a S - Children`s Memorial Hermann Hospital

Transcription

5TH ANNUAL TEXAS TWO-STEP CONFERENCE
Navigating Changes in Ob/Gyn:
Are You On Board?
Texas Two-Step Conference, Januar 9 - 10, 2015
Texas Two-Step Conference 2015
THANK YOU, SPONSORS
4407610
Cord Blood Registry • Exact Sciences • GE Healthcare
Houston Fertility Institute • Lumara Health
Sequenom • Xpress Med Solutions
1
AGEN
NDA |FRIDA
AY, JAN
NUARY
Y 9, 20
015 7:55 a.m. WELCOME A
W
AND INTROD
DUCTIONS ̶
Sean Blackwell, M.D., and Baha SSibai, M.D. 8 – 8:45 INTERACTIVE DEBATE: Shou
uld We Try to Decrease or Inncrease the C
Cesarean Delivery Rate?? ̶
Baha Sibai, M.D., a
and Clara Warrd, M.D. 8:45 – 9:30 Patient Safetyy Stories: Lesso
ons Learned from Tragedy
̶
Sean Blackwell, M.D. 9:30 – 9:45 9:45 – 10:30 BREAK B
10:30
0 – 11:15 a.m. INTERACTIVE DEBATE: Robo
otic Surgery in
n GYN – Fad o r the Future?
ael Adler, M.D
D., and Sara Ho
olcombe, D.O.. ̶
Micha
What Every O
W
B/GYN Needss to Know about In‐Utero Feetal Surgery ̶
Antho
ony Johnson, D
D.O. 11:15
5 – Noon Ramifications of Lapses in D
Detail During EEndoscopic Suurgery
Micha
ael Baggish, M
M.D. Noon
n – 12:45 p.m. 12:45
5 – 1:30 LUNCH L
Major Complications from IInappropriate Gynecologic Laparoscopic Procedures ̶
Micha
ael Baggish, M
M.D. 1:30 – 2:15 INTERACTIVE DEBATE: Whaat is the Best M
Management oof Mode of Deelivery for Twin Pregnan
T
cies: Is Vaginaal Delivery Still a Safe Optio n? ̶
Roberrt Silver, M.D. and Suneet C
Chauhan, M.D.. 2:15 – 2:30 2:30 – 3:15 BREAK B
3:15 – 4 Evidence‐Base
ed Guidelines for Use of Pro
ogestogens too Prevent PTB
̶
Adi Abramovici, M..D. 4 – 4:45 What Would Y
W
You Do? Comp
plicated Case Presentationss
̶
Hecto
or Mendez‐Fig
gueroa, M.D. 4:45 – 5 CLOSING RE
C
EMARKS Obstetrical M
O
anagement off Women with
h Recurrent Prregnancy Losss
̶
Roberrt Silver, M.D. 2
AGEND
A
DA |SA
ATURD
DAY JA
ANUAR
RY 10, 2015 7:55 a.m. WELCOME A
W
AND INTROD
DUCTIONS ̶
Sean Blackwell, M.D., and Baha SSibai, M.D. 8 – 8:45 Management of Placenta A
Accreta: How to Avoid Catasstrophes ̶
Baha Sibai, M.D. 8:45 – 9:30 INTERACTIVE DEBATE: Shou
uld NIPT for Fe
etal Aneuploiddy be Offered to All Patients? ̶
Georg
ge Saade, M.D
D. and Eleazarr Soto, M.D. 9:30 – 9:45 9:45 – 10:30 BREAK B
10:30
0 – 11:15 a.m. 11:15
5 – Noon Management of the Adnexaal Mass
̶
Adnan Munkarah, M.D. INTERACTIVE DEBATE: Shou
uld We Increasse or Decreas e the Numberr of Cervical Cerclage Plac
C
ements to Pre
event Preterm
m Birth? ̶
Alfred
do Gei, M.D. a
and Suneet Chauhan, M.D. Texas Perinata
T
al Levels of Caare Designatio
on: What Everyy OB/GYN Neeeds to Know ̶
Eugen
ne Toy, M.D. Noon
n – 12:45 p.m. 12:45
5 – 1:30 LUNCH L
All Uterine Ca
A
ncers are Nott Born Equal!
̶
Adnan Munkarah, M.D. 1:30 – 2:15 What Every O
W
B/GYN Should
d Know Aboutt Hospital Opeerations ̶
Susan
n Distefano, M
M.S.N., RN, NEA
A‐BC 2:15 – 2:30 2:30 – 3:15 BREAK B
3:15 – 4 3:45 – 4 What Every O
W
B/GYN Needss to Know about Surgical Woound Compliccations ̶
Josep
ph Lucci, III, M..D. What Would Y
W
You Do? Complicated Case Presentation s
̶
Micha
ael Adler, M.D
D. and Joseph Rodriguez, M..D., Ph.D. CLOSING RE
C
EMARKS 3
Cou
urse Description The 5th Annual TTexas Two‐SStep Confere
ence, Navigating Changees in OB/GYN
N: Are You O
On Board? brrings togetherr experts in obstetrrics and gyneccology to disccuss recent ch
hanges in heaalthcare policyy and practice guidelines aand their impaact on patientts, physicians,, nurses and h
hospital operrations. Conference attendees will learrn about ACOG and SMFM recommend ations for maanagement off high‐risk preegnancies o prevent nea r misses and medical erro
ors to avoid un
nnecessary and ggynecologicall conditions, aas well as tipss and tools to
harm
m. This year’s event will alsso include a se
eries of interaactive debatees surroundin
ng controversial topics in O
OB/GYN. Highllights of this yyear’s conference include:: • Inteeractive debaate series • Acttive audience participation
n • Com
mplicated casse studies • Unparalleled on
ne‐on‐one nettworking opportunities witth industry exxperts Con
ntinuing Ed
ducation Targget Audience
e Physicians (OB/GYYN, maternal‐‐fetal medicin
ne, family me
edicine), geneetic counselorrs, nurses, midwives, sono
ographers and
d healtthcare administrators Conttinuing Educcation Hourss for Nurses Mem
morial Herman
nn‐Texas Med
dical Center iss an approved
d provider of f continuing n
nursing educaation by th
he Texas Nursses Associatio
on, an accredited approverr by the Amerrican Nurses C
Credentialingg Center’s Com
mmission on Accreeditation. proved for 7.5
5 contact hou
urs on Day 1 aand 6.5 contaact hours on D
Day 2. This aactivity is app
Conttinuing Educcation Hourss for Physicians This aactivity has been planned and impleme
ented in accordance with tthe accreditation requirem
ments and policies of the Texas Medical Asssociation (TM
MA) through th
he joint proviidership of M
Memorial Herm
mann Health System and U
UTHealth Medical School. The Memorial Hermann He
ealth System iis accredited by the TMA tto provide co
ontinuing med
dical morial Herman
nn Health Sysstem designattes this live acctivity for a m
maximum of 1
14 AMA PRA educcation for phyysicians. Mem
Categ
gory 1 Creditt(s)™. Particip
pants should cclaim only the
e credit comm
mensurate wiith the extentt of their participation in the acttivity. The p
presentationss, “Understan
nding Hospital Operations in OB/GYN P ractice” and ““How Will thee Afforrdable Care A
Act Change OB
B/GYN Practicce?” have eacch been desiggnated by Meemorial Herm
mann Health System for 1 crediit of educatio
on in medical ethics and/orr professional responsibilitty. This conference is in collabo
oration with
h: 4
INTERACTTIVE DEB
BATEE: Sh
hould
d We Tryy to Deccreasse or Inccreasse th
he Cesarrean
n Delliverry Raate?? Baha SSibai, M.D.
Ward, M.D.. Clara W
5
Should we try to
increase the cesarean
delivery rate?
Baha M. Sibai, MD
Professor, MFM Division
Principal Investigator, Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Network
Director, Maternal-Fetal Medicine Fellowship Program
PRESERVE‐1 Study Design
Multicenter, randomized, placebo-controlled, double-blind, phase 3 trial
•
Patients treated with rhAT or placebo until delivery
120 pregnant women with PPE at 24‐28 weeks of gestation
RANDOMIZE
•
IV rhAT 2000 mg 24-h CI (n=60)
IV placebo (n=60)
Primary objective:
Prolong gestational age
Secondary objective:
Reduce neonatal morbidity and mortality
Maternal, fetal, and neonatal assessments and complications
Futility analysis after 50% of primary endpoint
Sample size re‐estimation after 75% of secondary endpoint
Having a healthy baby by C/S
is unforgettable experience
6
Angelina Jolie : Elective C/S
Saying, "It ended up
being the greatest thing.
I had a C-section and I
found it fascinating
I didn't find it a sacrifice
I didn't find it a
painful experience
I found it a fascinating
miracle of what a body
can do."
What is the appropriate cesarean rate ?
“We are not interested in targets for c/s rates , we are interested in healthy mothers and babies.” The Lancet, 1997
“Chasing an elusive ideal C/S rate (whatever that rate may be) is not a useful exercise”
ANZ J Obstet Gynaecol , 2014
Caesarean section was the last resort - 1666
7
Cesarean Section
From 1950
Gradually getting safer
Intubation
Epidural
Antibiotics
Blood transfusion
Lowers the threshold
Increasing CS rates
First in developing countries
Rest of the world follows
Fetal reasons and some maternal reasons
C-Section is the way to go
Cesarean section
is good for
mature women
Cesarean section
is safest for baby
Cesarean
Section
• Elective is safe
• Emergency is not
Cesarean section
is best for both
Mother/fetus
Past Cesarean
section bad for
mother
Why do women request C- Section?
Fear
• Birth experience
• Pain, use of oxytocic agents, multiple vaginal exams
• Prolonged labor , hooked to monitors/ catheters
• Chorio , bleeding, retained tissues , need for emergency delivery
• Past Experience (terror)
• Maternal pelvic floor damage : acute and long-term
• Prolapse
• Urinary/fecal Incontinence
• Sexual dysfunction
• Baby Damage
• Death
• Hypoxia, acidosis, trauma, neonatal infections
• Long-term injury
Planning
8
Britney Spears: planned C/S due to
tocophobia
Chose a C-section
because she didn't
want to go through
the pain.
My mom said giving
birth was the most
excruciating thing
she's ever gone
through in her life.
Planned C-section : date and time
Christina Aguilera : Elective C/S
“I didn’t want surprises
I didn’t want any tearing. I
heard horror stories of women
laboring for hrs. and having to
have an emergency C-section.
The hardest part was
deciding on his
birthday.”
9
Victoria 'Posh Spice' Beckham
Victoria Spice Beckham
inspired the phrase
"too posh to push,"
reportedly delivering all
four kids via C-section.
She had no accreta.
Women have changed and
practice patterns have
changed
Why shouldn’t C/S rate
change ?
Reasons for increased C-Section rate
AMA/Infertility
• G1 > 40 years IVF
• BMI > 40 kg/m2
• Multifetal gestation
Medical problems
• Cardiac, pulmonary
renal , etc. Placental abnormalities:
• previa, accreta • vasa previa , abruptio preeclampsia < 30 wk Severe FGR
• Prior C/S or other uterine cavity surgery
Maternal infections transmitted during labor
• HIV , Herpes, Hepatitis C, B‐ strep
Abnormal labor patterns:
• Latent phase
Active phase
Second stage
Abnormal fetal size /position/ presentation • Macrosomia, Breech, transverse lie, hydrocephalus
Abnormal FHR patterns:
• Category‐II
Category –III
Indeterminate
10
Obstetric complications continue to increase
Change in obstetric demographics
AMA during
pregnancy
• > 35 : 20%
• ≥ 40 : 5%
Increased obesity
• BMI ≥ 30 :3035%
• BMI ≥ 50 : 5 %
• Larger fetal size
Increased multifetal gestation
• Twins : 5%
Triplets : 1 %
C/S rate by maternal age, 2009-2011
Source: CDC/NCHS, National Vital Statistics System
C/S rate by BMI, 2002-2008
Source: Am J Obstet. Gynecol, 2010
11
By the numbers: Twin Birth in US
140,000
Twins
130,000
120,000
110,000
100,000
90,000
80,000
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2011
Reasons for increased induction or C/S
Increased Obstetric / medical disorders
• Obstetric complications
– Abnormal placentation : Previa , abruptio
– FGR / PROM : More interventions
– GHTN- preeclampsia : 25-30% in nullipara
• Increased prevalence of medical disorders
–
–
–
–
–
–
CHTN / renal disease : 5-7%
Type-2 DM : 3-5%
Moderate to severe asthma
Cardiac disease
Seizure disorder
Many others
Obstetric complications continue to increase
Change in obstetric practice ( Routine screening)
Abnormal
serum
screening
Serial U/S
screening
New
screening
guidelines
for GDM
• 1st-T: 5%
• 2nd -T: 5%
•
•
•
•
AC/ EFW <10th : 10%
LGA : 10 %
Oligo/ polyhydramnios: 10 %
Markers of aneuploidy : 10%
• First visit and at 24-26 wk.
• Lower threshold and 1 step DX.
(15-20%)
12
Cesarean Delivery rate in the US
1.3 Million Per Year
Total 32%
Primary 22%
VBAC 9.2%
CDC,NVSS
Preventing the first Cesarean section
Keep C/S
rise to a
minimum
• Reduce elective CS
• Improve information
• Breech, twins, inductions
Reduce
emergency
C/S
• Fetal distress
• Diagnosis & management
• Failure to progress
• Oxytocin/time after ROM
• Full dilatation
• Instrumental delivery
• Duration of 2nd stage
13
Algorithm for induced
labor.
NICHD Workshop
INDUCTION
P!nk: c/s for breech
"We tried everything
to turn her around.
Turns out this little
girl had other plans -she is my daughter,
after all."
Reason for Kate Hudson having C/S
Kate Hudson opted for
a c/s when her labor
wasn't progressing
"The doctor said I
could go home.. I was
like, 'I am not going
home, just don't want
to do this again.
Let's just have a C-
section.'
14
Camila Alves : C/S in labor
Labored for 40 hours .The vacuum didn't
work, and the doctor said, “C-section"
Ureter
Uterine
Vessels
Transverse
Laceration
Vertical
Laceration
Uterine Lacerations
B. Sibai
Should the rising cesarean section
rates be reversed ?
15
Leeds Institute of
Dr. Ward’s
Delivery Room
Bioscience and Clinical Science
Section of Obstetrics and Gynaecology
“THERE ARE MANY WHO BELIEVE
THAT THE DELIVERY OF WOMEN IS EASY…
AND IN TRUTH THERE IS NO MYSTERY
WHEN THINGS GO NORMALLY.
BUT, WHEN AN ACCOUCHEMENT
IS PRETERNATURAL IT BECOMES THE
MOST DIFFICULT, LABORIOUS AND
DANGEROUS OF ALL
SURGICAL PROCEDURES.”
FRANCOIS MAURICEAU, 1694
• French 17th century obstetrician
• Established obstetrics as a science (book)
• Breech delivery maneuver
Request for c- section or vaginal delivery
Objectives of counselling
– Women who need/want a vaginal are able to get it
•
•
•
•
•
Discuss all risks of waiting for onset of labor
Discuss all risks of induction of labor
Discuss all complications of labor
Discuss all complications of vaginal delivery
Care is adequate to support vaginal birth for those who
want attempted vaginal birth
– Women who need /want a C/S can have one
– Discuss all risks of C/S
Discuss all complications: current and long-term
16
Risks Included in consent for
Cesarean Delivery
• Injury to bowel, bladder, or ureter
• Brain damage, injury or death to the fetus
during cesarean section
• Neonatal respiratory complications
• Uterine disease or injury requiring
hysterectomy or resulting in sterility
• Thromboembolism
• Need for transfusions
• Wound complications/ infection
• Maternal death
Potential Costs of Waiting from 38 wks. to Labor
(meconium
injury)
cord accidents
Increased
macrosomia:
shoulder
dystocia
Fetal deaths
(1/1,000)
Abruptio
placentae
GHpreeclampsia
Increased
meconium
Decreased
fluid:
Emergent
surgery
HIE
B. Sibai
Neonatal Complication Rates by Week of
Gestation
GA (wk)
N
Meconium
(%)
≥ 4500 g
(%)
ICU Adm
(%)
38
4489
13.8
0.88
4.5
39
7626
18.3
1.15
3.1
40
9808
25.8
2.22
2.6
41
5717
31.9
3.58
3.4
≥ 42
2986
36.4
6.92
4.8
B. Sibai
17
Risks of attempted vaginal delivery
• Prolonged labor in latent phase
– Pain and suffering
– Medications , multiple pelvic exams
– Contractions, FHR monitors, catheters
• Prolonged ROM in active phase
–
–
–
–
Intermittent hypoxia : oxytocin, cord compression
Epidural monitoring
Chorioamnionitis, fetal infection
Prolapsed cord
• Prolonged second stage: Same as above
• Delivery: Same as above plus
–
–
–
–
–
Fetal / pelvic trauma: Instrumental delivery
Need for emergency C/S
Shoulder dystocia
Uterine atony, inversion : hemorrhage
Endometritis, retained placental tissue, infertility
Risks from attempted vaginal delivery
Uterine Atony: PPH
Maternal Trauma: 3rd, 4th degree tears Retained Placenta ; bleeding , infection
Chorioamnionitis : bad for both mom and infant
Fetal Infections
Uterine Inversion/Rupture
Fetal Trauma: Forceps , vaccum, prolonged 2nd stage
Cerebral Palsy, HIE, Hypoxia, acidosis
Shoulder dystocia, fractures, nerve injury
Fetal Death Need for emergency
crash C‐section
End result of successful vaginal delivery
18
Vaccum assisted vaginal delivery
Fractured clavicle
Shoulder dystoscia from vaginal delivery
Scars of attempted vaginal delivery are ugly
Vulvar hematoma
Vulvar necrotizing fascitis
Vulvar hematoma
Third degree tear
Leeds Institute of
Bioscience and Clinical Science
Section of Obstetrics and Gynaecology
19
Cesarean scars can be beautiful
Ethical Principles
Can a planned C-section for an uncomplicated pregnancy
be ethically justified?
Beneficence
Nonmaleficence
Voracity
Decision
making
based on
Justice
Autonomy
Ethical Principles
Patients retain a “negative
right”: right to decline care
• But do not hold a “positive
right”:the right to demand
care that may be
unnecessarily risky or
medically unproven
• Physicians recommend C/S at 23 wk
despite poor outcome
• But not at term with 100% survival
and excellent outcome
20
Autonomy
Obligates the physician to discuss
reasonable alternatives and elicit a
decision within the framework of
informed consent
What is the information to give?
Risks / benefits of planned C/S
Risks / benefits of attempted vaginal delivery
Planned C/S v labor with C/S if not successful
Non-maleficence
• This principle refers to physician’s
obligation to do no harm to the patient
– “First do no harm”
– This works both ways
• Is C/S more dangerous?
• Is vaginal birth more dangerous?
– How about harm to providers ?
• May be sued for doing “unnecessary” vaginal birth
–
–
–
–
Delayed C/S for non-reassuring tracing
Traumatic breech delivery
Traumatic shoulder dystocia
Traumatic instrumental delivery
Conclusions
Available data, though not robust,
suggest that overall maternal /perinatal
mortality, short- and long-term maternal
and neonatal and infant morbidity
favor a planned cesarean delivery at
39 0/7 wk in those who are not yet in
labor
21
What would men prefer
vaginal delivery or C-section?
22
Should We Try to Decrease or Increase the Cesarean Delivery Rate?
Vaginal Birth is not a Failed Cesarean: Reducing the Rate of Cesarean Delivery
Clara Ward, MD
Division of Maternal Fetal Medicine
University of Texas Health Science Center
Disclosures
• No disclosures
23
What this talk is NOT
http://www.nytimes.com
OBJECTIVES
• Extent
• Evidence
– Perceptions of benefit vs. harm
• Economics
– Consumerism
– Quality reporting
– Health care metrics
• Ethics
–
–
–
–
Informed consent
Autonomy vs. paternalism
Nonmaleficience/beneficience
Distributive justice
EXTENT
24
Trends in Cesarean Delivery
Overall CS
Primary CS
VBAC
25
Primary Cesarean Rates
• Multiparous: 11.5% of total c‐sections
• Primiparous: 30.8% of total c‐sections
• Of these 45% were in low risk women
Boyle et al, Obstet Gynecol 2013
Indications for Primary Cesarean Delivery
Boyle et al, Obstet Gynecol, 2013
Variation in Cesarean Section Rate
• AHRQ database • Variation in CS rates – Reflects underuse or overuse
– Suggests modifiable factors
• 10 fold variation in overall CS rate (7‐70%) • 15 fold variation (2‐37%) in low risk women
Kozhimannil et al, Health Aff, 2013
26
EVIDENCE
Benefits of Cesarean Delivery
•
•
•
•
•
•
Matter of Perception vs. Evidence
Reduction in maternal harm (incontinence)
Reduction in fetal harm (demise and injury)
Surgical control
Pain control
Scheduling convenience
Risk of Adverse Maternal and Neonatal Outcomes by Mode of Delivery
ACOG‐SMFM Obstetric Care Consensus, March 2014
27
Complications of Cesarean Delivery
