10)
ns
Acquired anomalies
ns
ns
0.028
ns
Values are % occurrence (n).
Jaslow and Kutteh. In Press, 2013.
Unicornuate Uterus
• Cause – agenesis or hypoplasia of one
mullerian duct
• Highest incidence of renal anomalies
(40%)
• Spontaneous loss rate = 51%
• High incidence of cervical incompetence
• Intervention
-No RPL – monitor cervical length
-RPL – consider prophylactic cerclage
-Rudimentary horn with cavity – resect
Diagrams of Unicornuate Uterus
Study
Anomalies/Patients
%
95% CI
Weiss et al. (2005)
1/165
0.6
(0.5-2.6)
Stephenson (1996)
1/197
0.5
(0.4-2.2)
Bohlmann et al. (2010)
0/206
0.0
(0.0-1.4)
Ghi et al. (2009)
1/284
0.4
(0.3-1.5)
Salim et al. (2003)
2/509
0.4
(0.0-1.2)
Jaslow et al. (2013)
6/904
0.7
(0.2-1.3)
11/2265
0.5
(0.2-0.9)
All Studies
Unicornuate
Uterus
0
0.5
1
1.5
2
2.5
Jaslow and Kutteh. Fertil Steril 99:1916-22, 2013
Percent of RM patients with a unicornuate uterus (+
95% CI)
3
Unicornuate Uterus on SHG
Bicornuate Uterus
• Partial failure of lateral fusion (fundal)
• Two separate but communicating cavities
• Single cervix
• Cleft at the top of the uterus
Study
Anomalies/Patien
ts
%
Weiss et al. (2005)
3/165
1.8 (0.2-4.6)
Stephenson (1996)
1/197
0.5 (0.4-2.2)
Bohlmann et al.
(2010)
5/206
2.4 (0.7-5.1)
Ghi et al. (2009)
8/284
2.8 (1.2-5.1)
Salim et al. (2003)
6/509
1.2 (0.4-2.3)
Jaslow et al. (2013)
8/904
0.9 (0.4-1.6)
All Studies
Bicornuate Uterus
95% CI
31/2265 1.2 (0.8-1.8)
Jaslow and Kutteh. Fertil Steril 99:1916-22, 2013
0
1
2
3
4
5
6
Percent of RM patients with a bicornuate uterus (+ 95%
CI)
Acquired Uterine Anomalies
Equal frequency in primary and secondary RPL
Equal frequency in 2, 3, or more losses
• Intrauterine Adhesions (Asherman’s)
• Submucosal leiomyomata
• Endometrial Polyps
Intrauterine Adhesions
-Causes – curettage, infection, surgery
-Mild to severe range of severity
Extent
Cavity
Menses
Mild
<1/3
Normal
Moderate 1/3 -2/3 Decreased
Severe
>2/3
None
-Hysteroscopic surgical excision advised
Intrauterine Adhesion on SHG
Study
Anomalies/Patients
Uterine Adhesions
%
95% CI
Ventolini et al. (2004)
5/23
21.7
(6.9-41.2)
Dendrinos et al. (2008)
9/48
18.8
(8.8-31.2)
Tulppala et al. (1993)
5/55
9.1
(2.7-18.4)
Guimarães Filho et al. (2006)
Souza et al. (2011)
Cogendez et al. (2011)
16/58
27.6 (16.8-39.9)
7/66
10.6
(4.1-19.3)
10/82
12.2
(5.9-20.3)
Raziel et al. (1994)
25/106
Weiss et al. (2005)
11/165
23.6 (15.9-32.2)
6.7
Stephenson (1996)
11/197
5.6
(2.8-9.3)
Bohlmann et al. (2010)
26/206
12.6
(8.4-17.5)
(3.3-11.0)
1/214
0.5
(0.4-2.0)
Valli et al. (2001)
15/344
4.4
(2.4-6.8)
Li et al. (2002)
17/453
3.8
(2.2-5.7)
Jaslow et al. (2013)
37/904
4.1
(2.9-5.5)
195/2921
5.5
(4.7-6.4)
Coulam (1991)
All Studies
0
5
10
15
20
25
30
35
40
45
Percent of RM patients with uterine adhesions (+ 95% CI)
Jaslow and Kutteh. Fertil Steril 99:1916-22, 2013
Endometrial Poly on SHG
Study
%
95% CI
Ventolini et al. (2004)
Anomalies/Patients
0/23
0.0
(0.0-12.2)
Dendrinos et al. (2008)
2/48
4.2
(0.1-12.1)
Tulppala et al. (1993)
