Transcript Document

New Developments in
Early Pregnancy
Roy G Farquharson
MD FRCOG
Liverpool Women’s Hospital, UK
[email protected]
Disclosure
• Act as NICE GDG member on pain and
bleeding in early pregnancy (2010-2012)
• Executive Committee member, ESHRE
(2011-)
• Chair, Association of Early Pregnancy
Units, UK (2006-2011)
• No external funding/payments received
from Pharma companies
Early Pregnancy Events and
Complications
• EP Loss diagnosed by TV Ultrasound with
set standards based on consensus criteria
(RCOG, NICE, NVOG) including:
• Pregnancy of uncertain viability (PUV)
• Pregnancy of unknown location (PUL)
utilising biochemical markers (HCG ratio/progesterone)
• Ectopic pregnancy
Predictive Modelling for Early Pregnancy
Best
Area of Interest Diagnostic
Utility
Parameter(s)
Ovulation
Biomarker
D21 Progesterone
Pregnancy of
Unknown
Location
(PUL)
Transvaginal
(TVU) Scan
and Biomarker
TVU Scan
+ HCG doubling
time/ratio
+/- Progesterone
Pregnancy of
Scan
Uncertain Viability Scan
(PUV)
Exclusively Scan
Fetal heart action
plus Crown-rump
length (>6mm or 1
week confirmation)
Positive Pregnancy Test What next?
TVS
90%
Intra-Uterine Ectopic Pregnancy
Pregnancy (IUP)
(EP)
10%
PUL
IUP Failing EP
PUL
PUL Assessment – a diagnosis in
evolution
Serum hCG and
progesterone
TVU
Intrauterine
Pregnancy
(IUP)
Failing PUL
Ectopic Pregnancy
(EP)
Pregnancy of Unknown Location
(PUL)
• Is not interchangeable term with ectopic pregnancy
• Rate of PULs is related to quality of scanning, ie.
high sensitivity for the detection of ectopic
pregnancy using TVS associated with a low PUL
rate (Kirk E, Papageorghiou AT, Condous G, Tan L, Bora S, Bourne T.Hum Reprod. 2007,
22, 2824-8; Bottomley C, Van Belle V, Mukri F, Kirk E, Van Huffel S, Timmerman D, Bourne
T Hum Reprod. 2009, 24, 1811-7.)
• Not every prediction model based on precise theoretical
reasoning works as efficiently when field-tested? (Barnhart
KT, Sammel MD, Appleby D, Rausch M, Molinaro T, Van Calster B, Kirk E, Condous G, Van
Huffel S, Timmerman D, Bourne T. Hum Reprod. 2010, 25, 2434-40
PUL Conclusions
•
Expectant management – low-risk EcP: positive indicators include low initial HCG level, decreasing
HCG trend, absence of gestational sac and longer time from LMP
•
Change in hCG over time, hCG ratio, and not the absolute serum hCG value makes final
diagnosis MORE likely until TVS confirms Dx.
•
Serum progesterone confirms viability of PUL but not LOCATION --------------- as Ectopic
Pregnancy levels can ‘mimic’ viable IUP in approx 8% of cases vis a vis EctP can ‘mimic’ failed
IUP
•
Symptoms of nausea, vomiting and diarrhoea can exist with Ectopic Pregnancy
•
Discriminatory zone not helpful in PUL population where EcP diagnosis is TVS based with ~75%
•
visualised on initial TVS.
Single blood test approach is not appropriate
•
Potential to decrease the number of visits but VIGILANCE essential.