•
•
•
•
•
•
•
•
•
TOLAC/uterine rupture
Thromboembolism
Abnormal placentation
Maternal surgical morbidity
Respiratory complications in the newborn
Recovery
Pain
Cost
Risk accumulates with each cesarean section
Reducing the Cesarean Section Rate
• Decreasing primary cesarean section rate
– Low risk women
•
•
•
•
Nulliparous
Term
Singleton
Vertex
– High risk women
• Increasing rate of trial of labor after cesarean
Linear Relationship between hospital VBAC rate and low risk primary cesarean section rate
Rosenstein et al, Obstet Gynecol 2013. 28
Self Fulfilling Prophecy of Cesarean
Safe Prevention of the Primary Cesarean Delivery •
•
•
•
•
Revisit definition of labor dystocia
Standardized fetal heart rate interpretation
Improving access to nonmedical interventions
External cephalic version
Trial of labor for twins
29
Defining labor dystocia
Cesarean Sections Prior to Active Labor
Cesarean Sections in the Second Stage of Labor Boyle et al, Obstet Gynecol, 2013
30
Cesarean Sections for Suspected Macrosomia
• Actual birth weights for neonates delivered by cesarean section for suspected macrosomia
– 97.3% <5000 grams
– 80.3% <4500 grams
– 41.9% <4000 grams
Cesarean Sections for Twin Gestation
• Twins – VTX‐VTX: 25%
– VTX‐nonVTX: 25%
– nonVTX presenting: 27%
– Not recorded: 23%
Fetal heart rate interpretation
31
Interobserver variability of intrapartum FHR
Chauhan et al, AJOG 2008.
Potentially Modifiable Indications for Cesarean Section
Spong et al, Obstet Gynecol 2012
32
• Success of TOLAC high
• Risk of uterine rupture low
• VBAC begets VBAC
33
In Perspective
National Institutes of Health Consensus Development Conference Statement
Vaginal Birth After Cesarean: New Insights March 8–10, 2010
NNT in the setting of TOLAC
• Number of c‐sections needed to prevent ONE
– Symptomatic uterine rupture: 370
– Uterine rupture related hysterectomy: 2941
– Uterine rupture related perinatal death: 7142
• Furthermore the difference between groups is so small…
– It would take only one misclassified case to negate any difference
Guise et al, BMJ, 2004
ECONOMICS
34
35
Financial Costs Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD):
Agency for Health Care Policy and Research (US); 2006-2014 May.
TOLAC
TOLAC
36
Unquantified losses and costs
• Increased recovery time
• Implications for bonding and breastfeeding
• Costs of sitters/food/parking for extra 2 days (or more)
37
Precedents
• SCIP
– Surgical Care Improvement Process – Initiated in 2003
– Surgery and anesthesia colleagues
– Antibiotics prior to surgery, SCDs
– Determines hospital accreditation and medicare reimbursement
• SART
– Society for Assisted Reproductive Technology
– Annual reporting to CDC
– Underperformance provokes formal improvement process
ETHICS
Challenge of Informed Consent
38
Most profound knowledge deficits
• The majority of patients in both groups did not know the chance of success
• Over half of the patients did not know the risk of rupture rate
• Half of patients undergoing ERCD did not know recovery was longer • Half of patients undergoing ERCD did not know that risk increases with each cesarean section
Provider influence
• When patients felt their provider had a preference
– 86% chose ERCD
– 78% chose TOLAC
• When patients did not perceive a provider preference
– 50% chose ERCD and 50% chose TOLAC
What Do Women Want?
• Healthy outcomes • Preferences studies
o >90% of women expressed preference for vaginal delivery
o A stronger preference correlated with higher success rate
39
How do we Proceed?
• Parties involved
– Physician
– Patient
– Payers
– Hospitals
– litigation
• Resources/expertise available
• Data Æ assessment
40
How can we reduce the rate of cesarean section?
• Support the patients
– Expectation management
– Doula support
• Support the providers
– Midwives
– Hospitalists
– Culture change
– Medicolegal reform
http://www.inhabitots.com
Dr. Sibai
Dr. Ward
41
Paatien
nt Saafetyy Sto
oriess: Lessson
ns Le
earned ffrom
m Traagedy Sean Blacckwell, M.D. 42
Perinatal Safety Stories:
Lessons Learned From Tragedy
Sean C. Blackwell M.D.
Chair, Department of Obstetrics, Gynecology and Reproductive Sciences
Director, Larry C. Gilstrap M.D. Center for Perinatal and Women’s Health Research
Assistant Dean for Healthcare Quality in Perinatal Medicine and Women's Health UT Health‐ University of Texas Medical School at Houston
E‐mail: [email protected]
43
L&D Unit vs. Aircraft Carrier
March 1‐March 28, 2014
CMH OB service TOTALS
• What was the highest number of admissions in one 24 hour period? N= 32
• What was the highest number of births in one day? N= 24 • What was the highest number of cesarean deliveries done 7 am – 7 pm? N=13 (2 rooms)
CMH OB service
• How many different attending physicians performed cesarean delivery? N=44
• Of these, how many did < 4 for the month (less than 1 per week)? N=10 44
CMH OB service
• How many different physicians worked on the OB service during this time? > 60
• How many different nurses worked on the OB service during this time? > 100
• How many total different patients were under our care over this time period? > 500
CMH OB service TOTALS
• In one shift (7 am‐7pm), how many different people work on L&D? • Not 1 doctor, 1 patient, and 1 nurse
• In one shift (7am‐7pm), how many patients and their family members travel through our unit? • Perviable PTB
• HELLP
• Normal labor • PTC’s Nuclear Submarine & Safety
45
Nuclear Submarine = Pregnant woman
• Expectation that those in charge (OB physician and nursing) will NOT fail • Adverse events (harm to pregnant woman or newborn child) = disaster We have 2 patients = Mother & unborn/newborn child Nuclear Submarine & Safety
What do women desire/expect when they come to the hospital? 46
What do women desire/expect when they come to the hospital? 1. Do not harm me.
2. Treat my condition to make me better
3. Be nice
What do women EXPECT when they come to TMC? What do women & families EXPECT from us? • Experts
• Best practice
• Leaders in Safety and Quality • Innovation 47
Case Presentation
Initial Presentation • 27 y.o. Gravida 1 at 39w 0 d presents to OB triage
• Contractions and vaginal spotting
• Early prenatal care with private physician
• Moved to Texas for OB care from Russia Clinical course • OB intern assessed patient
• Bedside ultrasound = no previa • Called chief resident who evaluated patient
after initial work up
48
April 21, 2014 @ 11:00 AM
180
150
120
April 21, 2014 @ 11:13 AM
April 21, 2014 @ 11:20 AM
49
April 21, 2014 @ 11:27 AM
April 21, 2014 @ 11:34 AM
April 21, 2014 @ 11:41 AM
50
April 21, 2014 @ 11:48 AM
April 21, 2014 @ 11:56 AM
April 21, 2014 @ 12:00 PM
51
April 21, 2014 @ 12:01 PM
April 21, 2014 @ 12:15 PM
• SSE: approx 20 cc blood seen pooled in vaginal vault and evacuated digitally; no bleeding/LOF per os on valsalva.
• Exam repeated under R4's supervision approx 10 minutes later, where minimal amount of blood was seen in vaginal vault protruding from cervix with clear‐yellow fluid and slight vernix seen leaking per os this time. Cervical os visibly closed. April 21, 2014 @ 12:23 PM
Decision was made to admit patient for SROM in latent labor for augmentation with pitocin and clindamycin for GBS ppx.
52
April 21, 2014 @ 12:33 PM
April 21, 2014 @ 12:37 PM
April 21, 2014 @ 12:44 PM
Cervix = 4 cm 200ml new bleed in L&D room 53
April 21, 2014 @ 12:51 PM
Decision for CD
At 12:46
CD AT 12:54
Presumed placental abruption Outcome • She was taken to the OR for suspected abruption.
• Emergent cesarean was performed under GETA.
• After delivery of the infant and placenta, the placenta was examined and it was noted that there was a velamentous cord insertion as well as vessels traveling through the membranes from one placental lobe to the other. Timeline Summary
Time
Event
4/21/14 11:00 AM
Triage evaluation for vaginal bleeding and CTx
4/21/14 11:13 AM
Evaluation by Junior resident, Concern for FHTs: “Difficult to interpret with a pseudo‐sinusoidal pattern/ Upper level called”
Bedside US: No previa
4/21/14 11:18
4/21/14 11:44
Evaluation by senior resident: strip review
Change in dilation noted: 0 ‐> 3 cm
4/21/14 12:22
Transferred to L&D for labor, SROM
4/21/14 12:40
Bradycardia, 200ml Fresh bleeding
4/21/14 12:46
Decision for CD
4/21/14 12:54
STAT CD
54
Outcome • Neonate handed to awaiting Neo team
• “Ashen” white c/w exsanguination • Unable to insert umbilical lines to give volume
• Expired at 25 minute of life Vasa Previa
Definition: Vasa previa is a condition in which the umbilical vessels, unsupported by either the umbilical cord or placental tissue, traverse the fetal membranes of the lower segment above the cervix.
Initial Summary • Causation due to undiagnosed vasa previa
• From decision to delivery = 8 minutes
• Undiagnosed vasa previa, the risk of fetal/neonatal death > 50% • “Nothing we could have done, inevitable adverse outcomes.” This is nature of obstetrics … 55
Evaluation of the Case
• Review medical records including prenatal ultrasound reports • Interview with patient and family • Root cause analysis • M&M review Interview with Patient • Husband in oil business from Russia; moved to US for better health care. Then switched to UT physician to get best care in TMC.
• Thought intern was student – Asked same questions x 3 (when is last time had sex)
– Told “joke” about accent – Intern told patient she was going home, reversed by chief resident • Chief resident did “teaching” 5‐10 minutes in room – GBS treatment • After event, our physician team met with the patient. The husband’s interpretation of the discussion (< 20 minutes after newborn death), was that what was emphasized that “we” did nothing wrong and they could have another child
Triage Dynamics • Intern issues
– Intern was in 1st day of rotation; had not worked at TMC (from different hospital).
– Intern had decided to leave OB for general surgery.
– Just returned from leave for “burnout”
• L&D triage nurse – Told intern that this was possible sinusoidal FHR strip – Told this to chief resident – Called her charge nurse and told her sinusoidal FHR and “be ready”
• Chief resident – FHR fine and you are over‐reacting – She and triage nurse had history • No one called attending physician who was on floor and in lounge (2 min away)
•
Attending not involved until called to room for bradycardia and bleeding 56
RCA
• Why didn’t call the attending physician ?
– Residents “If I called for every abnormal FHR or problem then I would be talking to them a lot and not be in charge; plus they don’t want to know everything”
– Nurses “Not my job”
– Attending “If they call me too much they won’t learn” Swiss Cheese Theory
What do we want & expect from you? 57
Assessment of Situation
• WTF moment • Culture problem – Communication
– Escalation
– Accountability • Could this happen at your place? • How often are we just lucky (near miss)?
• What would it take for you to be part of the solution vs. part of the problem?
– Don’t be selfish
3 inescapable facts 1. No one tries to be unsafe. 2. OB is complex, fast, and requires team care. 3. Unrealistic (and impossible) for every physician and/or nurse to be an expert and/or current in everything related to OB. What do we want/expect from you? 1. Put the patient first
2. Don’t walk by a problem
3. Be nice 4. What we do matters (in a big way)….
Communication is the #1 reason for failures, not lack of expertise, mistakes, inexperience, etc. 58
Ram
mificcatio
ons o
of Laapses in Detaail Duri
D ng EEndo
oscop
pic SSurgery Mich
hael B
Baggissh, M.D. 59
INTERACTTIVE DEB
BATEE: Rob
boticc Surrgeryy forr GYN – Fad or the F
t Future?
Micchael Adlerr, M.D
D. Saraa Holccomb
be, D.O
O. 60
Robotics for Benign GYN Surgery:
Fad or the Future?
Michael Adler, M.D. and Sara Holcombe, D.O.
Generalist Division
UT‐Health
Robotic Surgery ‐ Future
Michael T. Adler, M.D.
Assistant Professor
Generalist Division – Ob/Gyn
UT‐Health
Disclosure
• No relevant financial relationships with commercial interests related to the content of this presentation. 61
Objectives
• Describe the benefits and risks associated with robotic gynecologic surgery.
• List the procedures that are able to be completed via robotic surgery.
Robotic Surgery
• Goal: Perform the right surgery with the best possible outcome for the patient
– Minimize complications
– Minimize time in hospital
– Minimize recovery time at home
• Use the right tool for the job (Vaginal, Laparoscopic, Open?)
Robotic Surgery
62
Robotic Surgery
• The da Vinci Robot (Intuitive Surgical,Inc.) is a valuable tool and will continue to be valuable in the future
Robotic Surgery
Robotic Surgery ‐ Background
• Early robotic platforms (AESOP, HERMES, ZEUS)
• Da Vinci commercially available for Gynecologic Surgery since 2005 (FDA Approved – April, 2005)
• 1.5 million procedures in various specialties completed to date
• Currently fourth generation of da Vinci Surgical Platform
63
Robotic Surgery ‐ Background
• Gynecologic surgery
• Cardiac Surgery
• Urologic surgery
• Thoracic Surgery
• General Surgery
• Head and Neck Surgery
Robotic Gyn Procedures
Hysterectomy
Myomectomy
Endometriosis
Adnexal surgery (oopherectomy, cystectomy, salpingectomy)
• Sacrocolpopexy/vault suspension
• Oncology procedures, lymphadenectomy
•
•
•
•
Robotic Surgery ‐ Benefits
• Approx. 600,000 hysterectomies/year
– Rate of open hysterectomy?
• Robotics may allow minimally invasive approach
–
–
–
–
–
Shorter hospital stay
Decreased blood loss
Fewer complications
Less narcotic usage
Faster recovery with smaller scars
64
Robotic Surgery ‐ Benefits
• Compared to traditional laparoscopy:
– Improved dexterity of instruments (Endo‐wrist)
• Improved precision vs loss of tactile feedback
• Elimination of unintended hand movement
–
–
–
–
–
Excellent visualization: 3D HD camera system
Ergonomics, surgeon fatigue
Obese patients
Less need for skilled assistant
Decreased learning curve Robotic Surgery – Learning Curve
• Robot does not eliminate need for good judgment and appropriate patient selection for selected procedure
• Walk before you run!
• Need for structured training and credentialing
Robotic Surgery – Learning Curve
65
Robotic Surgery ‐ Training
• AAGL Credentialing/Privileging Guidelines
• Initial Training
– Train surgeons with adequate case volumes to get through learning curve
– More intense validated simulation training
– Perform simple/basic procedures with proper supervision before attempting more complex cases (protoring)
Robotic Surgery ‐ Training
• Annual Currency
– Perform at least 20 procedures annually, with at least one case every 8 weeks
– If operate less, then proficiency should be demonstrated on simulator
• Annual Recertification
– Demonstrate proficiency regardless of case volume
Robotic Surgery ‐ Cost
66
•
•
•
•
High initial investment Replacement of instruments
Maintenance
Longer operating times?
Will Robotic Surgery continue to be a financially viable option in the future?
• Statement by ACOG President James T. Breeden (March 3, 2013)
– “Robotic surgery not the only or best minimally invasive approach for hysterectomy. Nor is it the most cost‐efficient.”
– “Studies show there is a learning curve with new surgical technologies, during which there is an increased complication rate.”
– “…The use of expensive medical technology should be questioned when less costly alternatives provide equal or better patient outcomes.”
– “It is important to separate the marketing hype from reality when considering the best surgical approach for hysterectomies.”
http://www.acog.org/About‐ACOG/News‐Room/News‐
Releases/2013/Statement‐on‐Robotic‐Surgery
Robotic Surgery
• Letter of Response:
– At their peak, vaginal and laparoscopic approaches performed in only slightly > 1/3 of patients despite availability for decades
– Despite widespread and prolonged availability, neither has reduced the laparotomy rate
– Multitude of studies comparing learning curve robotic cases to steady‐state laparoscopic cases, which substantially skew the results.
67
Robotic Surgery
• Letter of Response:
“The facts are unassailable: despite widespread availability…… for decades, neither materially impacted the laparotomy rate. Robotic surgery, in a fraction of that time, has enabled minimally invasive surgery for nearly every one of our patients, and >100,000 more women were offered minimally invasive hysterectomy in 2012 as compared to 2005 as a direct result of the robotic platform. The relevant comparator is laparotomy, not vaginal or laparoscopy.”
Robotic Surgery
“Is she being offered a minimally invasive approach? The data indicates that prior to Robotic Surgery that was not the case for the majority of women. This carries a substantial cost benefit to the patient and to society which has not been acknowledged.” http://www.businesswire.com/news/home/20130316005039/en/Minimally‐Invasive‐
Surgeons‐Group‐Responds‐ACOG‐Presidents#.VI4ibmd0zIU
Robotic Surgery
AAGL Position Statement: Robotic‐Assisted Laparoscopic Surgery in Benign Gynecology
• Robotic‐assisted laparoscopic surgery should not replace conventional laparoscopic or vaginal procedures for women who could otherwise undergo conventional laparoscopic or vaginal surgery for benign gynecologic diseases.
• Efforts should be focused on the proper credentialing and privileging of surgeons to utilize robotic surgical systems as a means to minimize cases otherwise performed by laparotomy.
• Additional research is needed.
68
Robotic Surgery
Responsible for decrease in vaginal hysterectomy?
Any procedure performed robotically, can be performed via laparoscope or vaginal route?
Robotic Surgery
Robotic Surgery
69
Robotic Surgery
• Deja‐Vu?
– Traditional laparoscopy initially criticized
•
•
•
•
•
Dangerous and unproven
Expensive
Longer operating times
Unnecessary
“Unethical”
Robotic Surgery for GYN surgery:
Fad or the Future
Michael Adler, M.D. and Sara Holcombe, D.O.
Generalist Division
UT‐Health
Robotic Surgery ‐ Fad
Sara B. Holcombe, D.O.
Assistant Professor, Generalist Division
70
Disclosures
• I do not have relevant financial relationships with commercial interests related to the content of this presentation. FAD noun \`fad\
: something (such as an interest or fashion) that is very popular for a short time
