Live-birth rates and multiple-birth risk using in-vitro fertilization


Schieve, L.A.; Peterson, H.B.; Meikle, S.F.; Jeng, G.; Danel, I.; Burnett, N.M.; Wilcox, L.S.

JAMA 282(19): 1832-1838

1999


Context: To maximize birth rates, physicians who perform in vitro fertilization (IVF) often transfer multiple embryos, but this increases the multiple-birth risk. Live-birth and multiple-birth rates may vary by patient age and embryo quality. One marker for embryo quality is cryopreservation of extra embryos (if embryos are set aside for cryopreservation, higher quality embryos may have been available for transfer). Objective: To examine associations between the number of embryos transferred during IVF and live-birth and multiple-birth rates stratified by maternal age and whether extra embryos were available (ie, extra embryos cryopreserved). Design and Setting: Retrospective cohort of 300 US clinics reporting IVF transfer procedures to the Centers for Disease Control and Prevention in 1996. Subjects: A total of 35 554 IVF transfer procedures. Main Outcome Measures: Live-birth and multiple-birth rates (percentage of live births that were multiple). Results: A total number of 9873 livebirths were reported (multiple births from 1 pregnancy were counted as 1 live birth). The number of embryos needed to achieve maximum live-birth rates varied by age and whether extra embryos were cryopreserved. Among women 20 to 29 years and 30 to 34 years of age, maximum live-birth rates (43% and 36%, respectively) were achieved when 2 embryos were transferred and extra embryos were cryopreserved. Among women 35 years of age and older, live-birth rates were lower overall and regardless of whether embryos were cryopreserved, live-birth rates increased if more than 2 embryos were transferred. Multiple-birth rates varied by age and the number of embryos transferred, but not by whether embryos were cryopreserved. With 2 embryos transferred, multiple-birth rates were 22.7%, 19.7%, 11.6%, and 10.8% for women aged 20 to 29, 30 to 34, 35 to 39, and 40 to 44 years, respectively. Multiple-birth rates increased as high as 45.7% for women aged 20 to 29 years and 39.8% for women aged 30 to 34 years if 3 embryos were transferred. Among women aged 35 to 39 years, the multiple-birth rate was 29.4% if 3 embryos were transferred. Among women 40 to 44 years of age, the multiple-birth rate was less than 25% even if 5 embryos were transferred. Conclusions: Based on these data, the risk of multiple births from IVF varies by maternal age and number of embryos transferred. Embryo quality was not related to multiple birth risk but was associated with increased live-birth rates when fewer embryos were transferred.

ORIGINAL
CONTRIBUTION
Live-Birth
Rates
and
Multiple-Birth
Risk
Using
In
Vitro
Fertilization
Laura
A.
Schieve,
PhD
Herbert
B.
Peterson,
MD
Susan
F.
Meikle,
MD
Gary
Jeng,
PhD
Isabella
Danel,
MD
Nancy
M.
Burnett,
BS
Lynne
S.
Wilcox,
MD
S
INCE
THE
GOAL
OF
IN
VITRO
FER-
tilization
(IVF)
is
pregnancy
and,
ultimately,
live
birth,
clinical
de-
cision
making
about
IVF
prac-
tices
is
heavily
focused
on
maximizing
a
woman's
chances
of
becoming
preg-
nant.
One
common
practice
that
aims
to
increase
the
likelihood
of
pregnancy
is
to
transfer
multiple
embryos
(often
more
than
3)
into
the
uterine
cavity.
This
treatment
approach
also
presents
an
im-
portant
drawback,
however,
because
it
increases
the
risk
for
multiple
birth.
Mul-
tiple-birth
infants
are
at
significant
risk
for
a
number
of
adverse
outcomes
in-
cluding
preterm
delivery,
low
birth
weight,
congenital
malformations,
fe-
tal
and
infant
death,
and
long-term
mor-
bidity
and
disability
among
survi-
vors.
1-5
Twins
are
5
times
as
likely,
and
triplet
and
higher-order
infants
13
times
as
likely,
as
singleton
infants
to
die
dur-
ing
the
first
year
of
life.'
To
curtail
the
multiple-birth
risk,
sev-
eral
countries
have
passed
legislation
that
limits
the
number
of
embryos
that
can
be
transferred
to
3.
6
'
7
Such
a
policy
is
not
universally
supported
as
it
runs
counter
to
the
expectation
of
au-
tonomy
in
the
patient-physician
rela-
tionship.