2/55
3.6
(0.1-10.6)
Souza et al. (2011)
4/66
6.1
(1.3-13.4)
Cogendez et al. (2011)
7/82
8.5
(3.3-15.7)
Raziel et al. (1994)
2/106
1.9
(0.0-5.6)
Weiss et al. (2005)
2/165
1.2
(0.0-3.6)
Stephenson (1996)
0/197
0.0
(0.0-1.5)
15/206
7.3
(4.1-11.3)
Coulam (1991)
1/214
0.5
(0.4-2.0)
Ghi et al. (2009)
9/284
3.2
(1.4-5.6)
Valli et al. (2001)
2/344
0.6
(0.0-1.7)
Jaslow et al. (2013)
29/904
3.2
(2.1-4.5)
All Studies
75/2694
2.5
(1.8-3.2)
Bohlmann et al. (2010)
Uterine Polyps
0
5
10
15
20
Jaslow and Kutteh. Fertil Steril 99:1916-22, 2013Percent of RM patients with one or more uterine polyps (+
95% CI)
Leiomyomatas
• Equal frequency in primary and secondary RPL
• Submucosal fibroids protrude into the cavity
• Mechanism of RPL by altered uterine contour,
vascularity, or subacute endometritis
• Remove submucosal fibroids hysteroscopically
Study
Anomalies/Patients
%
95% CI
Ventolini et al. (2004)
2/23
8.7
(0.2-24.5)
Dendrinos et al. (2008)
4/48
8.3
(1.9-18.1)
Tulppala et al. (1993)
0/55
0.0
(0.0-5.3)
Souza et al. (2011)
2/66
3.0
(0.0-8.9)
Cogendez et al. (2011)
2/82
2.4
(0.0-7.2)
Raziel et al. (1994)
0/106
0.0
(0.0-2.8)
Weiss et al. (2005)
5/165
3.0
(0.9-6.3)
Stephenson (1996)
1/197
0.5
(0.4-2.2)
19/206
9.2
(5.6-13.6)
Bohlmann et al. (2010)
0/214
0.0
(0.0-1.4)
Ghi et al. (2009)
19/284
6.7
(4.0-9.9)
Valli et al. (2001)
13/344
3.8
(2.0-6.1)
Li et al. (2002)
19/453
4.2
(2.5-6.3)
Jaslow et al. (2013)
58/904
6.4
(4.9-8.1)
144/3147
4.6
(3.8-5.5)
Coulam (1991)
All Studies
Uterine Fibroids
0
5
10
15
20
25
Jaslow and Kutteh. Fertil Steril 99:1916-22, 2013
Percent of RM patients with one or more uterine fibroids (+ 95% CI)
Resection of Submucosal Fibroid
Summary of Uterine Anomalies
Primary RM compared with Secondary RM
Primary RM
(n = 479)
All uterine anomalies
22.8 (109)
Secondary RM
(n = 425)
P
15.8
(67)
0.009
Congenital anomalies
8.8
(42)
4.5
(19)
0.011
Bicornuate uterus
1.0
(5)
0.5
(2)
ns
Didelphic uterus
0.2
(1)
0.2
(1)
ns
Septate uterus
6.3
(30)
3.1
(13)
0.028
T-shaped uterus
0.4
(2)
0.2
(1)
ns
Unicornuate uterus
0.8
(4)
0.5
(2)
ns
14.6
(70)
11.8
(50)
ns
Adhesions
4.0
(19)
4.2
(18)
ns
Fibroid(s)
7.3
(35)
5.4
(23)
ns
Polyp(s)
4.0
(19)
2.4
(10)
ns
Acquired anomalies
Values are % occurrence
Jaslow
(n). and Kutteh. In Press, 2013.
Summary - Uterine Anomalies and RPL
 Congenital anomalies are present in 6.7% and
acquired anomalies in 13.3% of women evaluated for
RPL
 Septate uterus is the most common congenital
anomaly and is associated with the highest incidence
of reproductive failure
 3-D Sonohysterography is an optimal imaging method
and is the most cost-effective method of assessing
uterine abnormalities
 Uterine anomalies are found just as frequently in
patients with primary vs secondary RPL, with the
exception of the uterine septum which is more
prevalent in primary RPL
RECURRENT FIRST TRIMESTER PREGNANCY LOSS: ENDOCRINE FACTORS
PAUL R. BREZINA, MD, MBA
SATURDAY, 4:45 P.M.
LEARNING OBJECTIVES
After this lecture, you should be able to:

Describe the endocrinologic factors that may contribute to recurrent pregnancy
loss

Treat deleterious endocrine factors to better maximize pregnancy outcomes in
individuals with a history of RPL
This speaker has relevant financial relationships with the following commercial interests:
Speaker: AbbVie Pharmaceuticals
Recurrent First Trimester
Pregnancy Loss
Endocrine Factors
PAU L R . B R E Z I N A, M D , M B A
D I R E C T O R : P R E I M P L A N TAT I O N G E N E T I C S
F E R T I L I T Y A S S O C I AT E S O F M E M P H I S
MEMPHIS, TN
Clinical Assistant Professor of Obstetrics and Gynecology
Vanderbilt University Medical Center
Disclosures
 Nothing to disclose
 No conflict of interest
Learning Objectives
At the conclusion of this presentation, the
physician should be able to:
1. Describe the endocrinologic factors that may
contribute to recurrent pregnancy loss
2. Treat deleterious endocrine factors to better
maximize pregnancy outcomes in individuals with
a history of RPL
27-year-old Caucasian, G3 P0300
 CC: I keep loosing pregnancies
 HPI: Married 2 years ago. Conceives easily but has had







three documented intrauterine pregnancies in which no
FHR was documented past 8 weeks of gestation.
PMH: Noncontributory
POB HX: SAB*3, 2 with D+C (no karyotype obtained)
PGYN Hx: menarche age 13, regular cycles q28 days
with no hx of abn pap/stds
PSurg Hx: D+C *2
Meds: prenatal vitamins
All: NKDA
Soc: No ETOH, Drugs, Tob
33-year-old Caucasian, G4 P0400
 Work up
 TSH 4.8 uIU/mL
 CBC, CMP, Prolactin, HA1C all Normal
 CD3 testing





FSH 5.2, LH 6.5, E2 34
US: AFC 24, no uterine polyps or myomas, all other WNL
No abnormalities in antiphospholipid Abs, anti βIIGP1, Factor
II, Lupus anticoagulant
Hysterosalpingogram WNL
Paternal and Maternal karyotype normal
33-year-old Caucasian, G4 P0400
 What can we offer this patient?
 TSH is within normal limits per reference values
 Other testing is WNL
Is there anything else we can do?
Luteal phase deficiency
 Maintenance of early pregnancy depends on the
production of progesterone by the corpus luteum
 Between 7 and 9 weeks of gestation the developing
placenta takes over the progesterone production
 Luteal phase deficiency (LPD) is defined as an
inability of the corpus luteum to secrete
progesterone in high enough amounts or for too
short a duration
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A
Practical Guide. 2nd ed. New York, NY: Springer. (in press)
Luteal Phase Deficiency
Progesterone
Estrogen
Fetus
Placenta
Corpus
Luteum
Uterus
HCG
Ovary
Luteal Phase Deficiency
Progesterone
Estrogen
Fetus
Placenta
Corpus
Luteum
Ovary
Uterus
Diagnosing Luteal Phase Deficiency
 Classically diagnosis made with endometrial biopsy in
the luteal phase

Currently not recommended as a diagnostic modality (Brezina 2012)
 Many advocate using serum progesterone levels in the
luteal phase for the diagnosis of LPD with levels below
10ng/ml considered abnormal (Cummings 1985)


However, progesterone levels are subject to large fluctuations
because of pulsatile release of the LH hormone (Shepard 1977)
There is a lack of correlation between serum levels of progesterone
and endometrial histology (Shepard 1977)
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New York,
NY: Springer. (in press)
Cumming DC, Honore LH, Scott JZ, Williams KP. The late luteal phase in infertile women: comparison of simultaneous endometrial biopsy and progesterone levels. Fertil Steril.
1985;43:715-9.
Shepard MK, Senturia YD. Comparison of serum progesterone and endometrial biopsy for confirmation of ovulation and evaluation of luteal function. Fertil Steril. 1977; 28:541-8..
ACOG Committee Opinion 2011
 Normal Women have endometrial histology
suggestive of LPD in up to 50% of single menstrual
cycles and 25% of sequential cycles
 The association between LPD and RPL remains
speculative
American College of Obstetricians and Gynecologists. ACOG practice bulletin. Management of recurrent pregnancy loss. Number 24, February 2001. (Replaces Technical Bulletin
Number 212, September 1995). American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 2002 Aug;78(2):179-90.
Recommendations for treating LPD
 Many authors recommend only treating women with
progesterone support who have a documented LPD
 Recent Cochrane review evaluating 15 trials
concluded that there was a benefit to the routine
administration of progesterone to all women with a
history of RPL (Goldstein 1989, Haas 2009)
Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC. A meta-analysis of randomized control trials of progestational agents in pregnancy. BJOG.1989; 96:265-274.
Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2008;(2):CD003511.
Recommendations for treating LPD
 In our clinic
 We treat all women with a history of RPL with P4 support