: a practice or interest followed for a time with exaggerated zeal : CRAZE
Robotic Surgery in Gynecology
• 1990 First robot approved by FDA
• 2000 daVinci Surgery System
– 10 updates released since
– Rates of use increasing
71
Point 1
• With the rapid increase in robotic‐assisted hysterectomy we are seeing a decline in vaginal hysterectomy.
72
Green Journal, 2013
• Cohort of 7,438,452 women underwent hysterectomy
• 1998 ‐ 2010
• Nationwide Inpatient Sample – random sample of 20% of discharges from all hospitals in the U.S.
• Results: Decline in all other routes of hysterectomy
Wright T, Herzog T, Tsul J, et al. Nationwide trends in inpatient hysterectomy in the United States. Obstet Gynecol. 2013:122(2):233‐241.
Route of Hysterectomy
Robot
8.2%
Lap 10.6%
Lap
8.6%
Vag 24.8%
1998
Abd 65%
Vag
16.7%
2010
Abd
54.2%
Wright T, Herzog T, Tsul J, et al. Nationwide trends in inpatient hysterectomy in the United States. Obstet Gynecol. 2013:122(2):233‐241.
73
JAMA, 2013
• 264,758 women, 441 hospitals, 2007 – 2010, hysterectomy
• Malignancy excluded
• Hospitals where robotic hysterectomy available:
– Massive increase in robotic hysterectomy and decline in all other forms (vag, lsc, abd)
• Hospitals with no robot
– Decline in both vaginal and abdominal but increase in laparoscopic
74
Point 1
• Increasing robotic hysterectomy leads to decrease in vaginal hysterectomy
• Evidence: 2 recent large cohort studies with supporting data
75
Point 2
• Robotic‐assisted gynecologic surgery is too expensive.
Cost
•
•
•
•
•
•
Approximately $2 million initial
Hundreds of thousands annually
Robotic arm replacements after 10 uses
OR time?
Lifespan of robot?
Versus laparoscopy, costs of robotic‐assisted hysterectomy are 16‐34% higher
Wright, Jason D. et al. “An Economic Analysis of Robotically Assisted
Hysterectomy.” Obstetrics and gynecology 123.5 (2014): 1038–1048.
Green Journal, 2014
76
Cost
Laparoscopic ($)
Robotically Assisted ($)
P
Cost Differential ($)
Total cost
6,535
8,152
<0.001
1,617
Variable cost
2,965
3,591
<0.001
626
Fixed cost
3,440
4,384
<0.001
944
Cost
• Does cost decrease as surgeon and hospital volume increases?
Surgeon Volume
Hospital Volume
77
Point 2
• Robotic hysterectomy is 16 – 34% more expensive than laparoscopy.
• 40‐50% more expensive than vaginal hysterectomy! Wright, Jason D. et al. “An Economic Analysis of Robotically Assisted
Woelk, JL, et al. “Cost Differences Among Robotic, Vaginal, and Abdominal
Hysterectomy.” Obstetrics and gynecology 123.2 (2014): 255-262.
Does the evidence support the expense?
78
Point 3
• Robotic‐assisted gynecologic surgery has not been proven to improve patient outcomes.
Cochrane, 2012
2 RCTs, 158 patients
Robotic versus laparoscopic hysterectomy
Comparable rates of conversion to laparotomy
Analysis showed longer OR time and higher cost in robotic group (MD 66.00, 95% CI; P < 0.00001; MD 1936.00, 95% CI; P = 0.01)
• SAME outcomes, complications, LOS, quality of life
•
•
•
•
JAMA, 2013
• Retrospective cohort 264,758 women, hysterectomy for benign indication
• Robotic versus laparoscopic hysterectomy
– No significant difference in complications (5.5% vs 5.3%)
– No significant difference in transfusion rates (1.4% vs 1.8%)
– Robotic‐assisted less likely to have LOS > 2 days (19.6% vs 24.9%)
79
Robotics Offers No Benefit Compared to Conventional Laparoscopy
“Robotic‐assisted laparoscopic surgery should not replace laparoscopic or vaginal procedures… for benign gynecologic diseases.”
“At a time when there is a demand for more fiscal responsibility and transparency in health care, the use of expensive medical technology should be questioned when less costly alternatives provide equal or better patient outcomes.”
80
Point 3
• Robotic‐assisted gynecologic surgery has not been proven to improve patient outcomes.
• Need further studies to support the continued use of this expensive technology.
Some other things to consider…
• Marketing
• Haptics
• Training
81
“Aggressive direct‐to‐consumer marketing of the latest medical technologies may mislead the public into believing that they are the best choice. Our patients deserve and need factual information about all of their treatment options, including costs, so that they can make truly informed health care decisions.”
“It is important to separate the marketing hype from the reality when considering the best surgical approach for hysterectomies.”
82
• 432 hospital websites analyzed
• 44.4% contained marketing for robotic gyn surgery
• Most sites reported “improved perioperative outcomes”
• Limitations of robots including cost, complications, and operative time were discussed only 3.7%, 1.6%, and 3.7% of the time
• Guidelines for privileging for robotic‐assisted gynecologic laparoscopy, 2014
– Initial training
– Annual currency
– Annual recertification
Guidelines for privileging for robotic‐assisted gynecologic laparoscopy. J Minim Invasive Gynecol. 2014;21(2):157–167.
Some other disadvantages
•
•
•
•
Absence of tactile sensation
Special staff
Larger OR
More incisions
83
Robotic Surgery
Pro
Con
Bottom Line
• Any operation that can be done with the robot can be done with the laparoscope in:
– Less time
– Less money
– Same outcomes
Turning Fad into Future
• Need high quality studies showing patient benefit
• More cost efficient
• Rigorous training guidelines
• Don’t abandon preferred route of hysterectomy
84
Dr. Holcombe
Dr. Adler
85
W
Whaat Evvery OB//GYN
N Should
d Know abou
a ut Hospiital O
Operatio
ons
Anthony Johnson, D
D.O. 86
What Every Ob/Gyn Needs to Know
About
In Utero Fetal Surgery
Anthony Johnson, D.O.
Professor of Obstetrics and Gynecology
Professor of Pediatric Surgery
University of Texas School of Medicine at Houston
Co-Director
The Fetal Center
Children’s Memorial Hermann Hospital
Disclosures
• Receive royalty payments for authorship of
the twin twin transfusion syndrome chapters
in UpToDate®
• Have no Off-Label disclosures
Objectives
• Describe the current diagnoses that would
be eligible for in utero fetal surgery
• Discuss the various research activities
regarding in utero surgery with specific
diseases
87
Current Therapy Offered
•
•
EXIT procedure
Open fetal surgery for certain lessions
(CCAM, sacrococcygeal teratoma & fMMC)
•
Placental laser ablation for TTTS
•
Selective reduction for discordant fetal
anomalies in MC twins
•
Shunt placement (thoracic/urinary)
•
Intrauterine transfusions
Future Therapy Offered
•
•
•
•
•
Tracheal occlusion for diaphragm hernia
(FETO)
Invasive fetal cardiac therapy
Placental laser ablation in TAPS & sIUGR
Robotic surgery for fMMC or gastroschisis?
Fetal stem cell transplant
Definition of
Maternal-Fetal
Surgery
• Operating on two patients simultaneously where
both incur risks
• Benefits to mother probably not medically definable
• Opportunity to correct a surgically-treatable lesion or
diminish its sequelae
88
Myelomeingocoele
(fMMC)
The prevalence of spina bifida in
Texas
3.52 per 10,000 live births
Canfield MA, et al Paediatr Perinat Epidemiol. 2009 Jan;23(1):41-50.
89
Normal sheep spine
Spina bifida @ 75 days
Followed by closure @
100 days
Spina bifida @ 75
days w/o closure
Meuli et al. J Pediatr Surg 1996;31:397-402
In utero repair ~ neurologic rescue
Historical Perspectives
•1994: Bruner attempts laparoscopic repair of NTD (4
cases performed before stopping)
• 1998: Tulipan reports open repair at 28-30 weeks
gestation in 4 fetuses
– All with absent hindbrain herniation at birth
– 2 required ventricular shunts
• 244 open cases;
• 170-VUMC, 52-CHOP, 12-UCSF & 10 -UNC
• NIH consensus
Am J Obstet Gynecol 1997;176:256-7; Pediatr Neurosurg 1998;29:274-8
90
Feb 2003 – Dec 2010
$22.5 million
MOMS Inclusion Criteria (maternal)
•
•
•
•
•
•
Singleton pregnancy
Gestational age at randomization of 190/7 to 256/7 weeks
Maternal age > 18 years
Body mass index < 35
No previous uterine incision in the active uterine
segment
No risk factors for preterm birth (short cervix,
history of previous preterm delivery)
MOMS Exclusion Criteria (maternal)
• Insulin-dependent diabetes
• Infection with hepatitis B or C
• HIV infection
• Red cell/platelet alloimmunization
• Unwillingness to accept blood transfusions
for religious or other reasons
91
MOMS Inclusion Criteria (fetal)
• fMMC defect between levels T1 to S1
• No evidence of kyphosis (curved spine)
• No major fetal anomaly unrelated to the
spina bifida
• Normal chromosomes by amniocentesis
92
MOMS Outcomes (12 months)
Outcome
Fetal surgery
Postnatal surgery 68%
98%
Primary outcome
Death
2 2
Shunt criteria met
65%
98% Shunt placement
40%
82%
Any hindbrain herniation
64%
96%
MOMS Outcomes (30 months)
Outcome
Fetal surgery
Postnatal surgery
Bayley MDI
89.7 + 14.0
87.3 + 18.4
∆ motor/anat level
0.58 + 1.94
‐0.69 + 1.99
32%
12%
42%
21%
> 2 levels higher
Walking independently
MOMS Outcomes (Maternal)
Fetal surgery
Postnatal surgery
Membrane separation
Outcome
26%
0%
Rupture of membranes
46%
8%
Pulmonary edema
6%
0%
Abruption
6%
0%
Infection
3%
0%
Decreased amniotic fluid
21%
4%
Status of uterine incision at delivery
Very thin
25%
Partial separation
10%
93
MOMS Outcomes (Neonatal)
Outcome
Gest Age (wks)
Fetal surgery
Postnatal surgery
34.1 + 3.1
37.3 + 1.1
< 30 wks
13%
0% 30 – 34 wks
33%
5%
33%
2383 + 688
8%
3039 + 469
21%
6%
35 – 36 wks
Birthweight (gms)
Respiratory distress syndrome
1 in 5 delivered
at term
MOMs Centers
Current U.S. Centers
94
Outcomes
The Fetal Center Cohort
(N = 22)
MOMS Trial (N = 78)
Gestational age at Surgery
24.8 ± .8
23.6 ± 1.4
Gestational age at Delivery
34.2 ± 3.4
34.1 ± 3.1
Delivery < 30 weeks
2 (9%)
10 (13%)
Delivery 30 ‐ 34 weeks
9 (41%)
26 (33%)
Delivery 35‐36 weeks
4 (18%)
26 (33%)
Delivery ≥ 37 weeks
7 (32%)
16 (21%)
Perinatal Death
VP Shunt at 1 year 1 (5%)
2 (3%)
8/14 (57%)
31 (40%)
fMMC Repair
• Open in utero surgery for fMMC is not a cure or a panacea
• Selection of appropriate candidates is essential
• New centers providing fMMC repair should follow MOMs
protocol until comparable safety and efficacy is established
with expansion of sites.
• Focus on reducing maternal and fetal risks
– Fetoscopic access
– Membrane Healing/Scaffold ~ “fix the flat”
26% membrane separation
46% PPROM
80% PTD < 36 weeks
NEXT PREGNANCY
14% rupture
14% dehiscence
95
Current Approaches
• Coverage with patch
9 What is the correct material
¾ Will it adhere to the underlying dura (tethered cord in
future)?
¾ Will it allow for overgrowth of skin or will it require
revision after birth?
• Operating in CO2 environment
9 Damage to fetal membranes
9 Fetal acidosis
Kohl et al. Surg Endos 2010;24:432-44
Dermafill® with
underwater adhesive coacervate
Amnioguard® with suture
A
B
A
B
C
D
C
D
96
Results
Dermafill® + UAC
Amnioguard® with suture
Twin-twin
transfusion
97
Twin Twin Transfusion Syndrome
Diagnosis
Single placenta with thin dividing membrane
Polyhydramnios (8cm) / oligohydramnios (2cm)
Concordant for sex
+/- Discordant size
Monochorionic Twins/
TTTS Staging
Stage 1
Donor MVP <2 cm;
Recipient MVP >8-10 cm
14
cm
Stage 2
Absent bladder in donor twin;
normal Doppler studies
Monochorionic Twins/
TTTS Staging
Umbilical Artery
Donor
Umbilical Vein
Recipient
Ductus Venosus
Middle Cerebral
Artery
98
Monochorionic Twins/TTTS Staging
Stage 4
Stage 5
One or both fetuses have died
Laser Photocoagulation
Laser vs. Amnio for TTTS
RR = 2.04
A
B
C
D
99
TTTS Neurologic Outcome
Author
N
Percent
follow-up
Age @
follow-up
Normal
Minor
abnormal
Major
abnormal
Salomon
73
96%
60 mo
84%
—
16%
Rossi
895
96.8%
Birth
* 94%
—
* 6%
1255
96.8%
6-48 mo
# 89%
—
# 11%
• No difference between donor and recipient
Salomon et al. Am J Obstet Gynecol 2010;203:444.e1-7
Rossi et al. Obstet Gynecol 2011;118:1145-50
Laser Criteria
• 16 – 26 weeks gestation
• Stage II – stage IV TTTS
• Stage I TTTS with the following additional
conditions:
9symptomatic polyhydramnios
9shortening cervix
9cardiac dysfunction in recipient twin
RCT Stage 1 TTTS Laser vs. Observations
Laser Centers
100
Diaphragm Hernia
R
Lung
L
R
X
X
L
101
Diaphragm Hernia (LHR Ratio)
LHR = Transverse area of contralateral lung
Head circumference (mm)
Diaphragm Hernia (LHR Ratio)
LHR
Liver
N
Survival
> 1.4
NA
10
80%
1.0 – 1.4
↓
7
71%
↑
7
57%
↓
12
42%
↑
17
6%
< 1.0
Fetoscopic Tracheal Occlusion
(FETO)
Deprest, et al. Ultrasound Obstet Gyn 24:121, 2004
102
Diaphragm Hernia
• 26 – 28 weeks’ gestation
• General maternal anesthesia
• IM fetal pancuronium, atropine,
•
•
fentanyl
1.2 mm scope; 0.8 ml balloon
Remove at 34 weeks
Deprest et al. Semin Perinatol 2005;29:94-103
Fetoscopic tracheal occlusion for diaphragm hernia
(FETO)
Severe Diaphragm Hernia*
• 210 cases
• 47% PPROM
– median: 30 days post-procedure
– within 3 wks of procedure: 17%
– Gest age at delivery: 35.3wks (30% @ < 34 wks)
• 10 neonatal deaths related to balloon removal
• Overall survival
– L sided: 24% → 49%
– R sided: 0% → 35% Jani et al. Ultrasound Obstet Gynecol 2009;34:304-10
*LHR < 1 w/ liver herniation
103
TOTAL TRIAL
TRACHEAL OCCLUSION TO
ACCELERATE LUNG GROWTH)
Randomized Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) vs. Expectant Management During Pregnancy in Fetuses with Isolated Left Sided Diaphragmatic Hernia
TOTAL Trial
• Moderate disease
9 Left sided CDH
9 LHR 25 – 35% O/E or 35 – 45% w/liver up
9 Outcome: pulmonary function at 6 months of age
• Severe disease
9 Left sided CDH
9 LHR< 25 % O/E
9 Outcome: Survival
US FETO Consortium
Philadelphia, Baltimore, Cincinnati,
Houston, Denver & San Francisco
FDA IDE ~ 2015-16
Fetal Stem Cell
Amniocentesis
• Mesenchymal stem cells harvested
from amniotic fluid
• Bioengineering to form allograft
•Tendon
•Muscle
•Skin
•Cartilage
•Bone
• Avoids ethical controversy
associated with abortion
Isolated MSC
1.8%
Cultured
cells
Biodegradable
scaffold
D Fauza, Children’s Hospital Boston 2007
104
Fetal Stem Cell
Tissue Bioengineering
Congenital Diaphragm Hernia
D Fauza, Children’s Hospital Boston 2007
Time Line for Future Events in Fetal Intervention
Open Fetal Surgery
Fetoscopic Surgery
Fetal Tissue Engineering
Fetal Stem cell & Gene Tx
Fetal Therapy
CDH with Liver Herniation
1980
1990
2000
2010
2020
In Utero Maternal-Fetal Surgery
1 year post in utero fMMC repair
“Proceed with caution…and enthusiasm”
Thank you for you attention
105
Majo
M or Comp
plicaation
ns fro
om Inap
I pprop
priatte G
Gynecolo
ogic Laparosscop
pic Proceedurres Mich
hael B
Baggissh, M.D. 106
Major Complications from Inappropriate Gynecologic Laparoscopic Procedures
Michael Baggish, M.D. St. Helena’s Women’s Center
San Francisco, Calif. CONSEQUENCE OF ENDOSCOPIC SURGICAL ERRORS
• INJURY TO THE PATIENT AND UNFAVORABLE, UNEXPECTED OUTCOME.
• INEVITABLE MALPRACTICE SUIT.
• LETTER REQUESTING MEDICAL RECORDS SIGNED BY PATIENT.
• M.D. NEEDS TO NOTIFY MALPRACTICE INSURANCE CARRIER PROMPTLY.
SIGNIFCANT INJURIES
• Retroperitoneal Great Vessel Punctures/Lacerations
• Small or Large Bowel Perforation
• Bladder Laceration/ Ureteral Burn, Tear, Ligation
• DEATH
107
STANDARD OF MEDICAL CARE
• AN ACCEPTABLE STANDARD OF MEDICAL OR
SURGICAL CARE
• IS DEFINED AS: THE REASONABLY EXPECTED OUTCOME WHEN PERFORMED BY A SIMILARLY TRAINED PERSON IN THE SAME SPECIALTY ACTING IN A PRUDENT MANNER
Progression of a Lawsuit
Expert Witnesses are retained
Medical records are reviewed
Affidavit of merit is produced
Discovery Initiated
Depositions begin with the defendant and then the plaintiff
• The defense side completes depositions first including the plaintiff’s expert then the plaintiff deposes the defense expert (s) and fact witnesses
• Experts testify relative to: Causation, Standard of Care,and
Damages.
•
•
•
•
•
Costs to initiate malpractice suits
• An average cost to plaintiff’s attorney amounts $100,000. Defense may spend more.
• Occasionally before a trial ends a High‐Low agreement is reached with the insurance carrier
• Sometimes a jury is hung triggering a mistrial
• On average 75% of verdicts are in favor of the defense
108
GOOD HABITS
• Diictate or write details of informed consent.
• Include drawings AND GET PATIENT TO SIGN HER UNDERSTANDING. • Get data of past surgery and other treatments
• Dictate detailed op notes and specify when and how the ureter and bowel were inspected for injury • Give details about alternative treatments insituted and offered prior to surgery
HOW TO AVOID MALPRACTICE LITIGATION
• Do not take unnecessary chances
• Always provide alternatives to surgery and document
• Always provide a detailed consent and document
• Dictate a detailed op note with specific notation of bowel and ureter inspection
• Act promptly when pathway deviates from normal
ENERGY DEVICES
More or less required for laparoscopic and hysteroscopic surgery
Know the physics and tissue interaction of electrosurical and ultrasonic devices
MD is obligated to prevent unintended thermal injury
Standard of care focuses on injury recognition
109
Minimally Invasive Non‐Hysteroscopic
ENDOMETRIAL ABLATION
• Most are thermal and many instill liquid
• Perforation with heat=bowel burn/perforation
• Safety features to detect leakage of fluid or gas not fool‐proof
• If an indicator indicates fluid or gas loss STOP IMMEDIATELY.
• Any perforation with thermal component =
• abdominal exploration
ADHESIONS
• Prior abdominal surgery equates to presence of adhesions
• Multiple prior abdominal operations means more adhesions
• Subumbilical entry in presence of adhesions=russian roulette
• Do not hesitate to convert to an open procedure
ADVANTAGES OF LAPAROSCOPY
•
•
•
•
•
•
•
Minimally invasive
Up close magnification
Rapid recovery
Minimal adverse cosmetic effect
Less post op pain
Early discharge
More rapid return to normal activities
110
DISADVANTAGES OF LAPAROSCOPY
2 dimensional viewing—poor depth percep.
Limited angles for manipulation of structures
Requires trocar entry
No tactile sensation
Additional peculiar risks beyond beyond operative procedure
• Suturing difficult and time consuming
•
•
•
•
•
POST OP ASPECTS
• PATHWAY FOR LAPAROSCOPY=PROGRESSIVE
IMPROVEMENT
Post op problems require face to face eval.(avoid telephone Dx and Rx.)
Differentional diagnosis should start with a complication of the just completed surgery
Early diagnosis is key to rectify complication(s)
Tests: cbc with diff. elec, creatinine, ct scan