In
the
United
States,
the
is-
sue
of
embryo
transfer
has
thus
far
See
also
p
1813
and
Patient
Page.
Context
To
maximize
birth
rates,
physicians
who
perform
in
vitro
fertilization
(IVF)
often
transfer
multiple
embryos,
but
this
increases
the
multiple-birth
risk.
Live-birth
and
multiple-birth
rates
may
vary
by
patient
age
and
embryo
quality.
One
marker
for
embryo
quality
is
cryopreservation
of
extra
embryos
(if
embryos
are
set
aside
for
cryo-
preservation,
higher
quality
embryos
may
have
been
available
for
transfer).
Objective
To
examine
associations
between
the
number
of
embryos
transferred
dur-
ing
IVF
and
live-birth
and
multiple-birth
rates
stratified
by
maternal
age
and
whether
extra
embryos
were
available
(ie,
extra
embryos
cryopreserved).
Design
and
Setting
Retrospective
cohort
of
300
US
clinics
reporting
IVF
transfer
procedures
to
the
Centers
for
Disease
Control
and
Prevention
in
1996.
Subjects
A
total
of
35
554
IVF
transfer
procedures.
Main
Outcome
Measures
Live-birth
and
multiple-birth
rates
(percentage
of
live
births
that
were
multiple).
Results
A
total
number
of
9873
live
births
were
reported
(multiple
births
from
1
preg-
nancy
were
counted
as
1
live
birth).
The
number
of
embryos
needed
to
achieve
maximum
live-birth
rates
varied
by
age
and
whether
extra
embryos
were
cryopreserved.
Among
wom-
en
20
to
29
years
and
30
to
34
years
of
age,
maximum
live-birth
rates
(43%
and
36%,
respectively)
were
achieved
when
2
embryos
were
transferred
and
extra
embryos
were
cryopreserved.
Among
women
35
years
of
age
and
older,
live-birth
rates
were
lower
over-
all
and
regardless
of
whether
embryos
were
cryopreserved,
live-birth
rates
increased
if
more
than
2
embryos
were
transferred.
Multiple-birth
rates
varied
by
age
and
the
number
of
embryos
transferred,
but not
by
whether
embryos
were
cryopreserved.
With
2
embryos
transferred,
multiple-birth
rates
were
22.7%
,
19.7%,
11.6%,
and
10.8%
for
women
aged
20
to
29,
30
to
34,
35
to
39,
and
40
to
44
years,
respectively.
Multiple-birth
rates
increased
as
high
as
45.7%
for
women
aged
20
to
29
years
and
39.8%
for
women
aged
30
to
34
years
if
3
embryos
were
transferred.
Among
women
aged
35
to
39
years,
the
multiple-
birth
rate
was
29.4%
if
3
embryos
were
transferred.
Among
women
40
to
44
years
of
age,
the
multiple-birth
rate
was
less
than
25%
even
if
5
embryos
were
transferred.
Conclusions
Based
on
these
data,
the
risk
of
multiple
births
from
IVF
varies
by
ma-
ternal
age
and
number
of
embryos
transferred.
Embryo
quality
was
not
related
to
mul-
tiple
birth
risk
but
was
associated
with
increased
live-birth
rates
when
fewer
embryos
were
transferred.
!AMA.
1999;282:1832-1838
www.jama.com
remained
outside
the
legal
arena;
how-
ever,
the
American
Society
for
Repro-
ductive
Medicine
has
issued
practice
guidelines.
8
The
debate
about
embryo
limits
has
increasingly
focused
on
whether
to
consider
prognostic
fac-
tors
when
setting
guidelines,
particu-
larly
patient
age,
which
varies
in-
versely
with
a
woman's
chances
for
achieving
pregnancy.
8,1
°
Additionally,
as
studies
demonstrate
associations
be-
tween
various
markers
of
embryo
qual-
ity
and
implantation,
attention
has
fo-
cused
on
whether
such
data
can
be
Author
Affiliations:
Division
of
Reproductive
Health,
National
Center
for
Chronic
Disease
Prevention
and
Health
Promotion,
Centers
for
Disease
Control
and
Pre-
vention,
Atlanta,
Ga.
Corresponding
Authorand
Reprints:
Laura
A.
Schieve,
PhD,
Division
of
Reproductive
Health,
National
Cen-
ter
for
Chronic
Disease
Prevention
and
Health
Pro-
motion,
Centers
for
Disease
Control
and
Prevention,
Mailstop
K-34,
4770
Buford
Hwy
NE,
Atlanta,
GA
30341
(e-mail:
LJS9@cdc.gov).
