David H Barad MD MS Director of Assisted Reproductive Technology Center for Human Reproduction New York NY CHR Grand Rounds May 14 th 2013 Conflict of Interest Dr Barad and Dr Gleicher are listed as coinventors on a number of patents and pending patent applications claiming the ID: 672500
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Slide1
Androgen Gonadotropin Synergy
David H. Barad, MD MSDirector of Assisted Reproductive TechnologyCenter for Human ReproductionNew York, NY
CHR Grand Rounds
May 14
th
,
2013Slide2
Conflict of Interest
Dr. Barad and Dr. Gleicher are listed as co-inventors on a number of patents and pending patent applications claiming therapeutic benefits from DHEA and other androgens in treatment of infertility and claiming diagnostic and therapeutic benefits from determination of CGG repeat numbers and ovarian FMR1 genotypes and sub-genotypes.Dr. Kushnir has no conflicts of interest.Slide3
Follicles decline with age
The Lancet, Volume 376, Issue 9744, Pages 911 - 921
From
Menkin
J,
Trussel
J, Larsen U.
Science.
1986;233:1389-1394. Reprinted with permission from AAAS.
FertilitySlide4
Ovarian ReserveSlide5
Functional Ovarian Reserve
The Lancet, Volume 376, Issue 9744, Pages 911 - 921Slide6
Androgens decline with AgeSlide7
Rice S et al. JCEM 2007;92:1034-1040
©2007 by Endocrine Society
Primordial Follicle
Transitional Follicle
Primary Follicle
Secondary Follicle
Developing FolliclesSlide8
Rice S et al. JCEM 2007;92:1034-1040
©2007 by Endocrine Society
Androgen, AMH and FSH Receptors
Human Pre-antral FolliclesSlide9
Follicle development in AR KO mice
Molecular Endocrinology 24: 1393–1403, 2010Slide10
Polycystic Ovarian SyndromeSlide11
FSH and Androgen Receptors
Reproductive Biology and Endocrinology 2011, 9:116 doi:10.1186/1477-7827-9-116Slide12
Ovulation InductionSlide13
Follicle Growth
Functional Ovarian Reserve
Functional Ovarian Reserve
Functional Ovarian Reserve
Androgen effect
Androgen plus gonadotropin effectSlide14
Sequential Cycles
85 women with evidence of DFOR 3 consecutive IVF cycles while receiving androgen supplementation with dehyroepiandrosterone (DHEA, 25 mg, TID) for at least 6 weeks prior to the first IVF cycle and ovarian stimulation with 300-450 IU of FSH
68 women with intercycle intervals of < 120 days reflecting concomitant FSH exposure
17 with cycle intervals of ≥120 daysSlide15
Oocyte response to Serial Cycles
Linear trend t = 3.02, DF 51; p = 0.004
< 120 days
> 120 daysSlide16
Oocyte response to Serial Cycles
Linear trend t = 3.02, DF 51; p = 0.004
< 120 days
> 120 daysSlide17
Oocyte response to Serial Cycles
Linear trend t = 3.02, DF 51; p = 0.004
< 120 days
> 120 daysSlide18
Theca Cell Granulosa Cell
Cholesterol
Pregnenolone
17 OH Pregneneolone
Testosterone
Estradiol 17
β
LH
cAMP
cAMP
Protein
Kinase
A
Testosterone
DHEA
FSHSlide19
Federally Mandated IVF Outcome Reporting
(how not
to do it)
Vitaly
A.
Kushnir
M.D.Slide20
Disclosure
I consult for the CDC ART Surveillance TeamThe
Status of Public Reporting of Clinical Outcomes in Assisted Reproductive
Technology
Fertility & Sterility (in press) Slide21
Background
In 1992 President George H.W. Bush signed
The Fertility Clinic Success Rate and Certification Act
(FCSRCA; PL 102-493) into law.