KNOWLEDGE OF PELVIC ANATOMY
• Relationships of pelvic and abdominal
• Know how to safely gain entry to retroperitoneum
• topographical
111
112
Obturator neurovascular bundle
Umbilical vessels
Uterine vessels
Vaginal vessels
Inferior vesical vessles
Anterior division
of hypogastric artery
Urethra
Ureter
Obturator internus
muscle
Vagina
Posterior
division
of hypogastric
artery
Common
iliac
artery
and vein
Ureter
Levator ani
Iliolumbar vessels
Rectum
Arcus tendineus
fascia pelvis
(white line)
L 4-5
Sciatic nerve
Lumbosacral nerve trunk
(L 4-5)
Hypogastric vessels
Ischial
spine
Superior gluteal vessels
S1
Inferior gluteal vessels
Internal
pudendal vessels
113
CASE ONE
50 year old woman with BMI 25 and strong family history of breast and ovarian cancer
BRCA mutation positive
Scheduled for prophy BSO via robotic laparoscopy 11‐26‐09
Incision several cm above umbilicus
Veress needle inserted and pressure to 17 mm hg
114
CASE 1 (CONT)
A 28 cm long disposable trocar thrust through anterior abdominal wall.
Camera attached and intra‐peritoneal location confirmed
2 additional trocars under direct vision
Anes. Reports precip. Drop BP
End tidal CO2 also drops
Surgeon views and sees blood in paracolic gutter
CASE 1 (CONT)
• Anes. advises no BP and EKG shows pulseless activity
• Pneumo evacuated and trocar tip has blood on it and it is secured
• Stat laparotomy performed (4 minutes since BP drop)
• CPR simultaneously started with laparotomy
• A large retroperitoneal hematoma above aortic bifurcation and Inf.vena cava CASE 1 (CONT)
Gen. Surg. Called finds clotted and liquid blood on opening retroperitoneum
Vascular Surgeon scrubs‐in and finds 1.5 cm. lacer of distal aorta
Cell saver called for and 12,000 ml. blood loss recorded
Aorta and common iliacs cross clamped
Through and through lacerations of aorta sewn with 5‐0 prolene. Aorta very narrowed
115
CASE 1 (CONT)
• Decision to replace distal aorta and 14 mm dacron
graft anastomosed
• More retroperitoneal bleeding noted
• Laceration of inferior mesenteric repaired
• Numerous small venous bleeding controlled
• Intestine inspected and hole in transverse colon identified
• General surgeon who had scrubbed out recalled to repair perforation. Perforated segment resected and divided stapled colon dropped back because it was dusky
CASE 1 (CONT)
Patient very unstable hypotensive and coagulopathic
Abd. Packed and covered with sterile cassette film, towels cover open wound
Patient to PACU guarded condition
While in ICU BP drops and back to OR
Bleeding from right common iliac controlled with 5‐0 prolene
CASE 1 (CONT)
• Nov.27 (day after surg) returned to OR for 3rd time
• Bilateral S&O and transverse colostomy
• Bcause of colonic injury vascular surgeon feels graft contaminated
• Returns to OR for 4th time; graft taken down and left femoral autograft taken and reconstructive conduit created for terminal aorta
• Three additional procedures to repair anterior abdominal wall with mesh
• Mesh infected and removed
• After a month in hospial patient transferred to long term care facility
116
CASE 1 (CONT)
• Patient suffers long term neurologic inury
from prolonged hypoxia
• Continues to require supportive care
• Incidentally she is a doctors wife
117
ANALYSIS OF CASE ONE
•
•
•
•
Causation ?
Standard of Care ?
Damages ?
Verdict ? 118
CASE 2
• 36 year old woman para 3‐0‐0‐3 youngest 11 mos.
• 5 ft. 2 inches; 209 lbs; BMI greater than 30.
• Procedure scheduled in free standing physician owned surgicenter in rural community
• Plan: Hysteroscopy, D&C, Laparoscopic BPS
• Diagnosis: Irreg. Blding, elective sterilization
CASE TWO (CONT)
• HYSTEROSCOPY DONE FOLLOWED BY UNEVENTFUL D&C
• HUMI CANULA PLACE IN UTERUS
• SUBUMBILICAL INCISION FOLLOWED BY VERESS NEEDLE
• 3.5 L CO2 INSUFFLATED
• DISPOSABLE 11‐12 MM TROCAR THRUST
• LAPAROSCOPE INSERTED AND FAT VIEWED
CASE TWO (CONT)
• REPEAT TROCAR THRUSTS X 2‐SAME RESULT
• EXTRA LONG TROCAR OBTAINED AND THRUST AND PERITONEAL CAVITY ENTERED (4TH TRY)
• UTERUS AND ADNEXA NORMAL; 5 MM TROCAR PLACED SUPRAPUBICALLY AND BLUNT PROBE INSERTED
• BOWEL MOVED AND BLOOD SEEN; FIELD BECOMES UNCLEAR
119
CASE TWO (CONT)
• BLUNT PROBE OUT AND BLOOD SPURTS FROM SUPRAPUBIC SITE
• ALL TROCARS REMOVED
• STAT LAPAROTOMY DONE VIA PFANNENSTIEL INCISION‐BELLY FULL OF BLOOD
• 2 GENERAL SURGEONSCALLED AND SCRUB. A VERTICAL INCISION IS MADE
• PATIENT SEVERLY HYPOTENSIVE
CASE TWO (CONT)
• SURGEONS DESCRIBE BLOOD EMITTING THROUGH A HOLE IN THE PERITONEUM OVERLYING THE VENA CAVA AND AORTA; ALSO A LARGE RETROPERITONEAL HEMATOMA
• NO BLOOD IN SURGICENTER
• NEAREST BLOOD BANK 45 MINUTES AWAY
• CAR SENT FOR BLOOD
CASE TWO (CONT)
• SURGEONS WORK TO SUTURE TO SUTURE PERFORATION IN “VENA CAVA” FOR 2 ½ HOURS
• 2 UNITS OF BLOOD ARRIVE VIA CAR RUNNER THE PATIENT IS TRANSPORTED TO LOCAL HOSPITAL (10‐15 MINUTES AWAY AFTER ACRIMONIOUS ARGUMENTS BETWEEN SURGICENTER AND LOCAL HOSPITAL
120
CASE TWO (CONT)
ARRESTS IN AMBLANCE AND RESUSCITATED
ANOTHER 2 UNITS OF BLOOD IN AMBULANCE
ARRIVES AT LOCAL HOSPITAL ER
ARRESTS SECOND TIME AND DIES
MEDICAL EXAMINER: DEATH SECONDARY TO EXSANGUINATION
• POST MORTUM REVEALS LACERATIONS OF RIGHT COMMON ILIAC ARTERY AND VEIN
• NO SUTURES FOUND IN THESE VESSELS
•
•
•
•
•
SUMMATION
•
•
•
•
Causation ?
Standard of Care ?
Damages ?
Verdict?
CASE 3
• 37 YEAR OLD WOMAN; HXOF HYSTERECTOMY,
• ADHESIOLYSIS, STERILIZATION, CHOLECSTECTOMY
• RECENTLY UNDERWENT LAPAROSCOPY FOR BSO (DX PELVIC PAIN)
• OPERATION CONVERTED TO LAPAROTOMYFOR SEVERE ADHESIONS AND TOOK SEVERAL HOURS
121
CASE 3 (CONT)
• POST BSO DEVEL. LEFT HYDRONEPHROSIS
• URETERAL STENT PLACED (INFLAM. CYST)
• REF. TO GYN. ONCOLOGIST FOR PERSISTING PELVIC PAIN
• OCT.29, 2007 UNDERWENT OPERATIVE LAPAROSCOPY; ADHESIOLYSIS AND APPENDECTOMY
• NO RETROPERIT. EXPLORATION
CASE 3 (CONT)
• 10 MM PORT EXCISION ENLARGED TO 3 CM TO ALLOW INSPECTION DESCENDING COLON
• ADMITTED TO HOSPITAL FOR POST OP PAIN
• 10‐31‐07 T=102 degrees, TACHYCARD., TACHYPNEA, WBC, 2900
• DISCHARGED HOME
CASE 3 (CONT)
•
•
•
•
•
•
NEXT AM RETURNS TO HOSPITAL ER
WORSE ABD. PAIN, WEAKNESS, SOB
95.8 DEGREES, HR=135, R=32, BP=100/68
ABD.=DISTENDED, GUARDING ALL QUADS
BS=HYPOACTIVE; WBC=4200
CT SCAN (NO CONTRAST): FREE AIR IN ABD.;PNEUMOMEDIASTINUM, SUBQ GAS ABD. WALL AND CHEST WALL
122
CASE 3 (CONT)
• FOLLOWING DAY WBC DIFF=BANDS ELEVATED TO 25
• CARDIAC CONSULT DIAGNOSE HEART FAILURE ANDNOTES PNEUMOMEDIATINUM SHOULD NOT OCCUR POST ABDOMINAL SURGERY
• THAT EVENING GYN ONCOLOGIST DOES LAPAROTOMY AND FINDS FECAL CONTENTS IN PERITONEAL CAVITY
CASE 3 (CONT)
• A “2MM” PERFORATION IS NOTED IN DISTAL RECTOSIGMOID
• ONCOLOGIST STAPLES AREA BELOW DEFECT AND DOES DESCENDING LOOP COLOSTOMY
• POST OP PATIENT REMAINS SEPTIC AND VEGETABLE MATTER REMOVED FROM ONE OF DRAINS
• GENERAL SURGERY CONSULT CALLED 11‐9‐07
CASE 3 (CONT)
• OPERATION # 3 ON 11‐9‐07
• NECROSIS, HEMORRHAGE, ACUTE INFLAM. OF COLOSTOMY
• COLOSTOMY SEPARATED BY NECROSIS FROM ITS ANT. ABD. WALL LOCATION
• NECROSIS OF EXPOSED MUCOSA AT HARTMAN POUCH SITE
• PARTIAL COLECTOMY WITH NEW END COLOSTOMY AND RESECTION OF DISTAL COLON BACK TO RECTUM AND CLOSURE OF NEW HARTMAN POUCH
• NUMEROUS INTRA‐ABDOMINAL ABSCESSES DRAINED
123
CASE 3 (CONT)
• 2 DAYS LATER PATIENT BACK TO OR FOR ABSCESS (MULTIPLE) DRAINAGE
• DISCHARGED HOME 1 MONTH LATER
CASE 3 (CONT)
• JANUARY 2008 ER WITH NAUSEA AND VOMITING PLUS ABD. PAIN
• ADM. TO HOSPITAL WHERE 5 DAYS LATER A PLASTIC SURGEON DOES EXTENSIVE SKIN GRAFTING FOR CHRONICALLY OPEN ABD. WOUND
• MARCH 12 BACK TO ER ABD. PAIN ADMITTED NG TUBE DRAINAGE AND IV FLUIDS
CASE 3 (CONT)
•
•
•
•
•
APRIL 26 ER WITH PAIN
CT SCAN SHOWS CYSTIC MASS IN PELVIS
CT GUIDED DRAINAGE
JUNE, JULY SEEN IN ER 3 TIMES FOR PAIN
JAN. 2009 ADM. FOR LAPAROTOMY FOR COLOSTOMY TAKE‐DOWN; ANAS., ADHESIOLYSIS AND RESECTION OF LEFT 4 CM CYST (PATH =OVARIAN TISSUE)
124
CASE 3 (CONT)
• SUBSEQUENTLY UNDERWENT LEFT AND RIGHT MYOCUTANEOUS FLAPS TO ABD. WALL
• 16X20 CM SHEET ALLODERM TISSUE MATRIX TO DEFECT IN ABD. WALL
• MARCH 2009 REPEAT DRAINAGE OF PELVIC COLLECTION
• CONTINUES TO HAVEABDOMINAL PAIN
ANALYSIS
•
•
•
•
CAUSATION ?
STANDARD OF CARE ?
DAMAGES?
VERDICT ?
CASE # 4
• 83 yo complaining of pelvic pain and during ultrasound note to have 8mm endometrium and ? Polyp.
• Hysteroscopy scheduled
• Sound placed and cavity describ. as 8cm
• Uterus “dilated”and operative hysteroscope in
• Saw ant. Polyp or myoma
• Polyp forceps removed polyp
125
CASE # 4 (CONT)
• Hysteroscope reintroduc.another polyp seen
• Polyp forceps inserted and now pull out loop of bowel
• Decis. To do diagnostic laparoscopy
• Patient noted to have abd. Incis. Scar midline
• Incis above umbilicus; trocar inserted after pneumoperiton.Several attempts to insert
• Large amount of blood seen with laparoscope
CASE # 4 (CONT)
• Gynec. Oncol called and laparotomy done
• 0.5 cm laceration of bowel mesentery and Vasc. Surgery called to repair
• “small amt. bruising” to bowel ; hole in uterus
• Path revealed no polyp, no endometrium
• The vascular injury to the mesentery repaired
• Again large and small bowel inspected and abd. closed
CASE # 4 (CONT)
• In the surgical ICU patient shock, copius
output from drains, sepsis, DIC
• Return to O.R. and noted to have several liters of blood in belly
• Ischemic colon from cecum to transverse colon ; ileoascending colon resection
• Patient remains severe shock state
• One day after initial surgery patient dies.
126
INTERACTTIVE DEB
BATEE: Whaat iss the
e Besst Managgem
ment of Mod
M de off Deliverry fo
or Tw
win Pregn
nanccies: Is V
Vagin
nal D
Delivvery Stilll a SSafe Opttion? Robert SSilverr, M.D
D. Suneeet Ch
hauhaan, M.D. 127
What Is Best Management of Mode of Delivery for Twin Pregnancies: Is Vaginal Delivery Still a Safe Option?
Suneet Chauhan, M.D. Disclosures
• I do not have relevant financial relationships with commercial interests related to the content of this presentation. Disclosures
128
Disclosures
Disclosures
129
Objectives
• Utilize patient criteria and evidence based practice to determine the appropriate method of delivery of twins.
• Describe patient characteristics of the optimal patient for a twin vaginal delivery.
Twins Births In The United States
Twins: Intrapartum Mx
130
Twin Presentations
16 publications; N = 6,090
Experience With Twins
Total deliveries
1 Year
150
5 Years
750
10 Years
1,500
Twins
5
25
51
Vtx‐Vtx
2
11
23
Vtx‐Non vtx
2
9
17
Non‐vtx‐Others
1
5
11
National Guidelines on Twin Deliveries Vertex‐Vertex
ACOG
(2014)
Vag
CNGOF
RCOG
(2011)
(2008)
No one type NM
SOGC
(2000)
Vag
Vertex‐Non‐
vertex
Vag*
No one type
NM
Vag*
(1500‐4000 g)
Non‐vertex‐
Other
NM
No one type
NM
NM
*An obstetrician experienced in internal podalic version and vaginal breech delivery
131
National Guidelines on Twin Deliveries Vertex‐Vertex
ACOG
(2014)
Vag
CNGOF
RCOG
(2011)
(2008)
No one type NM
SOGC
(2000)
Vag
Vertex‐Non‐
vertex
Vag*
No one type
NM
Vag*
(1500‐4000 g)
Non‐vertex‐
Other
NM
No one type
NM
NM
*An obstetrician EXPERIENCED in internal podalic version and vaginal breech delivery
SOGC Statement
SOGC Statement on Twin
132
Jon Barrett, M.B.Bch., FRCOG, MD, FRCSC
Jon Barrett, M.B.Bch., FRCOG, MD, FRCSC
• “Principal investigator of the Twin Birth Study run by the Centre for Mother, Infant and Child Research at Sunnybrook Research Institute.
• The Twin Birth Study—$8.7‐million grant from the Canadian Institutes of Health Research. • More than 140 centres in 30 countries • Shown that planned vaginal birth is as safe as planned cesarean section for twin delivery—a finding that is changing clinical practice.”
133
RCT Of Planned CD vs. VD With Twins
• Inclusion
– Twins at 320/7 to 386/7 weeks
– EFW between 1,500 to 4,000 g
• Excluded
–
–
–
–
–
Mono‐amniotic twins
Fetal reduction after 13 weeks
Lethal anomalies
No contraindication to vaginal birth
Two or more cesarean delivery
Barrett JFR et al NEJM 2013
RCT Of Planned CD vs. VD With Twins
• Twin A delivered
• Ultrasound
• Twin B
– Vertex Æ VD, unless NR FHR
– Non‐vertex Æ
•
•
•
•
Spontaneous or assisted vaginal breech, Total breech extraction with or without internal podalic version
ECV Æ VD
Intrapartum CD
RCT Flow Diagram
134
RCT Flow Diagram
BEAM Trial
Flow Diagram for BEAM
135
Twin RCT vs. BEAM
Twin RCT vs. BEAM
With BEAM, 75% of women assessed for eligibility were excluded
Twin RCT: Conclusion
• Twins at 32‐38 wks
• Vtx‐other
• Planned cesarean vs. vaginal delivery—did not decrease or increase morbidity or mortality
136
Total deliveries
Twins
1 Year
150
5 Years
750
10 Years
1,500
5
25
51
Vtx‐Vtx
2
11
23
Vtx‐Non vtx
2
9
17
Non‐vtx‐Others
1
5
11
Total deliveries
Twins
1 Year
150
5 Years
750
10 Years
1,500
5
25
51
Vtx‐Vtx
2
11
23
Vtx‐Non vtx
2
9
17
Non‐vtx‐Others
1
5
11
Vtx‐Non vtx Deliveries vs. Cesarean Assuming CD rate of 25%
137
Vtx‐Non vtx Deliveries vs. Cesarean Assuming CD rate of 25%
Planned Recruitment • 20% of eligible twins will be randomized
• 0.1% of all births at a center
• Need 100‐150 centers
• To recruit 770 / year, need 470,000 births per year
• “EXPERIENCE?”
http://www.nejm.org.ezproxyhost.library.tmc.edu/doi/
suppl/10.1056/NEJMoa1214939/
suppl_file/nejmoa1214939_appendix.pdf
138
Corrections to RCT in NEJM
• In the 2nd paragraph of the Methods section the parenthetical in the 1st sentence should have begun, “ (e.g., fetal compromise, second twin substantially larger than the first twin . . . ,”
• Not “. . . first twin substantially larger than the second twin. . . .”
Differentiating Weight of Twins
• 242 twins
• To ensure 90% certainty that actual discordance is < 25%, SEFW discordance should be …6%
Obstet Gynecol 1997
A Randomized Trial of CD or VD For Twins
• GA At 32 to 38 weeks
• EFW between 1,500 g and 4,000 g
139
Prediction Limitation of Estimated Fetal Weight
SEFW (g)
1,500 4,000
90%
1,081 –
2,277
95% BW
(g)
9,66 –
2,392
3,265 –
4,461
3,150 –
4,576 Obstet Gynecol 1998
RCT of VD or CD for Twins
• Non‐vertex twin B
1.
2.
3.
4.
5.
6.
Spontaneous vaginal breech birth
Assisted vaginal breech birth
Total breech extraction with internal podalic version Total breech extraction without internal podalic version External cephalic version Æ Vaginal cephalic delivery Cesarean delivery
140
• Qualified obstetrician:
1.Experienced at vaginal twin delivery 2.Defined a priori as an obstetrician who judged himself or herself to be experienced at vaginal twin delivery and
3.Whose department head agreed with this judgment.17,18
• Qualified obstetrician:
17. Hannah ME et al Lancet 2000;356:1375‐
83.
18. Su M et al. Am J Obstet Gynecol 2003;189:740‐5.
Experienced At Breech Delivery 141
Experienced At Breech Delivery • Someone who considered himself or herself to be skilled and experienced at vaginal breech delivery, with confirmation by the individual’s head of department (A priori)
– A licensed obstetrician
– A clinician with > 10 years of experience of vaginal breech delivery – A clinician with >20 years of experience of vaginal breech delivery
Hannah ME et al Lancet 2000
Experienced At Breech Delivery Perinatal mortality, neonatal mortality, or serious neonatal morbidity
A priori Licensed MD
Planned CD
Planned VD
RR
(95% CI)
1.7%
1.6%
4.9%
4.6%
0.34 (0.20‐0.58)
0.34 (0.19‐0.64)
> 10 years experience 1.5%
3.5%
0.43 (0.23‐0.80)
> 20 years experience
1.6%
3.2%
0.49 (0.25‐0.96)
Hannah ME et al Lancet 2000
Where is the Experience?
• 2,786 twins recruited
• 13,930 twins delivered
• 3,290,000 total births
– 822,5000 CD (assuming 25% rate)
• TOTAL OF 214 VAGINAL BREECH DELIVERIES • 384,246% more CD than vaginal breech
http://www.nejm.org.ezproxyhost.library.tmc.edu/doi/
suppl/10.1056/NEJMoa1214939/
suppl_file/nejmoa1214939_appendix.pdf
142
RCT of VD or CD for Twins: Results
• 20 Countries with PNM < 15 / 1,000 births: Australia, Belgium, Canada, Chile, Croatia, Estonia, Germany, Greece, Hungary, Israel, the Netherlands, Oman, Poland, Qatar, Romania, Serbia, Spain, the United Kingdom, the United States, and Uruguay
143
• 7 Centers in the United States:
–
–
–
–
–
–
–
University of South Carolina, Columbia
University of Iowa Hospitals and Clinics, Iowa City
Jamaica Hospital Medical Center, New York
Texas Tech UHSC, Lubbock University of Miami, Miami East Bay Perinatal Medical Associates, Oakland
Maricopa Medical Center, Phoenix
The 7 Centers in the US Recruited (N = 2,786):
A. 2%
B. 12%
C. 22%
D. 32%
E. Do not know
• The 7 Centers in the US Recruited (N = 2,786): 2% (N = 57)
– About 8 women per center
– About 1 women per center per year
• Experienced clinician
144
Planned CD
1,393
Planned VD
1,393
CD for both
90%
40%
‐‐
VD and CD
1%
4%
‐‐
VD for A and B
9%
56%
‐‐
N
OR (95% CI)
CD, cesarean delivery; VD, vaginal delivery
Planned CD
2,783
N
1o Outcome
Death
Planned VD
2,782
OR (95% CI)
2.2%
1.9%
1.16 (0.77–1.74)
0.9%
0.6%
Fetal
0.5%
0.3%
Neonatal 0.4%
0.3%
1.3%
1.3%
Morbidity
CD, cesarean delivery; VD, vaginal delivery
Conclusions
145
Conclusions
• Unlikely that we will see a major change in use of cesarean delivery for twins nationwide
– Trends in patient demographic characteristics and preferences, – Virtual disappearance of vaginal delivery in cases of breech presentation, and – Dramatic reduction in instrumented vaginal delivery (associated gradual disappearance of the skills necessary to perform these procedures among obstetricians)
Greene MF et al NEJM 2013
Conclusions
• Questionable CONSORT compliance
• NOT generalizable to the United States
• Experience = Cesarean • No improvement with vaginal delivery
• Fewer than 250 vaginal breech deliveries
Conclusions
• Vertex‐Vertex Æ Vaginal
• Vertex‐Nonvertex Æ Cesarean • Nonvertex‐Other Æ Cesarean 146
Multiple Gestation:
Mode of Delivery
Bob Silver
University of Utah
Salt Lake City, Utah
Cesarean and Multiple Gestation
P = 0.011
Multiple Gestations
Cut them all?
Many people think so based
on current cesarean rates!
147
1
Multiple Gestations
Cut them all?
If you believe the
low quality studies
presented by Dr. Chauhan
Multiple Gestations
Cut them all?
Is this the best thing to do?
Cesarean and VBAC Rates
50
1970
1988
1996
2002
2006
40
%
30
20
10
0
CS Rate
VBAC Rate
148
2
Multiple Gestations
Trial of labor
Fetal position is important
Most would CS if A is breech
It varies for twin B due to
clinician training and experience
Twins
Presentation