1832
JAMA,
November
17,
1999—Vol
282,
No.
19
BIRTH
RATES
AND
MULTIPLE-BIRTH
RISK
USING
IVF
translated
into
policy
in
the
future.
Al-
though
current
grading
schemes
for
assessing
embryo
quality
have
limita-
tions,
both
embryo
morphology
grade
and
the
ability
to
select
embryos
for
transfer
have
been
associated
with
in-
creased
pregnancy
and
live-birth
rates
in
previous
studies."
-17
An
especially
provocative
study
that
used
population-
based
data
from
the
United
Kingdom
suggested
that
elective
transfer
of
2
rather
than
3
embryos
reduced
the
mul-
tiple-birth
risk
without
affecting
the
chance
of
live
birth
for
any
age
group."
To
determine
if
this
finding
is
sup-
ported
by
the
US
IVF
population,
we
used
a
population-based
dataset
of
IVF—
assisted
reproductive
technology
(ART)
cycles
initiated
in
US
clinics
in
1996
to
examine
associations
between
em-
bryo
number
and
pregnancy,
live-
birth,
and
multiple-birth
rates.
The
large
sample
afforded
us
an
opportunity
to
more
fully
explore
these
associations
by
examining
several
important
factors,
in-
cluding
patient
age
and
availability
of
extra
embryos
for
future
ART
cycles.
METHODS
Subjects
The
Fertility
Clinic
Success
Rate
and
Certification
Act
of
1992
requires
that
each
medical
center
performing
IVF
or
related
ARTs
report
data
for
each
ART
cycle
initiated
to
the
Centers
for
Dis-
ease
Control
and
Prevention
(CDC)
an-
nually
for
the
purpose
of
reporting
clinic-
specific
pregnancy
success
rates.
18
An
ART
cycle
is
considered
to
begin
when
a
woman
begins
taking
fertility
drugs
or
starts
ovarian
monitoring
with
the
in-
tent
of
having
embryos
transferred.
ART
centers
submit
data
obtained
from
clinic
records
for
each
cycle
initiated
during
a
given
reporting
year
(January
1
through
December
31)
in
a
standard-
ized
format.
The
datafile
is
organized
with
1
record
per
cycle.
Multiple
cycles
for
a
single
patient
are
not
linked.
Data
collected
include
patient
demograph-
ics,
medical
history
and
infertility
diag-
noses,
clinical
information
pertaining
to
the
ART
cycle,
and
information
on
re-
sultant
pregnancies
and
births.
The
first
full
year
for
which
the
CDC
collected
ART
data
was
1996.
In
1996,
300
US
centers
reported
more
than
60
000
ART
cycles
to
the
CDC.
Because
some
cen-
ters
did
not
report
their
data,
despite
the
federal
mandate,
this
number
does
not
represent
every
ART
cycle
performed
in
the
United
States;
however,
it
is
esti-
mated
that
data
on
more
than
95%
of
all
cycles
were
reported.
We
selected
fresh,
nondonor
IVF
cycles
for
inclusion
in
the
current
analysis
(N
=
44
723).
This
refers
to
cycles
in
which
eggs
were
removed
from
a
wom-
an's
ovaries,
combined
with
sperm,
and
if
fertilized,
the
resulting
embryo
(s)
was
replaced
into
the
same
woman's
uterus.
This
selection
excludes
cycles
in
which
embryos
derived
from
a
woman
serving
as
an
egg
donor
were
transferred
to
the
patient
(n
=
5162);
cycles
in
which
em-
bryos
derived
from
a
patient
were
trans-
ferred
into
another
woman
serving
as
a
gestational
carrier
or
surrogate
(n
=
688);
and
cycles
in
which
the
embryos
trans-
ferred
had
been
retrieved
and
fertilized
at
an
earlier
date,
frozen
via
cryopreser-
vation,
and
thawed
for
use
in
the
current
cycle
(n
=
9290).
It
also
excludes
cycles
in
which
embryos
or
oocytes
were
trans-
ferred
into
a
woman's
fallopian
tubes
rather
than
uterus
(n
=
4117),
cycles
in
which
embryos
were
transferred
to
both
the
uterus
and
the
fallopian
tubes
(n
=
619),
and
cycles
in
which
both
fresh
and
thawed
embryos
were
transferred
(n
=
125).