Sponsored by Ron Wyden (D-OR), the statute set out to establish a national public reporting framework for the clinical outcomes of ART programs.Slide22
JAMA. 2011 Sep 14;306(10):1135-6
.Slide23
Implementation
SART
Industry
Voluntary
CDC
Government
StatutorySlide24
Reported Information
Clinic-specific pregnancy & live birth rates stratified by ART modality and maternal age.
Live birth rate per initiated ART cycle, per oocyte retrieval, and per embryo transfer.
Only SART reports total number of initiated cycles
CDC identifies of non-reporting ART programs.Slide25
Reported Information
Program-specific procedural volumes.
Percentage of cycle cancellations.
Average number of embryos transferred
.
Implantation rate
Embryo/gamete cryopreservation capabilities.
Incidence of multiple pregnancies & births.
Aggregated annualized national data.Slide26
Not Reported
Cycles with no immediate outcomes such as
- EMBRYO BANKING
Reports do not
rank
,
rate
, or directly
compare
ART programs in recognition of the differences of their case mix and the variable scope of their practices.
Slide27
Does Public Reporting Improve Clinical Outcomes?
Public reporting of health care outcomes is premised on the tenets of transparency and accountability.
Can public reporting bring about improved clinical outcomes?
Does transparency change behavior of consumers & providers leading to change in quality? Slide28
Investigated Registries
_________________________________________________________________________________________________________ Registry
CDC
SART
Study period (years) 2005-2010 2005-2010
Number of ART clinics
Total 469-484
Reporting (%) 422- 443 (88.2-93.5) 341 (71.9)
Not Reporting (%) 31-57 (6.5-11.8) 133 (28.1)
Number of completed ART cycles 818,927 772,855
Number of started ART cycles 2005-2010 -- 812,400
2005 -- 123,200
2010 -- 146,693Excluded Cycles 2005- 2010 -- 39,545 (4.9%)
2005 -- 4,102
(3.3%)
***
2010 -- 10,821
(7.4%)
***
_________________________________________________________________________________________________________
***
P=<0.001Slide29
ART Cycles Reported and Excluded by SART Slide30
Excluded ART Cycles for 13 Outlier ClinicsSlide31
Pregnancy Rates in Non-Donor Fresh IVF Cycles in Women Under Age 35Slide32
2010 ART Cancellation and Pregnancy Rates
___________________________________________________________________________________________
Outlier Clinics Rest of SART CDC only
13 328 74
____________________________________________________________________________________________
Fresh Cancellation Rate <35 years (%)
Cycle outcome 3.0
***
6.7 8.1
*
Fresh Pregnancy Rate <35 years (%)
Cycle outcome 59.1
***
47.5 45.6Thawed Pregnancy Rate <35 years (%)
Cycle outcome 53.4
*** 37.1 34.2 ____________________________________________________________________________________________ * P=<0.05. *** P=<0.001Slide33
Patient Populations
_________________________________________________________________________________________________
Outlier Clinics Rest of SART CDC only
13 328 74
_________________________________________________________________________________________________
Distribution of Female Patient Population by Age
<38 years (%)
Cycle start
31.2
***
54.5 --
Cycle outcome
51.8***
57.4 60.0***___________________________________________________________________________________________________
***
P=<0.001.OLDER AND POOR PROGNOSIS PATIENT ARE DIRECTED TO EMBRYO BANKING Slide34
Excluded ART Cycles in 13 Outlier Clinics and
Market Share of ART CyclesSlide35
Conclusions
Public reporting creates a health care marketPoor prognosis patients are disproportionately affected
G
overnment agency (CDC) reports provide less transparency than industry group (SART) reports on which it largely relies for data collectionSlide36
Suggested Improvements
Total Reproductive Potential
Better approximates the “true” live birth rate per cycle by including births from fresh and frozen cycles
Prospective reporting
Good Perinatal Outcome
Slide37
Are twins good or bad for America?