Cephalic / cephalic: 40%
Cephalic / non-cephalic: 32%
Breech / any position: 8%
Non-cephalic increases with
decreasing gestational age
Morbidity and Mortality Associated
With Mode of Delivery in Twins

U.S. Vital Statistics
Multiple gestations 1995 – 2000
Twins ≥ 30 weeks gestation
Neonatal morbidities and death
Stratified by method of delivery
450,504 infants included
Stratified analyses (presentation /
discordance)
Peaceman et al. Am J Obstet Gynecol 2009;200:e1-462.e6
149
3
Infant Outcomes
Outcomes
Vtx/Vtx
CS
Vtx/Vtx
Vaginal
Vtx/Br
CS
Vtx/Br
Vaginal
5 Min
Apgar ≤ 3
0.1%
0.2%
0.1%
0.3%
Ventilation
< 30 min
2.6%
2.9%
4.5%
5.2%
Ventilation
≥ 30 min
1.9%
1.6%
3.2%
2.8%
Birth Injury
0.1%
0.1%
0.1%
0.5%
Infant Outcomes
Vtx/Vtx
CS
Vtx/Vtx
Vaginal
Vtx/Br
CS
Vtx/Br
Vaginal
0
0
0.1%
0.1%
Infant
Death
0.6%
0.5%
0.5%
0.6%
Composite
0.7%
0.8%
0.6%
1.3%
Outcomes
Seizure

Similar results if ≥ 34 weeks gestation
No increase in adverse events when twin B
weighed 25% or more than twin A
– Vtx / Vtx
– Vtx / Non Vtx
Concluded vaginal delivery and CS
equivalent for Vtx / Vtx
Minimal risk for vaginal delivery Vtx / Br

150
4

Retrospective cohort study
Mt Sinai 2005 – 2009
Single experienced practice
“Aggressive TDT”
– Breech extraction
– If vtx and unengaged, internal podalic version
with breech extraction

Planed TOL compared to planned CS
Fox et al. Obstet Gynecol 2010;115:229-33

N = 287 (157 planned CS; 130 planned TOL)
No difference between groups
– Apgar score of twin B
– Low UA ph of twin B
CS rate in planned TOL: 15.4%
CS of B after vaginal delivery of A: 0
Factors associated with vaginal birth

– Young maternal age / prior vaginal birth
Fox et al. Obstet Gynecol 2010;115:229-33
Twins: RCT
Planned Vaginal or Cesarean Delivery

Prospective RCT
Israel 1983 – 1985
Twins > 35 weeks gestation
Vertex / breech and vertex / transverse
Planned CS (N = 27)
Planned vaginal delivery (N = 33)
Primary outcomes: neonatal morbidity and
mortality and maternal morbidity
Rabinovici et al. Am J Obstet Gynecol 1987;156:52-6
151
5
Twins: RCT

Planned CS – 4 vaginal births due to second
twin spontaneously changing to vertex
Planned vaginal delivery – 2 cesarean
First twin had fewer low Apgar scores than
second twins (regardless of delivery route)
No difference in any adverse neonatal
outcomes in second twins delivered
vaginally or by cesarean
Increased febrile morbidity in CS group
No power!
Rabinovici et al. Am J Obstet Gynecol 1987;156:52-6
Twins: Canadian RCT

Multicenter, international RCT; 2003 - 2011
Twins; Cephalic twin A; 32 – 38 6/7 weeks;
1,500 – 4,000 grams
Planned vaginal or cesarean delivery
Elective delivery planned for 37 5/7 – 38 6/7
Primary outcome:
– Composite of fetal or neonatal death
or serious neonatal morbidity

Unit of comparison: individual fetus
Barrett et al. N Engl J Med 2013;369:1295-1305
Twins: Canadian RCT

1,398 women
2,795 fetuses
Planned CS: 90.7% CS rate
Planned vaginal delivery: 43.8% CS rate
(56.2% rate of vaginal delivery)
Date of delivery from randomization:
– Planned CS: 12.4 days
– Planned vaginal delivery: 13.3 days (P = 0.04)
152
6
Twins: Canadian RCT

Primary composite outcome:
– Planned CS: 2.2% (OR 1.16 (95% CI 0.77, 1.74)
– Planned vaginal delivery: 1.9%

Planned stratified analysis by parity and
gestational age at randomization

Maternal composite outcome:
– No differences among groups
– Planned CS: 7.3%
– Planned vaginal delivery: 8.5% (P = 0.29)
Twins: Canadian RCT

Planned subgroup analysis:
– No interactions for primary outcome and treatment
group for parity, gestational age at randomization,
maternal age, presentation of second twin,
chorionicity, or national perinatal mortality for
country of residence

Second twin was more likely to have primary
outcome (OR 1.90; 95% CI 1.34, 2.69)
– Not significantly related to treatment group
Twins: Canadian RCT

What conclusions can be made?
– TOL is a reasonable option in many cases if twin A
is in the cephalic presentation
– Note that the obstetricians in the study were trained in
vaginal breech extraction
– Note that the institutions in the study had facilities
comfortable with vaginal twin delivery
– Note that the obstetricians used good judgment with regard
to appropriate candidates for TOL before and after
randomization
– Should all twins be delivered by TOL? NO
– Is TOL a reasonable option in most cases? YES
153
7
Twins:
Prediction of Safe Vaginal Delivery

Prospective multicenter cohort study in
Ireland / 2007 – 2009 / serial sonograms
Twins 11 – 22 weeks gestation / enrollment
Secondary analysis
Excluded monoamnionitic twins, anomalies,
aneuploidy
Successful and failed TOL compared
971 twins included
441 considered a TOL
Breathnach et al. Am J Obstet Gynecol 2011;205:237.e1-7
Twins:
Prediction of Safe Vaginal Delivery

Successful vaginal delivery in 338/441 (77%)
CS rate for second twin: 4%
Predictors of vaginal birth:
– Multiparity
– Spontaneous conception

NOT associated with vaginal birth:
– Advancing gestational age
– Presentation of second twin!
– Concordant growth! Even if B was 20% > A!
Breathnach et al. Am J Obstet Gynecol 2011;205:237.e1-7
Multiple Gestations
What about triplets?
CS is “standard of care”
154
8
Triplets

United States vital statistics
Triplets ≥ 24 weeks 1995 – 1998
Assessed mode of delivery and neonatal
outcomes – could not assess
“intended route of delivery” 95% CS
RR stillbirth (vaginal) 5.7 (3.8 – 8.5)
RR neonatal death (vaginal) 2.8 (1.9 – 4.2)
RR infant death (vaginal) 2.3 (1.6 – 3.3)
Vintzileos et al. Am J Obstet Gynecol 2005;192:464-9
Triplets: RCT

No such thing!
Same issues as twins but more so
Many case series and anecdotal reports of
successful vaginal delivery
Impossible to “vet” safety
due to small numbers
Not important for overall CS rate
May be very important for individual women
Highly selected cases
Triplets
Trial of labor