•
Need multi-centre trials to validate or otherwise the use of such models as protocols replace
‘thinking’ and critical analysis by senior clinicians
Updated Gestational Age Measurement in
early pregnancy
• Total number of pregnancies: 6666 (2002-2008)
• Exclusions, n= 2956 (uncertain dates, redated, infertility treatment,
miscarriage, stillbirth, genetic or congenital abnormalities)
• Inclusions, n= 3710 normal singleton pregnancies dated according
to known and recorded last menstrual period (LMP) with confirmed
viability at the time of subsequent nuchal scan
• Predominantly transvaginal ultrasound below 10 weeks by contrast
with Robinson transabdominal derived CRL curve (BMJ, 1972)
• The gestational age (GA) ranged between 35 and 98 days
• Linear mixed-effects model in order to account for possible codependency of multiple CRL measurements in the same patient
Reference: Bottomley C ,Bourne T. Dating and
growth in the first trimester. Best Practice and
research Clin Obstet Gynaecol 2009 ; ESHRE
precongress course, Roma, 2010
Comparison of the CRL curve (solid line) with the Robinson
curve (dashdotted) and the Hadlock curve (dotted)
90
80
70
CRL (in mm)
60
50
40
30
20
10
0
40
50
60
70
GA (in days)
80
90
100
TV Ultrasound
Fetal loss with CRL =7mm
Embryoscopy – the close-up
H=head/heart prominence, Y=yolk sac, B=bubble
TVU – small embryonic structure in
disproportionately large sac
Embryoscopy – short body stalk with 6mm CRL
- cytogenetics = 47XY+7
microarrays
• technique
high resolution WHOLE genome scan
cytogenetics
FISH
arrays
• Trisomy 10 - TR
Karyotype = Normal Female
Array = Abnormal MALE result +10
FISH = confirmed +10 (70% MCC)
• 14q deletion - JS
Karyotype = Normal
Female
Array = Abnormal Female –
deletion 14q
FISH = confirm deletion in
11% of cells (89% MCC)
EPL & RM - Array CGH v St’d Cytogenetics
(McNamee et al, ESHRE abstract, Stockholm 2011)
Array CGH and
conventional
cytogenetics
N=62
Normal result
N=36(58%)
Abnormal result
N=26 (42%)
Conventional
cytogenetics
not
performed
N=6
Diagnosed with
conventional
cytogenetics
Missed with
N=12
N=8
NUMERICAL
+16 x2
+15 x2
+21 x2
+13 x2
+10
+14
-X x2
conventional
cytogenetics
NUMERICAL
+22♂ +10♂
+15♂ +8♀
+16♀
STRUCTURAL
>dup(22)(q11.2q11.2) ♂,
>del(14q)(q31.1)♀,t(1:q1
6)mat
>del(13q)12.3-q34
Commonest Complication - Miscarriage
Timeline Sequence of Early Pregnancy Events
Conservative or medical or surgical Rx
Patient choice and EBM
Opportunityisnowhere
Standards in Early Pregnancy
Standard CORE
Aspirational
Patient
Information
Designated Reception Area
Universal use of clear, understandable
terminology by all staff
Dedicated staff constantly at reception desk to provide greeting, obtain
patient details and explain structure and triage function of EPU
Patient Choice
In
Management
Education of patient relevant to diagnosis
and management
Open explanation of expectant, medical and
surgical options
Dedicated phone line for patient queries and electronic access to
protocols from outside unit
Dedicated Quiet
Room
Room for breaking bad news away from
work area
Single-use room only with soft furnishing and absence of medical
equipment
Availability of
Service
5 day opening during office hours
7/24 opening and service provision with full staffing and daily scan
support
Competence of
Scanning
Recognised ultrasound training and
preceptor assessment and validation
(RCOG/BMUS)
Register of staff competent at scanning
Lead Clinician Presence of RCOG/BMUS trainer in EPU
Annual assessment of audited activity
Standards in Early Pregnancy (2)
Blood HCG
level
measurement
Laboratory access to blood HCG
measurement and result within 48 hours
of sampling
Same day sampling and result with electronic result link to
laboratory
Written
Information
Leaflets
Visible open access to written information
leaflets in EPU
Online external access to PIL
Acknowledgment
To provide individualised patient support
and acknowledge confidentiality
Place one to one care as best practice at all times
Bereavement
Counselling
All staff trained in emotional aspects of
early pregnancy loss
To enable access to counselling and
provide immediate support
To provide all emotional and psychological counselling
requirements within EPU and supported by dedicated staff and
related agencies
Site of EPU
Geographically separate from all
maternity areas
Own EPU entrance/exit
of Privacy
and Dignity
Management of Miscarriage
RCOG Guideline 25, 2006
Early Pregnancy Unit
TVU Scan diagnosis
(confirmed by second observer)
Informed Choice
Appropriate Information
Patient Counselling
Efficient management
Medical
Expectant
Surgical
Misoprostol
+/- Mifepristone
24 hour access
to EPU
Planned elective
Evacuation of uterus
Infection 3%
Haemorrhage 6%
Infection 3%
Haemorrhage 2%
Uterine perforation 1.6%
Infection 2%
Haemorrhage 3%
Management of Early Pregnancy Loss
•
•
•
•
•
Formal meta-analysis is hampered by heterogeneity of the available studies on
various subjects, which often differ in the type of patients, setting, dosages and route
of administration, and time frames allowed in expectantly and medically managed
patients.