Grandrounds, CHR-NYMay 14th, 2013
Norbert Gleicher, MD
Medical Director and Chief
Scientist
,
Center for Human Reproduction – New York
President, Foundation for Reproductive
MedicineSlide38
The Issue
Assuming we can really produce at will singletons and twins, which is the “better” outcome for women who don’t mind twins, and have no medical contraindications for twins?SET, in comparison to 2-ET, reduces pregnancy chances, thereby causing potential medical harm to patients.Not even the most accomplished R.E. can ever guarantee a second consecutive successful pregnancy. Therefore, splitting up potential pregnancy chances into 2 consecutive chances is, ethically, a very questionable proposition.
McLemon
et al., BMJ 2010
Gelbaya
et al., F&S 2010Slide39
We often accept treatment harm IF COMPENSATED BY POTENTIAL TREATMENT BENEFITS!ARE THERE SUCH BENEFITS FROM SET?Slide40
Twin pregnancies carry higher risk than singleton pregnancies!
How do we know?Obstetrical outcome studies!Slide41
Obstetrical Outcomes
Compare: Outcome of one new born (SINGLETON) to outcome of two newborns (TWINS)Slide42
OBSTETRICS:Retrospective
Compares 1 to 2 newborns (1 singleton to 1 twin pregnancy)INFERTILITY:ProspectiveCompares 2 to 2 newborns
(2 singletons to 1 twin pregnancy)Slide43
Twin pregnancy, contrary to consensus, is a desirable outcome in infertility
Norbert Gleicher,
MD, David
H
Barad, MD, MS
Objective
:
To determine whether the worldwide consensus that twin pregnancy after fertility treatment represents an adverse outcome to be avoided is correct.
Design
:
Literature search via
PubMed
and MEDLINE, going back to 1990.
Setting
: Academically affiliated, private fertility center.
Patient(s)
:
Mothers and offspring in singleton and twin pregnancies.Intervention(s): None.
Main Outcome Measure(s)
:
M
aternal and
perinatal
/neonatal risks as well as cost considerations for singleton versus twin pregnancies.
Result(s)
:
Most risk assessments of twin pregnancies after fertility treatment have used spontaneous conceptions data, which reflect different treatment paradigms and outcome benefits from pregnancies after fertility treatments. In vitro fertilization (IVF) twins demonstrate approximately 40% lower outcome risks than spontaneous twin conceptions. Most risk assessments in the literature are calculated with pregnancy as the primary outcome, but in a fertility-treatment paradigm where patients want more than one child the statistically correct risk assessment should refer to born children as the primary reference. If published data are corrected accordingly to achieve statistical commonality of outcome (i.e., one child in singleton versus two children in twins), twin pregnancies no longer demonstrate a significantly increased risk profile and/or cost for mothers or individual offspring.
Conclusion(s)
:
For infertile patients who want more than one child, twin deliveries represent a favorable and cost-effective treatment outcome that should be encouraged, in contrast to the current medical consensus.
Gleicher et al. Fertil Steril
2009;91(6):2426-31.Slide44
Errors Imported by Obstetrical Paradigm
Non-comparable outcome 1 vs 2 newborns;Excessive perinatal risks for IVF twins (ca. 40%)
(
Helmerhorst
et al 2004
)
Too low
perinatal
risks for IVF singleton (Helmerhorst et al 2004)Slide45
Helmerhorst et al 2004 (BMJ 328:261)
Systematic review of 17 matched and 8 non-matched studies, comparing singleton and twin pregnancy outcomes between natural and ART conceptionsSingleton pregnancies after ART
had significantly
worse
perinatal
outcome
Twin
pregnancies after ART had 40% lower perinatal mortalitySlide46
Conclusions
When risk/cost in a prospective infertility paradigm are statistically correctly compared between 2 singleton and 1 twin delivery, twins no longer carry excessive risk/costSlide47
Lemazou et al. Obtaining two children with IVF: a comparison between one twin and two consecutive single pregnancies. J
Gynecol Biol Reprod 2011 (Paris)
Retrospective study of couples desirous of 2 children
115 IVF twin pregnancies
115 consecutive singleton x 2
205 singleton delivery without secondSlide48
“A twin pregnancy after IVF represents a reasonable option to accomplish a parental desire of having two children.”