Micronized vaginal P4 suppositories
 100 mg TV daily to 10 weeks gestation
Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC. A meta-analysis of randomized control trials of progestational agents in pregnancy. BJOG.1989; 96:265-274.
Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2008;(2):CD003511.
Hypothyroidism
 A study of over 700 patients with recurrent
pregnancy loss identified 7.6% with hypothyroidism
(Ghazeeri 2001)
 Antithyroid antibodies are elevated in women with
recurrent pregnancy loss (Kutteh 1997)

No definitive treatment for isolated finding of antithryoid
antibodies in the absence of abnormal TSH (ACOG 2001)
Ghazeeri GS, Kutteh WH. Immunological testing and treatment in reproduction: frequency assessment of practice patterns at assisted reproduction clinics in the USA and Australia.
Hum Reprod. 2001;16:2130-5.
Kutteh WH, Yetman DL, Carr AC, Beck LA, Scott RT, Jr. Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing
assisted reproduction. Fertil Steril. 1999; 71:843-8.
American College of Obstetricians and Gynecologists. ACOG practice bulletin. Management of recurrent pregnancy loss. Number 24, February 2001. (Replaces Technical Bulletin
Number 212, September 1995). American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 2002 Aug;78(2):179-90.
Treating Hypothyroidism
 Hypothyroidism is easily diagnosed with a sensitive
TSH test and patients should be treated to become
euthyroid before attempting a next pregnancy (De
Groot 2012)

“Normal” TSH between 1.0 and 2.5 uIU/mL
 For TSH levels found to be between 2.5-10 mIU/mL
 Starting levothyroxine dose of at least 50 μg/d is
recommended (De Groot 2012)
De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ, Mestman J, Rovet J, Sullivan S. Management of Thyroid
Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2012;97:2543-65.
Abnormal Glucose Metabolism
 Poorly controlled diabetes is known to increase the risk
of spontaneous miscarriage and birth defects

This increased risk is eliminated euglycemic control is
preconceptually achieved (Mills 1998)
 Testing for fasting insulin and glucose is simple and
treatment with insulin-sensitizing agents can reduce the
risk of recurrent miscarriage (Sills 2000)
 Testing of hemoglobin A1C is being increasingly utilized
to evaluate insulin resistance (ASRM)
Mills JL, Simpson JL, Driscoll SG, Jovanovic-Peterson L, Van Allen M, Aarons JH, Metzger B, Bieber FR, Knopp RH, Holmes LB, et al. Incidence of spontaneous abortion among
normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. N Engl J Med. 1988;319:1617-23.
Sills ES, Perloe M, Palermo GD: Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and
reproductive outcomes. Eur J Obstet Gynecol Reprod Biol. 2000; 91:135-141.
The Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012 Jul 24. [Epub
ahead of print]
Abnormal Glucose Metabolism
 Diabetes
 Referral to Endocrinologist
 Consider birth control prior to pursuing pregnancy
 Likely need for insulin management
 Need for aggressive management and documentation of
normalized blood glucose levels prior to attempting pregnancy
Mills JL, Simpson JL, Driscoll SG, Jovanovic-Peterson L, Van Allen M, Aarons JH, Metzger B, Bieber FR, Knopp RH, Holmes LB, et al. Incidence of spontaneous abortion among
normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. N Engl J Med. 1988;319:1617-23.
Sills ES, Perloe M, Palermo GD: Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and
reproductive outcomes. Eur J Obstet Gynecol Reprod Biol. 2000; 91:135-141.
The Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012 Jul 24. [Epub
ahead of print]
Treatment of Abnormal Glucose Metabolism
 Pre-diabetes (metabolic syndrome)
 Weight reduction



Nutrition counseling
Comprehensive weight loss program/center
Metformin
Seems to improve pregnancy outcome
 Evidence for this treatment is limited to a few cohort studies
(Brezina 2012, Sills 2000)
 Category B medication in the first trimester of pregnancy