Because
these
cycle
types
may
vary
with
respect
to
implantation
and
pregnancy
rates,
and
also
with
respect
to
the
importance
of
various
prognostic
fac-
tors,
they
were
not
combined.
Separate
analysis
for
each
cycle
type
was
precluded
by
small
sample
sizes
in
many
key
sub-
groups.
Therefore,
this
analysis
is
re-
stricted
to
the
most
common
type
of
ART
treatment:
fresh,
nondonor
IVF.
Among
fresh,
nondonor
IVF
cycles
that
were
initiated
in
1996,
we
excluded
cycles
that
did
not
progress
to
embryo
transfer
(n
=
8890)
and
cycles
for
which
patient
age
was
either
missing
(n
=
79)
,
younger
than
20
years
(n
=
6),
or
older
than
44
years
(n
=
194).
Our
final
sample
included
35
554
fresh,
nondonor
IVF
cycles.
Because
these
cycles
were
lim-
ited
to
those
that
progressed
to
embryo
transfer,
this
number
actually
represents
35
554
IVF
transfer
procedures.
Definitions
of
IVF
Outcomes
We
defined
pregnancy
as
the
presence
of
1
or
more
gestational
sacs
observed
on
ultrasound
(with
or
without
the
pres-
ence
of
a
fetal
heart).
In
rare
instances
(<1%),
the
number
of
fetal
sacs
ob-
served
on
ultrasound
was
not
recorded
or
was
recorded
as
0,
but
a
pregnancy
outcome
was
recorded
(live
birth,
still-
birth,
spontaneous
abortion,
therapeu-
tic
abortion);
these
cycles
were
also
coded
as
pregnancies.
A
total
of
12
115
pregnancies
were
reported.
Since
ART
centers
do
not
routinely
treat
patients
beyond
the
first
trimester,
live
births
and
fetal
losses
later
than
the
first
trimester
were
based
on
verbal
or
written
reports
from
either
the
patient
or
her
obstetric
health
care
professional.
ART
centers
of-
ten
actively
follow-up
patients
to
ascer-
tain
pregnancy
outcome.
An
outcome
(live
birth,
stillbirth,
spontaneous
abor-
tion,
therapeutic
abortion)
was
re-
corded
for
all
but
457
(4%)
of
these
preg-
nancies.
A
total
of
9873
live-birth
deliveries
were
reported.
We
consid-
ered
each
live-birth
delivery
as
a
single
live
birth;
eg,
a
live-birth
delivery
of
trip-
lets
was
counted
as
1
live
birth.
We
classified
a
pregnancy
as
a
mul-
tiple
gestation
if
either
2
or
more
fetal
hearts
were
noted
on
an
early
ultra-
sound,
or
2
or
more
infants
were
born.
We
defined
multiple
gestation
based
on
the
more
stringent
criterion
of
fetal
hearts
(rather
than
number
of
sacs
only)
because
multiple
gestations
that
do
not
progress
to
fetal
hearts
are
generally
not
considered
to
be
clinically
relevant.
We
classified
a
live-birth
delivery
as
a
mul-
tiple
birth
if
2
or
more
fetuses
were
born
and
at
least
1
of
these
was
liveborn.
We
also
separately
examined
triplet
and
higher-order
gestations
and
triplet
and
higher-order
births.
Data
Analysis
We
categorized
each
IVF
procedure
ac-
cording
to
2
factors:
(1)
the
number
of
embryos
transferred
(1,
2,
3,
4,
5,
6,
or
and
(2)
patient
age
at
cycle
start
(20-29,
30-34,
35-39,
or
40-44
years).
JAMA,
November
17,
1999—Vol
282,
No.
19
1833
Table
1.
Percent
Distribution
of
In
Vitro
Fertilization
(IVF)
Transfer
Procedures
by
Patient
Age
and
Factors
Related
to
Patient
Medical
History
or
IVF
Procedure*
Patient
Age
at
IVF
Cycle
Start,
y
20-29
(n
=
4590)
30-34
(n
=12
774)
35-39
(n
=
13
174)
40-44
(n
=
5016)
Previous
pregnancies,
No.
0
64.2
54.3
44.5
38.1
1
19.6
24.4
26.1
25.4
2
9.0
11.1
15.0
15.3
>3
7.1
10.2
14.4
21.2
Previous
live
births,
No.