Lemazou et al. 2010 Cont.Slide49
The irrational attraction of elective single-embryo transfer (
eSET
)
Norbert Gleicher,
MD
Abstract
: In this issue of the journal,
Niinimäki
et al., colleagues from a pioneering Finnish center in the development of elective single-embryo transfer (
eSET
), propose the expansion of
eSET
to suitable women at ages of 40-44 years. This paper offer not only a critique of their proposal but also of
eSET
in general.
Gleicher
N. Hum
Reprod 2013;28(2):294-297.
human
reproduction
INVITED COMMENTARYSlide50
Sazonova et al., Fertil Steril 2013
Patient selection biasesHigher maternal risks: Abruption (OR 1.30) CS (OR 4.19) PROM (OR 0.12)
Previa
(OR -0.37)
Preeclampsia =
Gestational DM =
Maternal mortality =Slide51
Mistaken advocacy against twin pregnancies following IVF
Norbert Gleicher,
MD; David
H
Barad, MD, MS
Purpose
:
A recent publication by Swedish colleagues in Fertility & Sterility for the first time, statistically correctly, attempted to assess risks of twin IVF pregnancies in comparison to two consecutive singleton IVF pregnancies. Historic comparisons have been statistically incorrect, comparing risks of one twin to one singleton pregnancy. We here analyze data and conclusions presented in this Swedish study.
Methods
: We reviewed the manuscript by
Sazonova
et al. (Fertil Steril 2013)..
Results
: Based on incorrect statistical methodology, twins after in vitro fertilization (IVF) have come under attack as “adverse” outcomes. Above noted study recently, for the first time, correctly compared one twin to two consecutive singleton pregnancies. Investigators, however, in our opinion interpreted their own data incorrectly by claiming “dramatically” higher maternal and neonatal risks in twin pregnancies. Our interpretation of reported data, indeed, in contrast suggests surprisingly
minor differences in observed twin risks. Moreover, such minor risk increases do not offer adequate compensatory benefits for significantly lower pregnancy chances in first IVF cycles with
eSET
in comparison to two-embryo transfers (2-ET)
.
Conclusions
: As significantly higher maternal and neonatal risks of twin IVF pregnancies represent the principal rationale for
eSET
, the Swedish study actually suggests that
eSET
offers neither patient-friendly nor cost-effective treatment options for IVF, except where patients object to twins or have medical contraindications. The need for a second pregnancy to achieve equal outcome (2 children), resulting
treatment delays, increased efforts and costs, in absence of any guarantees that a second successful singleton pregnancy/delivery will ever be accomplished, invalidates
eSET
as a routine procedure.
Gleicher
and Barad, J Assist
Reprod
Genet 2013;30(4):575-579.
ASSISTED REPRODUCTION TECHNOLOGIESSlide52
Higher neonatal risks:Respiratory complications (OR 4.42)Jaundice (OR 5.13)
Perinatal mortality =Apgar < 7/5 minutes =Mortality in 1st year =Congenital abnormalities =Slide53
March of Dimes Stakeholder Workshop, June 20-21, 2012 in collaboration with Hastings InstituteSlide54
There is hope!Slide55
PRINCIPAL COLLABORATORS:
David H Barad, MD, MS, CHR
Vitaly A Kushnir, MD, CHR
Andrea Weghofer, MD, PhD, MBA, MS, Medical University Vienna
Ho-Joon Lee, PhD, CHR
Aya Shohat-Tal, PhD, CHR
Yan-
Guang
Wu, PhD CHR
Yao Yu, PhD, CHREmanuela Lazzaroni, MS, CHR
Aritro Sen, PhD, Rochester University School of Medicine & Dentistry & CHRSlide56