Sills ES, Perloe M, Palermo GD: Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and
reproductive outcomes. Eur J Obstet Gynecol Reprod Biol. 2000; 91:135-141.
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New York,
NY: Springer. (in press)
Hyperprolactinemia
 Repeat fasting prolactin level
 If still elevated
 Must evaluate cause of elevated prolactin
 Pituitary causes


Micro/Macro pituitary adenoma
Production or stalk compression

Iatrogenic


Pregnancy/Breastfeeding
Stress
PCOS

Idiopathic



Medications
 Psychiatric meds, Reglan, sleeping medications, αMD
Some PCOS have slightly elevated prolactin levels
Dlugi AM. Hyperprolactinemic recurrent spontaneous pregnancy loss: a true clinical entity or a spurious finding?[comment]. Fertil Steril. 1998;70:253-5.
Hirahara F, Andoh N, Sawai K, Hirabuki T, Uemura T, Minaguchi H. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials.[see comment].
Fertil Steril. 1998;70:246-52.
Hyperprolactinemia
 Data from animal studies suggest that elevated
prolactin levels may adversely affect corpus luteal
function (Dlugi 1998)

Not definitively demonstrated in humans
 A recent study of 64 hyperprolactinemic women
showed that bromocriptine therapy was associated
with a higher rate of successful pregnancy and that
prolactin levels were significantly higher in women
who miscarried (Hirahara 1998)
Dlugi AM. Hyperprolactinemic recurrent spontaneous pregnancy loss: a true clinical entity or a spurious finding?[comment]. Fertil Steril. 1998;70:253-5.
Hirahara F, Andoh N, Sawai K, Hirabuki T, Uemura T, Minaguchi H. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials.[see comment].
Fertil Steril. 1998;70:246-52.
Diminished Ovarian Reserve (DOR)
 The frequency DOR levels in women with recurrent
miscarriage is similar to the frequency in the infertile
population
 The prognosis of recurrent miscarriages is worsened
signs of DOR (Hofmann 2000)

Could fewer available follicles predispose to an increased risk
of recruiting abnormal follicles?
Brezina PR, Kutteh WH. Recurrent Early Pregnancy Loss. In: Falcone Tommaso, Hurd William, eds. Clinical Reproductive Medicine and Surgery: A Practical Guide. 2nd ed. New York,
NY: Springer. (in press)
Hofmann GE, Khoury J, Thie J. Recurrent pregnancy loss and diminished ovarian reserve. Fertil Steril. 2000; 74(6):1192-5.
Diagnosing DOR: Early Follicular Phase
 Follicle stimulating hormone (FSH)


Tested in the early follicular phase (cycle day 2 or 3)
Levels greater than 10 ng/ml are considered worrisome for DOR
 Estradiol (E2)


Tested in the early follicular phase (cycle day 2 or 3)
Levels greater than 50 pg/ml are considered worrisome for DOR
 Transvaginal ultrasound to determine antral follicle count


Tested in the early follicular phase (cycle day 2 or 3)
Fewer than 10 antral follicles on each ovary is considered
worrisome for DOR
Diagnosing DOR
 Anti Müllerian hormone (AMH)
 Tested at any time during the menstrual
cycle
 Levels greater than 1 are considered
worrisome for DOR
Sowers M, McConnell D, Gast K, Zheng H, Nan B, McCarthy JD, Randolph JF. Anti-Müllerian hormone and inhibin B variability during normal menstrual cycles.
Fertil Steril. 2010 Sep;94(4):1482-6.
Diagnosing DOR
 No treatment is available
 Testing may be especially helpful in women over the
age of 35 with recurrent pregnancy loss
 Appropriate counseling should follow
 May modify the treatment course moving forward
 May be more aggressive if DOR diagnosed/suspected
27-year-old Caucasian, G3 P0300
 HPI: Married 2 years ago. Conceives easily but has
had three documented intrauterine pregnancies in
which no FHR was documented past 8 weeks of
gestation.
 Work up

TSH 4.8 uIU/mL
 Plan
 Begin treatment with synthroid 50 mcg PO daily and repeat
TSH in 6 weeks with goal of keeping values < 2.5 uIU/mL
 Initiate P4 vaginal suppositories in the luteal phase
 If failed pregnancy occurs in the future, obtain POC for 23
chromosome pair karyotypic analysis
UPCOMING COLLEGE FREESTANDING POSTGRADUATE COURSES
2014
December 4-6
Update on Cervical Diseases
Mark Spitzer, MD
The Sheraton Times Square
New York, New York
December 11-13
Practical Obstetrics and Gynecology
Patrick Duff, MD
Hyatt Regency Chicago
Chicago, Illinois