Case series and retrospective cohorts
No increase in morbidity with planned TOL:
–
–
–
–
Northwestern: 33 cases
Stony Brook: 8 cases
Leiden: 39 cases
Paris: 78 cases
Grobman et al. Am J Obstet Gynecol 1998;179:942-5
Alamia et al. Am J Obstet Gynecol 1998;1791133-5
Wildschut et al. BJOG 1995;102:292-6
Alran et al. Acta Obstet Gynecol Scand 2004;83:554-9
155
9
Multiple Gestations
What about triplets?
Vaginal delivery is a reasonable
option in selected cases
Honest counseling would
acknowledge the potential for
unknown risks
Dr. Silver
Dr. Chauhan
156
10
O
Obste
etriccal M
Manaagem
mentt of Wom
men
n witth Recurrrent Preegnaancyy Losss Robert SSilverr, M.D
D. 157
Recurrent Pregnancy Loss
Bob Silver
University of Utah
Salt Lake City, Utah
Sporadic Pregnancy Loss
9Extremely common event
• 10 - 12% clinical pregnancies
• Up to 20% implantation failures
• High rate of aneuploidy (60%)
• de novo non-dysjunction
• Other abnormalities
• Normal individuals
Epidemiology
• Depends upon definition
• 0.5 - 1.0% of couples
• Higher than anticipated
based on chance alone
– 0.3 - 0.4%
• Challenging and frustrating for
both patients and physicians
158
Definition
• 3 or more consecutive losses
– no more than one live birth
•
•
•
•
? 2 or more losses
? Consecutive losses
? Live births
? Most recent pregnancies
Purpose of Definition
• Counseling and prognosis
• Research consistency
• Avoidance of unnecessary tests
and anxiety
• Clinical Arena - Be flexible
– But be honest
Recurrence Risk for Pregnancy Loss
Number of Recurrence
Prior Losses
Risk
Women with
livebirths
0
1
2
3
4
10%-15%
20%-25%
25%-30%
25%-30%
25%-30%
Women without
livebirths
1
2
3
4
15%-25%
35%-50%
159
Types of Loss
9Characterize prior losses
•
•
•
•
•
•
Clinical course
Gestational age
Sonogram
Embryonic / Fetal cardiac activity
Karyotype / MIcroarray
Histology
Preembryonic
2
4
LMP
Fetal
Embryonic
6
8
10
12
14
Weeks’ Gestation
CONCEPTION
Spontaneous Pregnancy Loss
Data from Serial Transvaginal Ultrasound
• 232 low risk women
in early 1st trimester
• Serial transvaginal ultrasound exams
at 1st prenatal visit
and thereafter if indicated
• Overall pregnancy loss rate of 13.4%
Goldstein, Obstet Gynecol 1994;84:294
160
Spontaneous Pregnancy Loss
Data from Serial Transvaginal Ultrasound
Percent
40
30
20
10
Gest Sac; 1-5 mm 6-10 mm 10-30 mm
No Embryo Embryo Embryo Embryo
Fetus
Goldstein, Obstet Gynecol 1994;84:294
Pregnancy Loss
Timing in Gestation
• Implantation Failure
– Positive pregnancy test
• Pre-embryonic
– Empty gestational sac
– “blighted ovum”
• Embryonic
– No cardiac activity: CRL < 30mm
• Fetal
– No cardiac activity: CRL > 30 mm
Pregnancy Loss
Causes
• May vary with gestation
• Abnormal karyotype
– 54% in best series
– Higher in pre-embryonic losses and
embryonic demises
– Higher with advanced maternal age
• APS / Thrombophilia
– Stronger association with fetal death
161
Pregnancy Loss
Timing in Gestation
EAGeR Trial: 189 Losses
•
•
•
•
•
Implantation Failure (29.6%)
Pre-embryonic (19%)
Embryonic (38%)
Fetal Death < 20 weeks (4.8%)
Fetal Death > 20 weeks (2.1%)
Known or Suspected Causes
•
•
•
•
•
•
•
Uterine Abnormalities
Genetic Abnormalities
Autoimmune Disorders (APS)
Hormonal / Metabolic Disorders
Thrombophilias
Infections
Alloimmune Disorders
Uterine abnormalities
• 10 – 15% of women with RPL
• Congenital
– Mullerian anomalies
• 8 – 10% of women with RPL
– DES exposure
– Cervical Insufficiency
• Acquired
– Intrauterine adhesions
– Fibroids
162
Uterine abnormalities
• Mechanism of pregnancy loss?
– Decreased blood flow
– Poor placental development
– Inadequate uterine volume
• Cervical insufficiency
Mullerian Anomalies
• Overall Incidence (normal women)
is uncertain
– Reported as 0.02 – 74%
– Uterine manual exploration: 3%
– Hysteroscopic tubal: 2-3%
– Higher in selected populations
• Outcomes vary for each anomaly
– Worst for septum, best for didelphys
Mullerian Anomalies
•
•
•
•
•
Prospective study (N = 1089)
Three dimensional ultrasound
Non-Obstetric clinical indications
9% abnormal (including arcuate)
Worse obstetric outcome with
uterine anomalies
• Outcomes better than prior reports
Woelfer et al., Obstet Gynecol 2001;98:1099
163
Uterine Abnormalities: Diagnosis
•
•
•
•
•
Sonohysterogram
Hysterosalpingogram
Three dimensional sonogram
MRI
Newer modalities do not
require pelviscopy
164
165
Uterine Abnormalities: Treatment
• Efficacy of treatment unproven
• Improved outcomes reported in
retrospective series
– Uterine septum
– Submucosal fibroids
– Intrauterine adhesions
– Cervical incompetence
• Benefits less clear for metroplasty
Uterine Septum: Treatment
Successful Pregnancies
Before Resection
12/240 (5%)
(N=57)
After Resection
55/63 (87%)
(N=57)
March and Israel, AJOG 1987;156:834
Antiphospholipid Antibodies
Antiphospholipid antibodies (aPL) are a
heterogeneous group of autoantibodies
recognizing epitopes expressed
by negatively charged
phospholipids, proteins, or
a protein-phospholipid complex
166
9Clinical Associations
•
•
•
•
•
•
Recurrent pregnancy loss
Fetal death
Severe preeclampsia / IUGR
Arterial and Venous Thromboses
Antiphospholipid Syndrome
Connective tissue disease
• Best Characterized
– Lupus anticoagulant
– Anticardiolipin antibodies
• Moderate-High titer IgG
– Anti-β2-Glycoprotein-I antibodies
• ? Clinical Utility
– Antiphosphatidylserine antibodies
– Antiprothrombin antibodies
– Antiannexin antibodies
– IgA antibodies
Serologic Testing for aPL
Lupus Anticoagulant
• Detected by phospholipid-dependent
clotting tests
– Activated partial thromboplastin time
– Dilute Russel viper venom time
– Kaolin clotting time
– Plasma clotting time
• Citrated plasma (“blue top tube”)
• Present or absent (no level)
167
Anticardiolipin Antibodies
•
•
•
•
•
•
•
Immunoassays (ELISAs)
Purified Cardiolipin
Beta-2-Glycoprotein-I cofactor
Standard Sera (Galvaston, TX)
“GPL” and “MPL” Units
Semi-quantitative
“Red top” tube
Anti-beta-2-glycoprotein-I
•
•
•
•
•
•
•
•
? True epitope for aPL
Cofactor for anticardiolipin
Anticoagulant protein
Immunoassays
Standardized Sera (Galvaston, TX)
Semi-quantitative
“SGU” and “SMU” Units
Red top tube
Antiphospholipid Antibodies in Women
with Recurrent Pregnancy Loss (RPL)
Data from Petri (1987), Barbui (1988), Parazzini (1991), Parke (1991),
and Out (1991)
LA
Medians
Range
IgG aCL
LA or IgG aCL
RPL
Cntrls
RPL
Cntrls
RPL
Cntrls
7%
0%
8%
2%
11%
2.5%
7-11%
0-2%
5-14% 0-5%
10-16% 0-5%
168
Pregnancy Loss Rates with LA and aCL
Results from Unselected Pregnancies
Lockwood
N=737
Pattison
N=900
Lynch
N=389
Yasuda
LA
100%
aCL
38%
LA-aCL
38%
Negative
6%
N=718
N=2
N=16
N=16
18%
33%
16%
2%
N=11
N=9
N=19
N=915
NA
NA
Katano
N=1125
Medians
6%
N=294
20%
20%
20%
N=60
N=60
N=800
NA
25%
25%
0.5%
N=8
N=8
N=1100
59%
29%
20%
6%
NA
N=860
16%
N=95
Pregnancy Outcomes in RPL
Patients with and without aPL
100
N=1112
aPL negative
aPL positive
60
N=145
N=136
40
20
N=128
Anembryonic Pregnancy
or Embryonic Death
Fetal Death
(>10 wks)
Oshiro et al, Obstet Gynecol, 1996; 87:489
Heparin (and Low-Dose Aspirin)
Versus Aspirin Alone
Percent Live Births
Percent
80
100
Heparin & LDA
LDA alone
80
60
40
20
Kutteh
Rai et al
169
Other Autoimmune Disorders
9Thyroid antibodies
• associated with sporadic
pregnancy loss
• Not associated with RPL
• No treatment
• Testing is not advised
Other Autoimmune Disorders
9Antinuclear antibodies
• 15% of women with RPL
• Common in normal individuals,
especially during pregnancy
• No prospective association with
pregnancy loss
• No relationship with APS
• Negative treatment trial
Genetic Abnormalities
• Balanced parental translocations
– 3 - 5% of RPL couples
– 5X higher than general population
• Other genetic problems
– Malformations (34% in one series)
– Microdeletions (CNVs)
– Recurrent aneuploidy
– Confined placental mosaicism
– ? Skewed X inactivation
– Single gene disorders
170
Parental Cytogenetic Abnormalities
• Balanced parental translocations
– Reciprocal
– Robertsonian
– Risk of pregnancy loss and
abnormal live birth varies
• Inversions
• Translocations more common
• More common in females - 2:1
Recurrent Aneuploidy
• Karyotype in subsequent Loss
in women with RPL
–Abnormal in 48% of
abortus specimens
–Abnormal in 60% of CVS
–Abnormal in over 50% of
all embryos using PGD
Recurrent Fetal Aneuploidy
A Cause of Recurrent Pregnancy Loss?
First Abortus
Karyotype of Second Abortus
Normal
Aneuploid
Normal Karyotype 81%
19%
(N=175)
Aneuploid
45%
55%
(N=107)
171
Why obtain karyotypes?
•
•
•
•
•
•
Emotional closure
Avoid unnecessary treatment
Implications for offspring
Prognosis
? Treatment – PGD
Chromosomal Microarray
Single Gene Disorders
• Embryonic lethal mutations in
“Knockout mice”
– Placental growth factors
– Angiogenic factors
– Development genes
• Evidence in humans
– Increased female offspring: X-linked
– RPL associated with some mutations
172
Parental Cytogenetic Abnormalities
•
•
•
•
IVF / PGD
Theoretical benefit
Good anecdotal results
192 couples with translocation
– 88.3% loss rate prior to PGD
– 13% loss rate after PGD
• 70% success without treatment!
• No efficacy in RCTs
• Expensive / invasive
Fischer et al, Fertil Steril 2010;94:283
Hormonal and Metabolic Disorders
•
•
•
•
Diabetes mellitus (uncontrolled)
Thyroid disease (uncontrolled)
Luteal phase defect?
Polycystic ovarian syndrome?
Luteal Phase Defect
• Progesterone essential to
maintain early pregnancy (7 wks)
– Removal of corpus luteum
– RU486
• Diagnosis by endometrial biopsy
– Lag of 48 hours in two cycles
• Serum levels less reliable
173
Luteal Phase Defect
• 25 – 40% incidence in RPL
• Improved outcome with treatment
– Uncontrolled studies
• Progesterone, hCG, clomid
• Progesterone from ovulation through
8 – 12 weeks gestation
• Optimal dose / delivery route
is uncertain
Luteal Phase Defect: Problems
• Present in normal women
– Up to 50% of single cycles
– 25% sequential cycles
• Variability in evaluation of
endometrial histology
• Lack of controlled studies
Thrombophilias
Pregnancy Loss
• Fetal death
• Consistent association with
most thrombophilias
• Early Pregnancy Loss
• Weaker - No association with
most thrombophilias
174
Thrombophilias
Pregnancy Loss
•
•
•
•
TIPPS trial
RCT (open label)
Thromophilia and prior adverse event
Thromboprophylaxis
– Dalteparin 5000 (daily < 20 wks; bid > 20)
• Composite outcome
– Adverse obstetric events
– Thrombosis
Rodger et al, Lancet 2014;384:1673
Thrombophilias
Pregnancy Loss
•
•
•
•
12 years!
Dalteparin – 143 women
No Dalteparin – 141 women
Intention to treat:
– Dalteparin: 25/146 (17.1%)
– No Dalteparin 28/143 (18.9%)
• No major bleeding
• Increased minor bleeding Dalteparin
Rodger et al, Lancet 2014;384:1673
Infection
• Association with sporadic losses
– Listeria, toxoplasma, syphilis, BV, CMV,
parvovirus, and other viruses
• Requires chronic, non-debilitating
organism that infects uterus
• ? Endometrial mycoplasma
• No convincing link to RPL
175
• Maternal tolerance of the
“fetus as a semi-allograft”
• Concept that RPL involves an
immunologic rejection of the fetus
• Evidence in murine pregnancy that
maternal immune system must:
– Not “reject fetus”
– Recognize fetus for normal placentation
• Evidence in human pregnancy
– Increased HLA sharing in RPL
– Failure to make “blocking” antibodies
– Increased T-helper type 1 cytokines
– Abnormal (both increased and
decreased ) natural killer cells
– Embryotoxic factor
• Proposed treatment
– Maternal immunization
– Intravenous immune globulin (IVIG)
• Leukocyte immunization
– Paternal
– Donor
• Trophoblast immunization
• Initial reports of success
• No increase in live birth rate in more
recent RCTs and meta-analyses
Scott JR, 2002;The Cochrane Library, Issue 2
176
RCT of Paternal Leukocyte Immunization
in Couples With Idiopathic RPL
70
60
N = 85
50
40
N = 86
30
20
10
0
Immune
Control
Ober et al., Lancet 1999;354:365
• IVIG
– Includes “blocking” antibodies
– Maternal immunosupression
– Benefit in one RCT
• No increase in live birth rate in more
recent RCTs and meta-analyses
• Expensive and cumbersome
Scott JR, 2002;The Cochrane Library, Issue 2
177
What about
idiopathic recurrent
pregnancy loss?
At least 50% of cases
Low Dose Aspirin:
•
•
•
•
•
•
•
•
•
Placebo: N = 121
LDA (100 mg): N = 120
LDA + LMWH: N = 123
Placebo and LDA started at
randomization (pre-conception or < 6)
LMWH started at 6 weeks gestation
LDA and placebo stopped at 36 wks
Standard obstetric care
Contacted every 3 months
Intention to treat analysis
Kaandorp et al; N Engl J Med 2010;362:1586
178
Low Dose Aspirin:
• Received and complied with the
assigned study drug
– Placebo: N = 103 (85.1%)
– LDA (100 mg): N = 104 (86.7%)
– LDA + LMWH: N = 103 (83.7%)
•
•
•
•
Mean age 34 years
Median losses: 3
Similar characteristics among groups
299 (82.1%) became pregnant
Intention to treat analysis
Analysis: Pregnancies
179
Low Dose Aspirin:
• Multicenter, International (Scotland)
• SPIN: 2004 – 2008
• Recurrent pregnancy loss
–
–
–
–
Two or more consecutive losses < 24 wks
Unexplained losses (not all had W/U)
APS excluded
If prior live birth, most recent two – losses
• Antenatal care < 7 weeks gestation
• Thrombophilia testing (blinded)
Clark et al; Blood 2010;115:4162
Low Dose Aspirin:
• Randomization
– Rx: Enoxaparin (40 mg) + LDA (75 mg)
N = 147
– No treatment
N = 147
– Open label
– All patients had intensive surveillance
– Sonograms every 2 weeks until 12 weeks
– Monthly sonograms 12 – 28 weeks
180
Low Dose Aspirin:
• Canada; Toronto and Hamilton
• Hep ASA Trial
• Prior RPL and autoantibodies
–
–
–
–
–
–
–
18 – 44 years of age
At least 2 consecutive losses < 32 weeks
Unexplained losses
ANA or aPL or thrombophilia
Confirmed pregnancy
SLE / thrombosis excluded
Evaluation every 6 weeks
Laskin et al; J Rheumatol 2009;36:279
Low Dose Aspirin:
• Randomization
– LDA alone; N = 43
– LDA / LMWH; N = 45
– Open label
– Dalteparin 5000 IU/day
– LDA – 81 mg
• 859 women with RPL screened
• 88 met inclusion criteria
• Trial stopped after 4 years
• 47.7% had some level of aPL
181
EAGeR Trial
Study Design
• Aim: Assess the effects of pre-conception LDA
(81mg) + folic acid on pregnancy outcomes
• Prospective, double-blind, placebo, RCT
• Eligibility:
– healthy women (18-39 yrs) attempting
pregnancy
– 1-2 prior pregnancy losses
– no diagnosis of / or treatment for infertility
• RX: up to six menstrual cycles and / or
through pregnancy (36 weeks)
Schisterman et al; Lancet 2014;384:29
EAGeR Trial
Study Design
• Block Randomization was stratified by
center and by eligibility strata:
– Restricted: a single documented pregnancy
loss <20 weeks of gestation in the past 12
months and no more than one live birth
– General: one or two documented pregnancy
losses regardless of gestational age
or the date of the loss in the past
and up to 2 live births
(not eligible for restricted stratum)
74
EAGeR Trial
Results
• 1228 randomized participants
– 1078 Completed the Trial
– 150 (12%) withdrew early (No Differences
by Rx Arm)
• 131 (10%) non-pregnant
• 19 (2%) pregnant
• Over the trial period there were:
– 728 (59%) confirmed pregnancies
– 133 (11%) clinically confirmed losses
– 595 (48%) live births
75
182
EAGeR Trial: Results
RD 5.1%
p=0.093
RD 9.2%
p=0.039
RD 1.7%
p=0.679
% Live Birth
66
62.4
61
57.8
56
52.7
53.2
LDA
Placebo
53.9
52.2
51
46
Overall
Restricted General
PGD / IVF
• Theoretical benefit
– Especially with recurrent aneuploidy / AMA
• Often done for RPL
• No increase in live birth rates after IVF /
PGD in women with AMA!
• May be chromosomal mosaicism
in early embryos
• Not recommended for idiopathic RPL 77
Recommended Evaluation
•
•
•
•
•
•
Uterine imaging study
Parental karyotypes
Lupus anticoagulant screen
Anticardiolipin antibodies
Anti-beta-2-glycoprotein-I antibodies
Karyotype or microarray of
conceptus
183
Treatment: APS
• Lupus anticoagulant or Medium-High
levels of IgG anticardiolipin
– Thromboprophylactic heparin
(5,000 – 7,500 units bid) (or LMWH)
– ? Low dose aspirin
– Confirmation of viability – 6 wks PP
• Low positive IgG anticardiolipin or
IgM anticardiolipin
– ? Heparin
Treatment: Uterine Abnormality
• Uterine septum
– Hysteroscopic resection
• Uterine synechia
– Hysteroscopic resection
• Bicornuate or didelphys
– ? ? ? Metroplasty – NO!
• Submucous fibroids
– ? Hysteroscopic resection
Treatment: Genetic
• Balanced translocation
– No treatment
– Donor sperm / egg
– IVF / Preimplantation diagnosis
– NO proof of efficacy
184
Treatment: LPD
• Luteal phase defect
– Progesterone 100mg bid PO
– ? IM or vaginal progesterone
– ? hCG or clomid
– NO proof of efficacy
Treatment: Idiopathic
• Idiopathic RPL
–At least 50% of RPL
• No effective treatments
• Leukocyte immunization, IVIG,
heparin, LDA should not be used
• ? Donor sperm / egg; IVF-ET
• Anti-inflammatory agents?
– Plaquenil / anti-TNF / Anti-Complement
Idiopathic
• Take a sympathetic and
caring approach – “TLC”
• Educate the couple
• Provide prognostic information
• Provide treatment options,
including experimental therapy
185
EEvide
ence
e‐Based Guid
delin
nes ffor U
Use of P
Proggesto
ogen
ns to
o Preeven
nt PTTB Adi Abram
movicci, M..D. 186
Use of Progesterone for Preterm Birth Prevention: Clear As Mud
Adi Abramovici, MD
Assistant Professor
Maternal‐Fetal Medicine
Objectives
• Utilize the guidelines for use of progestogens to prevent PTB in the appropriate patient population.
• Describe patient characteristics of optimal candidates for the use of progestogens to prevent PTB.
Disclosures
• I do not have relevant financial relationships with commercial interests related to the content of this presentation. 187
March of Dimes Prematurity Campaign
www.marchofdimes.org
Incidence of Preterm Birth in the US
11
20
09
07
20
20
05
03
20
20
01
99
19
20
97
95
19
19
93
91
19
19
89
87
19
19
83
19
19
19
85
12
11
10
9
8
7
6
5
4
3
2
1
0
81
% Preterm
Healthy People 2020 Goal (9.6%)
Year
Incidence of Preterm Birth in the US
Healthy People 2020 Goal (9.6%)
188
March of Dimes Prematurity Initiative 2014 Report Card
TEXAS GRADE = C
PRETERM BIRTH = 12.3%
March of Dimes Prematurity Initiative 2014 Report Card
Preterm Birth
Sequelae for Infants
• Responsible for majority of perinatal morbidity and mortality
–Cerebral palsy
–Developmental delay
–Visual and hearing impairment
–Chronic lung disease
189
Preterm Birth
Sequelae for Infants
• Morbidity and mortality are related to GA at delivery
–Mortality rate at 24 wks ~50%; <10% by 28 wks
–Specialized education required for 25% born at 32‐36 wks; 45% born at 28‐31 wks
My Preterm Birth Story….
Epidemiology of Preterm Birth
PPROM
28 %
Indicated
Preterm
Delivery
26 %
46 %
Spontaneous
Preterm
Labor
(Andrews 1995)
190
Preterm Birth Prevention
Promises and Failures
Preterm Prevention Strategies
•
•
•
•
•
•
•
•
Antibiotics
Dental Therapy
Fish Oil/Omega‐3 Fatty Acids
Vitamin C
Cerclage
Pessary
Bedrest/hospitilization
Progesterone
Progesterone
191
Biologic Activity of Progesterone
• Uterine quiescence Decreased sensitivity of oxytocin receptors
• Anti‐inflammatory effects
Suppression of cytokines production/release
Decreased cellular immune responsiveness Decreased expression of cell adhesion molecules