Surgical aspiration curettage results in the highest complete evacuation rate in
comparison to non-surgical management options.
Medical management (i.e. misoprostol PO or PV) reduces the need for curettage by
81% - 99%
Expectant management reduces the need for surgery by 28-94%, depending on the
type of pregnancy loss eg incomplete miscarriages, or those with a intact gestational
sac still present, and on the time frame of expectancy.
In view of the available evidence, non-invasive treatment modalities can now be
offered with confidence to women with first trimester pregnancy loss who wish to
avoid surgery. This is important, since freedom of treatment choice improves quality
of life in these unfortunate women
MIST trial: Design
•
•
Miscarriage < 13 wks
– empty gestational sac / no FCA (3/4)
– incomplete miscarriage (1/4)
Third party randomisation
•
Power calculation based on infection
– 10% in surgery = ½ incidence other Th/
– N = 3x 474 = 1422
•
Δ infection = 2 out of 4 criteria
1) purulent discharge
2) fever
3) painful uterus
4) L>15x109
•
Medical therapy
– Mifepristone 200mg p/o (empty sac)
– Misoprostol 800 μg (vag. after 1-2d)
– Curettage whenever no expulsion after 8 hrs
Trinder, J et al. BMJ 2006;332:1235-1240
Flow of patients through MIST trial
MIST RCTrial
Trinder, J et al. BMJ 2006;332:1235-1240
Copyright ©2006 BMJ Publishing Group Ltd.
Conclusions
Prostaglandins more effective than expectancy
• Reduced need for surgery
• Place in management?
– immediate at diagnosis
– delayed, after “failed” expectant management
• Dosage / Route?
– dose / interval
– oral / vaginal
– ± mifepristone
• Quality of life?
– preferences
– side effects
• Costs
– Expectant management
– Prostaglandins
– Surgery
UK
£1086*
£1410
£1585
NL
€ 915**
€ 1107
* Trinder et al. BMJ 2006;332:1235
•** Graziosi et al. Hum Reprod 2004;19:1894
•
prostaglandins vs expectant management
RCTs: succes = no curettage
Nielsen
Sweden ’99
N
49/60
N
46/60
25/30
14/29
17/27
5/27
Ngai
Hong Kong ’01
Kovavisarach
Bangkok ’02
Wood
Canada ’02
18/25
4/25
Herabutya
Bangkok ’97
35/42
6/42
46/52
23/52
221/398
256/398
Bagratee
UK ’04
Trinder
UK ’06
Mist-trial
20
40
60
80 % succes
References
•
•
•
Trinder J, Brocklehurst P, Porter R, Read M, Vyas S, Smith L. Management of
miscarriage: expectant, medical, or surgical? Results of randomised controlled trial
(miscarriage treatment (MIST) trial). BMJ 2006;332:1235-40.
Neilson JP, Hickey M, Vazquez J. Medical treatment for early fetal death (less
than 24 weeks) Cochrane Database of Syst Rev 2008 Issue 4.
Ankum WM. Management of first trimester miscarriage. Br J Hosp Med
2008;69:380-3.
The Patient’s Journey
• “It is always a good
thing to walk a mile in
another man’s shoes”
• Nelson Mandela
Long Walk to Freedom The view
from Robben Island Prison
The opportunity for EP care
• ‘A small
opportunity can
lead to great
enterprise’
Demosthenes of
Athens, 384-322 BC