0
88.0
82.0
74.8
70.3
8.9
13.6
18.1
20.2
3.0
4.4
7.1
9.5
Previous
IVF
cycle,
No.
0
70.7
59.4
53.9
48.2
1
17.4
21.3
22.3
23.3
2
7.4
10.4
11.6
12.7
4.5
8.9
12.3
15.7
Primary
infertility
diagnosis
Endometriosis
12.2
16.3
14.9
12.2
Tubal
factor
32.3
32.5
34.5
27.1
Male
factor
33.8
27.8
25.2
22.4
Ovulatory
dysfunction
11.5
9.8
8.6
11.9
Uterine
factor
0.7
1.2
1.9
3.4
Idiopathic
infertility
4.3
6.5
7.6
9.9
Other
5.1
5.9
7.2
13.2
Embryos
transferred,
No.
1
3.4
4.4
6.6
10.3
2
8.9
8.6
10.8
14.6
3
33.2
28.0
18.4
17.1
4
33.2
34.3
34.0
20.7
5
12.0
14.3
17.4
18.3
6
6.4
7.4
8.6
11.4
>7
2.9 3.0
4.2
7.5
Cryopreservation
of
embryos
retrieved
during
cycle
No
56.4
63.0
74.5
89.3
Yes
43.6
37.0
25.5
10.7
Use
of
intracytoplasmic
sperm
injection
No
56.1
61.1
63.0
66.1
Yes,
with
some
embryos
9.3
8.5
7.6
5.0
Yes,
with
all
embryos
34.6
30.4
29.5
29.0
Use
of
assisted
hatching
No
72.9
69.0
56.4
38.4
Yes,
with
some
embryos
6.7
8.1
10.4
12.0
Yes,
with
all
embryos
20.4
22.9
33.2
49.6
*P<.01,
X
2
to
test
for
differences
in
distributions
by
age.
Sample
size
was
reduced
for
some
analyses
due
to
missing
values;
maximum
number
of
missing
values
was
3.5%
for
intracytoplasmic
sperm
injection.
BIRTH
RATES
AND
MULTIPLE-BIRTH
RISK
USING
IVF
Within
each
age-embryo
number
stra-
tum,
we
present
the
percentages
of
live
births
per
transfer
procedure,
mul-
tiple
births
per
live
birth,
triplet
or
higher-order
births
per
live
birth,
and
triplet
or
higher-order
gestations
per
pregnancy.
We
present
both
triplet-
birth
and
triplet-gestation
rates
be-
cause
these
rates
were
not
parallel;
trends
for
triplet
and
higher-order
birth
rates
were
often
less
pronounced
than
trends
for
triplet
and
higher-order
ges-
tation
rates.
In
addition
to
embryo
number
and
patient
age,
we
examined
the
effects
of
potential
markers
of
patient
prognosis,
embryo
quality,
and
clinic
success.
We
evaluated
trends
in
live-birth
and
mul-
tiple-birth
rates
after
additionally
strati-
fying
on
several
such
factors.
These
in-
cluded
previous
pregnancies,
previous
live
births,
number
of
previous
ART
cycles,
primary
infertility
diagnosis,
use
of
intracytoplasmic
sperm
injection
(a
technique
used
often
in
male-factor
in-
fertility
in
which
a
single
sperm
is
directly
injected
into
the
oocyte),
use
of
assisted
hatching
(use
of
chemicals,
lasers,
or
me-
chanical
means
to
create
an
opening
in
the
zona
pellucida),
and
whether
1
or
more
embryos
that
were
retrieved
and
fertilized
during
the
current
cycle
were
cryopreserved
for
use
in
later
cycles.
The
availability
of
extra
embryos
for
cryo-
preservation
indicates
that
more
embryos
were
available
for
transfer
than
were
ac-
tually
transferred
and
therefore
the
em-
bryos
transferred
were
electively
chosen;
this
variable
may
be
a
surrogate
for
em-
bryo
quality.
Embryo
cryopreservation
has
been
used
since
the
early
1980s
and
is
now
a
standard
component
of
most
ART
programs.
However,
because
whether
or
not
extra
embryos
are
cryo-
preserved
is
a
function
of
patient
choice
as
well
as
embryo
availability
and
clini-
cal
assessment,
the
cryopreserved
vari-
able
is
a
nonspecific
marker.
Finally,
we
examined
all
results
after
stratification
by
clinic-level
characteristics.
We
clas-
sified
each
clinic
as
having
a
pregnancy
rate
above
or
below
the
mean
pregnancy
rate
for
all
clinics
combined.