Increased production of PIBF Delalutin
17‐Alpha‐Hydroxyprogesterone Caproate
Delalutin
192
Delalutin
• 17‐Alpha‐Hydroxyprogesterone Caproate
• FDA Approved in 1956 (NDA 10‐347 ‐ Delalutin® ) through Bristol Myer Squibb
• Indication (1971): Use in pregnant women for the treatment of habitual and recurrent abortion, threatened abortion, and post‐partum “after pains”
Delalutin
• On September 13, 1999, Bristol Myer Squibb requested withdrawal of NDA for Delalutin citing it had not marketed the drug for several years
• FDA withdrew approval of Delalutin on September 30, 2000 – Not for concerns of regarding safety or efficacy
• May 2003, NICHD MFMU 17OHPC RCT published in NEJM
17α‐Hydroxyprogesterone Caproate
• November, 2003 ACOG Committee Opinion No. 291: Use of Progesterone to Reduce Preterm Birth “ Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and a prior SPB due to spontaneous PTL or PPROM”
193
Progesterone
Potential High Risk Populations
•
History of Previous Spontaneous Preterm Birth
•
Multi‐fetal Gestation
•
Short Cervix
•
Arrested Preterm Labor
•
PPROM
History of Previous Spontaneous Preterm Birth
Preterm Birth Prevention:
Vaginal Progesterone
• Double‐blind placebo controlled study
• High‐risk women • Singleton 24‐34 weeks gestation
• Randomized to receive:
Placebo (n = 70)
Vaginal progesterone supp. 100 mg daily (n = 72)
Da Fonseca AJOG 2003
194
Vaginal Progesterone and PTB
% Women with PTB
30
p < 0.05
20
28.5%
10
13.8%
0
Placebo
Progesterone
Contraction Frequency
Progesterone vs Placebo
7
Placebo
# Contractions/hour
6
5
p = 0.004
4
3
2
Progesterone
1
0
28
29
30
31
32
33
34
Gestational Age (wks)
17α-Hydroxyprogesterone Caproate (17P)
• Double‐blind placebo controlled study
• Women with previous SPB
• Singleton 16‐20 weeks gestation
• Randomized to receive:
Placebo IM Injections (n = 153)
17P IM Injections 250 mg weekly (n = 310)
Meis NEJM 2003
195
NICHD MFMU Progesterone Study
High-Risk Women
Relative Risk
0.66
PTB < 37 wk
0.67
PTB < 35 wk
0.58
PTB < 32 wk
0.1
1
10
Meis NEJM 2003
ACOG Committee Opinion
Progesterone Use for PTB Prevention
• Endorsed 17P • Single indication: Prior preterm birth
• Cautions against
Multiple gestation
US short cervix
+ Fetal fibronectin
ACOG Committee Opinion # 291
November, 2003
Multi‐Fetal Gestations
196
Progesterone - Twins
• Randomized trial (n = 661; 14 centers)
• Twin gestation 16‐20 weeks
• Double‐masked
• Treatment:
17‐OHPC 250 mg weekly Placebo
Rouse 2007 NEJM
Progesterone ‐ Twins
• No difference in fetal demise/PTB < 35 weeks:
41.5% Progesterone vs 37.3% Control (p=NS)
• No difference in composite serious neonatal outcome:
20.2% Progesterone vs 18% Control (p=NS)
Rouse 2007 NEJM
Progesterone - Triplets
• Randomized trial (n = 134; 14 centers)
• Triplet gestation 16‐20 weeks
• Double‐masked
• Treatment:
17‐OHPC 250 mg weekly (n=71)
Placebo (n=63)
Caritis 2009 OB/GYN
197
Progesterone ‐ Triplets
• No difference in fetal demise/PTB < 35 weeks:
83% Progesterone vs 84% Control (p=NS)
• No difference in composite serious neonatal outcome:
20.2% Progesterone vs 18% Control (p=NS)
Caritis 2009 OB/GYN
Progesterone – Multifetal Metaanalysis
Author
(Year)
Mutifetal
Gestation
Included
Reference
Group
n
Treatment Group
n
Start GA
Briery
(2009)
Twins
Norman
(2009)
Twins
Placebo
14
Placebo
250
Combs
(2011)
Triplets
Placebo
25
Cetingoz
(2011)
Twins
Singletons
Placebo
28
Combs
(2011)
Twins
Placebo
80
HartikainenSorri
(1980)
Twins
Placebo
38
Rouse
(2007)
Twins
Placebo
Caritis
(2009)
Triplets
Placebo
Primary
Outcome
17 alpha-Hydroxyprogesterone
Caproate IM weekly
17
24-25 weeks
Delivery
< 35 wks
90 mg vaginal progesterone
gel daily
250
24 weeks
Delivery
< 34 wks
Caproate IM weekly
56
16-22 weeks
Composite
Neonatal
Morbidity
100 mg vaginal progesterone
suppositories daily
39
24 weeks
Delivery
< 37 wks
Caproate IM weekly
160
16-24 weeks
Composite
Neonatal
Morbidity
Caproate IM weekly
39
28 weeks
Perinatal
Morbidity
Mortality
330
Caproate IM weekly
325
16-20 weeks
Delivery
< 35 wks
63
Caproate IM weekly
71
16-20 weeks
Delivery
< 35 wks
Progesterone – Multifetal Metaanalysis
Group
Odds Ratio
Confidence Interval
p
Twins
< 34 wks
1.2
0.9-1.7
0.24
Twins
< 28 wks
1.4
0.76-2.4
0.30
Triplets
<35 wks
1.6
0.8-3.1
0.17
Triplets
< 32 wks
1.0
0.6-1.8
0.91
Triplets
<28 wks
1.2
0.5-2.9
0.73
Vaginal Progesterone
< 34 wks
1.3
0.9-1.9
0.22
Page-Ramsey ACOG AFD 2011
198
Progesterone – Twins
Patient Level Meta‐Analysis
• Patient level meta‐analysis from 13 RCT in twins (3768 women/7536 babies)
• Neither 17P nor vaginal progesterone reduced the incidence of adverse perinatal outcome • In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome
Schuit BJOG 2014
Short Cervix
Progesterone – Short Cervix
• Randomized trial (n = 250)
• Singleton/Twin 20‐25 weeks/Cervix < 15mm
• Treatment:
Placebo (n=125) Vaginal Progesterone (n=125)
Fonseca 2007 NEJM
199
• Reduced SPB < 34 weeks:
19.2% Progesterone vs 34.4% Placebo (p=0.02)
• No difference in birthweight < 2500 gm:
41.2% Progesterone vs 42.8% Placebo (p=NS)
• No difference Composite Neonatal Morbidity:
8.1% Progesterone vs 13.8% Placebo (p=0.19)
Fonseca 2007 NEJM
• Singleton/Cervix 10‐20 mm
• Treatment:
Placebo (n= 235) Vaginal Progesterone (n=458)
Hassan 2011
Ultrasound Obstet Gynecol
8.9% Progesterone vs 16.1% Control (p=0.02)
• Composite Neonatal Morbidity:
Hassan 2011
Ultrasound Obstet Gynecol
200
Arrested Preterm Labor
Progesterone – Arrested PTL
Total N
Progestin
Control
Latency Latency
Progestin Control
∆
Neo. Morb
Facchinetti
2007
60
RCT
17P IM
No Rx
341 mg 2x/week
35 d
19 d
15 d * -----
Borna
2008
70
RCT
Vag P4
400 mg qd
Placebo
36 d
24 d
12 d * RDS *
11 vs 36%
Sharami
2010
173
RCT-DB
Vag P4
200 mg qd
Placebo
24 d
17 d
7d*
NS
Vag P4
200 mg qd
Historic
No Rx
53 d
44 d
9d*
NS
Bomba-Opon 190
2011
Retro
* P < 0.05
Facchinetti 2007 AJOG (194:435, e1-4);
Borna 2008 ANZJOG (48: 58-63);
Sharami 2010 (Int J Fertil Steril (4: 45-50);
Bomba-Opon 2011 (J Matern Fetal Neonat Med (Epub)
PPROM
201
Progesterone – PPROM
• Singleton/PPROM/< 24 weeks
• Treatment:
Placebo (n=36) 17‐P (n=33)
Briery 2011 AJOG
Progesterone ‐ PPROM
• No difference in GA at delivery:
27.3 wk Progesterone vs 29.5 wk Placebo (p=0.15)
• No interval to delivery:
11.2 days Progesterone vs 14.5 days Placebo (p=0.25)
• No difference neonatal morbidity:
73% Progesterone vs 78% Placebo (p=NS)
Briery 2011 AJOG
Progesterone – PPROM
p = 0.18
Briery 2011 AJOG
202
ACOG Practice Bulletin #130
Prediction and prevention of preterm birth
October 2012/Reaffirmed 2014 Obstet Gynecol 2012;120:964–73
Progesterone - Level A Evidence
• A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16–24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth
(Obstet Gynecol 2012;120:964–73)
• Vaginal progesterone is recommended as a management option to reduce the risk of preterm birth in asymptomatic women with a singleton gestation without a prior preterm birth with an incidentally identified very short cervical length less than or equal to 20 mm before or at 24 weeks of gestation. (Obstet Gynecol 2012;120:964–73)
203
• Progesterone treatment does not reduce the incidence of preterm birth in women with twin or triplet gestations and, therefore, is not recommended as an intervention to prevent preterm birth in women with multiple gestations (Obstet Gynecol 2012;120:964–73)
Progesterone Products
17α‐Hydroxyprogesterone Caproate
ACOG
SMFM
Compounded 17P
Makena
March of Dimes
Makena
Cytec Corporation
204
Delalutin/Gestiva/Makena
• 17‐Alpha‐HydroxyprogesteroneCaproate
• In May 2006, Adeza Biomedical submitted NDA 21‐945 to FDA for approval of “Gestiva”
• October 2006, FDA requests more data regarding Gestiva
• Adeza acquired by Cytyc Corp. on April 2, 2007
Delalutin/Gestiva/Makena
• October 22, 2007, Hologic acquires rights to Gestiva
• January 22, 2008, Hologic sells rights to Gestiva to KV Pharmaceutical Co (valued at $82 million) contingent on FDA approval
• 2009 Gestiva not approved by FDA – additional data requested
• February 4, 2011 – FDA approves Hologic/KV Pharmaceutical NDA 12‐945 for Makena: 7 years of exclusivity under Orphan Drug Act 1983
Makena – FDA Approved IM 17‐OHPC
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205
Makena
FDA Statement – March 30, 2011
“In order to support access to this important drug, at this time and under this unique situation, FDA does not intend to take enforcement action against pharmacies that compound hydroxyprogesterone caproate based on a valid prescription for an individually identified patient unless the compounded products are unsafe, of substandard quality, or are not being compounded in accordance with appropriate standards for compounding sterile products.”
Makena
FDA Statement – November 8,2011
“In October 2011, FDA received information from K‐V Pharmaceuticals regarding the potency and purity of samples of bulk hydroxyprogesterone caproate active pharmaceutical ingredients (APIs) and compounded hydroxyprogesterone caproate products. According to the analysis of this information provided by K‐V, there is variability in the purity and potency of both the bulk APIs and compounded hydroxyprogesterone caproate products that were tested. Although FDA has not validated or otherwise confirmed the analyses provided by K‐V, FDA has carefully reviewed the data and will conduct an on‐site review of the laboratory analyses.”
Makena
FDA Statement – November 8,2011
“FDA has begun its own sampling and analysis of compounded hydroxyprogesterone caproate products and the bulk APIs used to make them. That process is ongoing. In the meantime, we remind physicians and patients that before approving the Makena new drug application, FDA reviewed manufacturing information, such as the source of the API used by its manufacturer, proposed manufacturing processes, and the firm’s adherence to current good manufacturing practice. Therefore, as with other approved drugs, greater assurance of safety and effectiveness is generally provided by the approved product than by a compounded product.”
206
Makena
FDA Statement – June 15, 2012
“FDA tested 16 samples of hydroxyprogesterone caproate
API using the methods specified in the United States Pharmacopeia (USP) as well as the methods used in the Makena new drug application (NDA). ‐ All 16 API samples passed USP tests for potency (97‐103 percent) and purity and all 16 API samples passed the potency tests in the Makena NDA. ‐ All 16 of the API samples passed the total purity standard in the Makena NDA but failed the Makena NDA’s limit for unidentified impurities.”
Makena
“FDA also isolated and identified four impurities that appeared at levels above those permitted in the Makena NDA. Based on information available to FDA, the impurities observed in these samples do not raise safety concerns.”
Makena
“FDA also tested 13 samples of compounded hydroxyprogesterone caproate prepared by eight pharmacies. ‐ One of 13 samples was subpotent and was in the range of 80 percent of declared potency. (The standard for potency is 90‐110 percent). All 13 of the samples met the standard in the Makena NDA for total purity. Two of the 13 samples failed to meet the standard for unidentified impurities in the Makena NDA.”
207
Makena
“FDA also obtained the available retained samples of compounded products from the laboratories that K‐V hired to perform the tests on the compounded products that were submitted to the agency in October 2011. FDA’s testing of the retained samples found that three of 26 samples that failed the original standard for potency (90‐
110 percent) using the method in the Makena NDA were in the 115 percent range.”
Makena
“Although the analysis of this limited sample of compounded hydroxyprogesterone caproate products and APIs did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products.
FDA emphasizes that it is applying its normal enforcement policies for compounded drugs to compounded hydroxyprogesterone caproate. The compounding of any drug, including hydroxyprogesterone caproate, should not exceed the scope of traditional pharmacy compounding.”
Makena
FDA Q & A – June 29, 2012
“Should health care professionals prescribe and patients take the FDA‐approved drug product rather than the compounded product? If there is an FDA‐approved drug that is medically appropriate for a patient, the FDA‐approved product should be prescribed and used….”
208
Makena
KV Pharmaceutical vs FDA
Makena
KV Pharmaceutical vs FDA
•
July 7, 2012: KV Pharmaceutical and Ther‐Rx Corporation file Motion for Temporary Restraining Order and Preliminary Injunction and Compliant for Declaratory and Injunction Relief in US District Court for the District of Columbia
•
Listed Defendants: United States and Drug Administration
United States Department of HHS
Margaret A. Hamburg, MD (FDA Commissioner)
Kathleen Sebelius (Secretary HHS) Makena
Lumara Health
•
FDA prevailed in Federal Court
•
In 2014, KV Pharmaceutical converted to
Lumara Health
•
November 12, 2014, AMAG Phamaceutical
acquires Lumara Health
•
More to come….
209
Compounded 17P Preparations
Purity Assessments
•
NICHD: analysis of 18 specimens from 15
compounding pharmacies
•
Concentration of 17-OHPC in all samples was
within the specification limits, and all tested
samples passed sterility and pyrogen testing.
•
Only 1 of 18 samples was out of specification
limits for impurities
•
No safety concerns when assessed for potency,
sterility, pyrogen status, or impurities
AJOG 2014
17P Preparations
Cost
• Compounded 17‐OHPC 250 mg IM Weekly:
$13 per week ($260/pregnancy)
• Makena 250 mg IM Weekly: $690 per week ($13,800/pregnancy)
Prochieve/Crinone/Prometrium
210
Vaginal Progesterone Preparations
Cost
• Prochieve 8% Intravaginal Daily:
$74/week ($1,480/pregnancy)
• Crinone 8% Intravaginal Daily
$160/week ($3,200/pregnancy)
• Prometrium 200mg Intravaginal Daily
$450/week
($9,000/pregnancy)
Safety
Progesterone – Safety
Meis Study – Primary Outcomes
Relative Risk
0.66
PTB < 37 wk
0.67
PTB < 35 wk
0.58
PTB < 32 wk
0.1
1
10
Meis NEJM 2003
211
Meis Study F/U – Mean 48 months
17P
(n=193)
Placebo
n=82)
P
11%
NS
Scores below cut‐off on Ages & Stages Questionnaire
Communication 11%
Gross Motor 3%
4%
NS
Fine Motor 21%
18%
NS
Problem Solving 10%
11%
NS
Motor Skills Problem 1%
1%
NS
Developmental Delay 7%
8%
NS
10%
NS
Diagnoses from Health Professionals
Attention or Learning Problems 8%
Northen Obstet Gynecol 2007 (110:865-72)
18 Month F/U Study - Twin Trial
P4
Placebo
P
Ages & Stages Questionnaire
ASQ Scores at 6 months
215 +/‐ 38
218 +/‐ 37
NS
ASQ Scores at 18 months
193 +/‐ 43
194 +/‐ 41
NS
Score < 115 at 18 months
3.8%
3.7%
NS
Rode et al Ultrasound Obstet Gynecol
2011
Progesterone – Perinatal Loss
• 2003 Meis Trial (singleton/prior SPTB)
17P: 5 miscarriages < 20 weeks, 6 IUFDs
11 losses of 306 (3.6%)
Placebo: 0 miscarriages < 20 weeks, 2 IUFDs
2 losses of 153 (1.3%)
• 2010 Combs Trial (triplets)
17P: Loss of 13/168 offspring (8%) IUFD/previable
Placebo: 0 of 75 lost
p < 0.05
212
“We should be vigilant about
interfering with systems we poorly understand in the absence of benefit”
Kenyon et al. Lancet 2008
Diethylstilbesterol
“The DES Story humbles us. It serves as a reminder that through the narrow lens of today might reassure us that an intervention is safe.
It is only with the wisdom of time that the full consequences of our actions are revealed”
Goodman et al NEJM 2011 (364:2084)
213
“Because questions exist regarding miscarriage and other risks, progestins
should be used only for indications where benefit has been established or in controlled clinical trials”
Combs et al AJOG 2011
SUMMARY
Best Evidence
• 17P effective for women with singleton gestation and history of prior singleton spontaneous preterm birth
• Progesterone ineffective in multifetal
gestations
SUMMARY
Best Evidence
• 17P and vaginal progesterone preparations appear to be safe
• Compounded progesterone appears to be as safe to FDA approved Makena
214
SUMMARY
Best Evidence
• Whether FDA approved product or compounded, strong evidence supports progesterone as an effective intervention to prevent preterm birth in select populations
Progesterone for Preterm Birth Prevention
Cost Effectiveness
• If universal treatment of selected population, discounted lifetime medical costs of their offspring could be reduced by more than $2,000,000,000 annually
Bailit JL – AJOG 2007
Questions
adi.abramovici
@uth.tmc.edu
215
Whaat Wo
ould
d You
u Do
o? Co
omp
plicated
Case
C e Pre
esentatio
ons Hecctor M
Mendeez‐Figgueroa, M.D. 216
What Would You Do: Complicated Case Presentations
Hector Mendez-Figueroa, M.D.
Assistant Professor
Department of Obstetrics, Gynecology And Reproductive Sciences
UT Health Sciences in Houston
Disclosure Statement
I do not have relevant financial relationships with commercial interests related to the content of this presentation. Learning Objectives
1. Understand literature and its limitations
2. Understand the limitations of some come tests used by clinicians 3. Review the ACOG/SMFM guidelines regarding timing of delivery
217
CLINICAL SCENARIO #1
40 y/o G2P1 @ 15 weeks is returning your call to discuss her Non‐invasive prenatal testing results. Earlier that day you discovered that she had tested “positive” for trisomy 21, Down syndrome.
How do you counsel this patient?
A. The test is just so new that we should repeat it before we do anything else (false positive)
B. Wait for the MFM sonogram, this will tell us if the baby has T21 or not
C. The sensitivity and specificity of this test is over 99%, I am sure you baby has T21
D. This is still a screening test, I recommend we proceed with a diagnostic invasive test in order to confirm
Would you address this differently if the patient were 30 years old with no family history of genetic disorders and no past medical history?
A. YES
B. NO
218
Would your approach be different if the results were “positive” for trisomy 18?
A. YES
B. NO
VIDEO
www.bostonglobe.com
219
CIRCULATING CELL‐FREE FETAL (CFF) NUCLEIC ACIDS
Source of ccff DNA
PLACENTAL and fetal‐derived cells
Breakdown of fetal cells in circulation
Percentage in circulation
~3‐6% of circulating DNA in maternal plasma is fetal in origin
>10% in recent studies
Need >4% fetal fraction in most labs for valid study
Clinically available
November 2011 in the United States for high risk
Low risk – is currently company dependent
NIPT
Targeting Chromosomes 21, 13, 18, X and Y
Two different quantification techniques commonly used
MPSS : Generates a Z‐score for each chromosome studies
¾
¾
¾
Generally above Z‐score of 3 is abnormal cut‐off
Sequenom (materniti21plus) = pure cut‐off
Verinata (verify) = gray zone where further testing may be warranted
DANSR + FORTE ‐ Digital Analysis of Selected Regions plus Fetal‐
fraction Optimized Risk of Trisomy Evaluation (Ariosa)
One SNP based technique
NATUS = Next‐generation Aneuploidy Test Using SNPs [NATUS] algorithm (Panorama – Natera)
220
Z‐Scores
DANSR + FORTE
Norton et al AJOG 2012 SNP BASED TESTING
Rabinowitz et al from Natera
221
NIPT VALIDATION
NIPT has been validated by prospective studies:
In high risk pregnancies

AMA
Abnormal serum screen
Family or personal hx of child with aneuploidy
Abnormal ultrasound suggestive of aneuploidy
Between 10‐22 weeks gestation
NIPT VALIDATION
Blinded nested case-control Study – high risk
212 cases trisomy 21 and 1471 matched controls
• 209/212 trisomy 21 screen positive –
True positive rate = 98.6% (SENSITIVITY)
• 105 -1st trimester;107 - 2nd trimester, 13 samples failed
3/1471 euploid screen positive - False positive rate = 0.2%
1468/1471 euploid screen negative - True negative rate
99.8% (SPECIFICITY)
3/212 trisomy 21 screen negative - False negative rate 1.4%
Palomaki et al, Genetics in Medicine 2011
More difficult to identify trisomy 18 and 13 due to higher variability of genomic representation in euploid
pregnancies
Trisomy 18
• 3/62 failures due to low fetal fraction
• Detection rate of the 59 than were run 100% (59/59); CI [93.9‐100]
• False positive rate of 0.3% (5 out of 1,688)
Trisomy 13
• Detection rate of 91.7% (11/12); 95% CI [61‐99]
• False positive rate of 1% (16 out of 1,688)
Palomaki et al, Genetics in Medicine 2012
222
NIPT VALIDATION
2,882 samples from singleton pregnancies at 60 US sites
High risk; having invasive procedure
Sponsored by Verinata
3.0% of samples had no fetal DNA detected
Trisomy 21 = 100% detection rate (89/89); CI [95.9-100]
Trisomy 18 = 97.2% detection rate (35/36); CI [85.5-99.9]
Trisomy 13 = 78.6% detection rate (11/14); CI [49.2 – 99.9]
Monosomy X = 93.8% detection rate (15/16); CI [69.8-99.8]
Bianchi et al, OB GYN 2012
NIPT VALIDATION
Trisomy 21 using DANSR and FORTE algorithm • 81/81 detected (100%)
• 0.03% false positive rate (1/2,888)
• The 1 false positive case had risk estimate of 1.1% or 1 in 92
• Also one mosaic t21 classified as low risk
Trisomy 18
• 37/38 detected (97.4%)
• The 1 missed affected case had risk estimate of 1 in 10,000
• 0.07% FPR (2/2,888)
• False positive cases:
• 73% risk
• 99% risk Approximately 0.5% of women will have scores between the >99% or Norton et al, Genetics 2012
< 1in 10,000 used in other labs
WHAT ARE THE LABS REPORTING?
Laboratory
Technology
Conditions Tested For
Sensitivity
Specificity
Reporting
Sequenom
MPSS
Trisomy 21
Trisomy 18
Trisomy 13
SCA
T21 = 99.1%
T18 = >99.9%
T13 = 91.7%
SCA = 96.2%
T21 = 99.9%
T18 = 99.6%
T13 = 99.7%
SCA = 99.7%
Positive Negative
Failure
No Call SCA
MPSS
Trisomy 21
Trisomy 18
Trisomy 13
Monosomy X
T21 = 100%
T18 = 97.2%
T13 = 78.6%
45X = 95%
T21 = 100%
T18 = 100%
T13 = 100%
45X = 100%
Positive
Negative
Unclassifiable
Failure
DANSR (assay) +
FORTE (algorithm)
Trisomy 21
Trisomy 18
Trisomy 13
T21 = 100%
T18 = 97.4%
T21 = 99.9%
T18 = 99.9%
Risk Ratio via algorithm
1/10,000 –
99/100
(MaterniT21Plus)
Verinata
(Verify/Illumina)
Ariosa
(0.5% results fell between the two extreme values)
223
Frozen samples on 2,049 women who had combined FTS in 2010‐2011
95.1% had a result
2.2% low fetal fraction
2.6% assay failure (1 of these 54 turned out to have t18)
Trisomy 21 8/8 had high risk score (>99%) [average maternal age 39.6 in this group]
No false positives
Trisomy 18
2/2 had high risk score (>99%) [average maternal age 39.4 in this group]
2/1939 had false positive high risk score
9.8%
11.7%
No Trisomy 13 or SCA information
Ariosa group = began offering to low risk when launched
Nicolaides et al, AJOG 2012
Low risk women (mean age 29.6) having routine maternal serum screening, largely combined FTS, Quad, Sequential screens
Run on Verinata’s platform 1,914 women; 8 aneuploidy
Serum Screens
NIPT
Trisomy 21
3.6% False positive (69/1909) [51/1365]
5/5 detected
4.2% PPV
0.3% false positive (6/1909) [4/1365]
5/5 detected
45.5% PPV
Trisomy 18
0.6% false positive (11/1905)
2/2 detected
8.3% PPV
2/2 detected
40% PPV
Trisomy 13
0.1% (1/899)*
(*also 2 false positive in group that had other
screens that did not include t13 = 3/?1909 =
0.15%)
SCA
Not analyzed
Bianchi et al, NEJM 2014
STATS 101
One thing to remember is that sensitivity and specificity are statistical properties of the test itself, measures validity
–
–
–
–
–
–
Compare the test to a “gold standard”
Does not take into consideration any “indeterminate” test results Independent of the prevalence of the disease
How likely is the test to pick up a disease?
Tests with high sensitivity are useful for ruling out a disease
Sensitivity and specificity are better aimed at evaluating population
224
STATS 101
A more clinically important question would be to evaluate the test characteristics for an individual patient • How likely I am to have the disease if I have a positive test?
• How precise is this test?
PREDICTIVE VALUE
PREDICTIVE VALUE ‐ PREVALENCE
SENSITIVITY = 99%, SPECIFICITY = 99%
Disease prevalence 5%
Disease prevalence 1%
Test results
Sick
Positive
99
99
Negative
1
9,801
100
9,900
10,000
Totals
Totals
Not Sick
Totals
Test results
Sick
198
Positive
495
95
590
9,802
Negative
5
9,405
9,410
500
9,500
10,000
PPV = 99/198 = 50%
Not Sick
Totals
PPV = 495/590 = 84%
PREDICTIVE VALUE ‐ NIPT
SENSITIVITY = 99.1%, SPECIFICITY = 99.9% (SEQUENOM)
Age 30, Disease prevalence 1/703
Test results
Sick
Positive
141
100
241
Positive
1,303
99
1,402
Negative
1
99,758
99,759
Negative
13
98,585
98,598
142
99,858
100,000
Totals
1,316
98,684
100,000
Totals
Not Sick
Totals
Age 40, Disease prevalence 1/76
PPV = 141/241 = 58.5%
Test results
Sick
Not Sick
Totals
PPV = 1,303/1,402 = 92.9%
225
NIPT – TRISOMY 21
AGE
PPV
20‐24
25‐29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
45.3%
48.3%
58.5%
61.9%
65.7%
69.8%
74.0%
78.0%
81.9%
85.4%
88.4%
90.9%
93.0%
94.7%
95.9%
97.0%
97.7%
98.3%
NIPT – OTHER ANEUPLOIDIES
Trisomy 18
AGE
20‐24
25‐29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
Trisomy 13
PPV
9.1%
10.2%
14.7%
16.5%
18.9%
21.9%
25.6%
30.1%
35.4%
41.4%
48.0%
54.7%
61.6%
68.1%
73.9%
79.3%
83.6%
3.8%
4.2%
6.3%
7.1%
8.3%
9.8%
14.2%
14.3%
17.6%
21.5%
26.3%
31.9%
38.2%
45.1%
52.3%
59.5%
66.4%
CLINICAL SCENARIO
40 y/o G2P1 @ 15 weeks with a “positive” NIPT result for trisomy 21, Down syndrome.
1. Would your approach be different if the patient were 30 years old (low‐risk)?
2. Would you approach be different if the results had been positive for trisomy 18?
226
FUN FACTS
‐ Between 450,000 to 800,000 NIPT tests have been performed in the United States since 2011
‐ In one study 6.2% (22/356) of women with abnormal results terminated without an invasive confirmatory test ‐ At Stanford University, there have been at least three cases of women aborting healthy fetuses after a positive result
MICRODELETIONS – MORE CONFUSION
Offered as a August 2014
Sequenom
Verinata
Natera
22q DiGeorge
5p Cri‐du‐chat
15q PraderWilli/Angelman
1p36
4p‐ Wolf‐Hirschhorn
8q Langer Giedion
11q Jacobsen
Trisomy 16
Trisomy 22
22q11
5p‐
15q11
1p36
4p‐
22q11
5p‐
15q11
1p36
4p‐
94.4% sensitivity (17/18)
99.4% specificity (156/157)
91.6% sensitivity
99.84% specificity
? Internal validation Trisomy 16
Trisomy 9
???
MICRODELETIONS – MORE CONFUSION
22qdel
94.4% sensitivity
99.4% specificity
1/1,000 incidence
PPV = 13.6%
15qdel
8qdel
94.4% sensitivity
99.4% specificity
1/10,000 incidence
94.4% sensitivity
99.4% specificity
1/50,000?? incidence
PPV = 1.5%
PPV = 0.31%
227
TIMING OF DELIVERY CLINICAL SCENARIO #2
32 y/o G2P1 @ 30 3/7 weeks with a history of a prior cesarean section has been diagnosed with complete anterior placenta previa since week 20. A recent ultrasound is now highly suspicious for placenta accreta. Does the “39 week” rule apply to everyone?
When should this patient be delivered? ACOG STATEMENT
“Planned deliveries before 39 weeks 0 days should occur only when there are significant health risks to a woman and/or the fetus in continuing the pregnancy”
228
Tita et al, NEJM 2009
• Based on the 2005, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) workshop • Infants born late preterm are more likely to have long‐term neurodevelopmental problems and infant death than those born at term
• Neonates born before 39 weeks are at increased risk for significant complications compared with those born after 39 weeks
• Continuing pregnancy in the face of medical or obstetric complications potentially can increase the risk to mother, the fetus, or both.
Spong et al, OB GYN 2011
NEW TERMINOLOGY
1. Early preterm – < 34 0/7 weeks
2. Late preterm – 34 0/7 – 36 6/7 weeks
3. Early term – 37 0/7 – 38 6/7 weeks
4. Full Term – 39 0/7 – 40 6/7 weeks
5. Late term – 41 0/7 – 41 6/7 weeks
6. Post term ‐ ≥ 42 0/7 weeks
229
30 3/7 weeks prior C/S with possible placenta accreta. A.
B.
C.
D.
32 weeks?
34‐36 weeks?
37 weeks?
39 weeks?
ACOG 2013
You refer a 20 y/o G1 @ 35 3/7 weeks with no past medical history to the MFM ultrasound unit because her fundal height is measuring 4 weeks behind. Her pregnancy has been uncomplicated thus far. On ultrasound the fetus has an EFW at the 5th percentile with normal AFI, BPP 10/10 and a normal S/D ratio on umbilical artery Dopplers. What is the best timing for delivery?
230
20 y/o G1 @ 35 3/7 weeks with IUGR and normal antenatal testing
A.
B.
C.
D.
Deliver now
36 weeks?
37 weeks?
38‐39 weeks?
ACOG 2013
32 y/o G2P1 @ 35 3/7 weeks diagnosed with GDM is in your office to review her BG log. You notice she is poorly complaint with her testing and when does test, she has several postprandial values over 200 mg/dl and some fasting values over 120 mg/dl.
Best timing for delivery?
231
32 y/o G2P1 @ 35 3/7 weeks non‐compliant poorly controlled GDM
A.
B.
C.
D.
Deliver now
36 weeks?
37 weeks?
38‐39 weeks?
ACOG 2013
QUESTIONS?
232
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for
Attending!
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