We
analo-
gously
classified
clinics
as
having
high
or
low
age-specific
pregnancy
rates.
We
stratified
trends
in
live-birth
rates
and
multiple-birthrates
according
to
whether
a
cycle
was
performed
in
a
clinic
with
low
or
high
overall
and/or
age-specific
pregnancy
rates.
For
all
analyses,
the
statistical
signifi-
cance
of
differences
in
rates
between
cat-
egories
was assessed
with
x
2
tests.
This
research
was
approved
by
the
in-
stitutional
review
board
at
the
CDC.
RESULTS
Patient
medical
history
and
IVF
pro-
cedural
factors
varied
significantly
by
patient
age
(TABLE
1)
.
Both
previous
1834
JAMA,
November
17,
1999-Vol
282,
No.
19
BIRTH
RATES
AND
MULTIPLE-BIRTH
RISK
USING
IVF
pregnancies
and
previous
live
births
in-
creased
with
each
successive
increase
in
patient
age.
Older
women
were
also
more
likely
to
have
undergone
IVF
pre-
viously;
younger
women
were
more
likely
to
be
diagnosed
as
having
infer-
tility
related
to
tubal
or
male
factors.
The
distribution
of
the
number
of
em-
bryos
transferred
also
varied
by
age;
older
women
were
more
likely
to
be
in
both
of
the
outlying
categories
(1
or
embryos
transferred)
than
women
in
the
younger
age
groups.
Additionally,
use
of
both
cryopreservation
for
extra
embryos
and
intracytoplasmic
sperm
injection
declined
with
age,
while
use
of
assisted
hatching
procedures
in-
creased.
Pregnancy
rates
declined
from
41%
among
women
aged
20
to
29
years
to
20%
among
women
aged
40
to
44
years.
Live-birth
rates
declined
from
35%
to
13%
in
these
same
categories.
In
addi-
tion
to
age,
live-birth
rates
varied
sig-
nificantly
by
the
number
of
embryos
transferred
(TABLE
2).
Among
the
2
youngest
age
groups,
the
live-birth
rate
increased
considerably
with
increas-
ing
number
of
embryos
transferred
up
to
3;
beyond
3
embryos,
there
was
no
additional
increase
and,
in
fact,
de-
clines
were
noted
in
a
few
categories.
Among
women
aged
35
to
39
years,
the
live-birth
rate
continued
to
increase
with
up
to
4
embryos
transferred
and
then
declined
slightly.
Among
women
aged
40
to
44
years,
the
live-birth
rate
continued
to
increase
with
up
to
5
em-
bryos
transferred.
However,
even
at
this
maximum
rate,
the
live-birth
rate
among
women
in
the
oldest
age
group
was
still
substantially
lower
than
the
maximum
rate
observed
among
women
in
the
youngest
age
group
(20.3%
vs
37.7%).
Similar
patterns
were
observed
for
multiple
births,
triplet
and
higher-
order
gestations,
and
triplet
and
higher-
order
births.
In
general,
younger
women
were
at
greater
risk
for
each
of
these
outcomes
given
the
same
num-
ber
of
embryos
transferred.
Among
women
aged
20
to
29
years,
the
pro-
portion
of
live
births
that
were
mul-
tiple
increased
substantially
with
each
embryo
transferred
up
to
3
when
it
reached
46%.
The
multiple-birth
rate
continued
to
increase
beyond
3
em-
bryos,
although
the
magnitude
of
the
increase
was
much
smaller.
Among
women
aged
30
to
34
years
and
35
to
39
years,
increases
in
the
multiple-
birth
rate
were
observed
with
up
to
4
embryos
transferred
(45%
and
38%
for
women
aged
30-34
years
and
35-39
years,
respectively).
Increases
in
the
multiple-birth
rate
among
women
aged
40
to
44
years
were
less
striking
and
did
not
reach
the
high
levels
noted
for
other
groups
until
7
or
more
embryos
were
transferred
(39%).
The
triplet-gestation
and
triplet-
birth
rates
were
substantially
elevated
among
women
in
the
2
youngest
age
groups
when
3
or
more
embryos
were
transferred.
Among
women
20
to
29
years
of
age
with
3
embryos
trans-
ferred,
the
triplet-gestation
and
triplet-
birth
rates
both
reached
10%.
Among
women
30
to
34
years
of
age
with
3
em-
bryos
transferred,
the
triplet-gestation
rate
reached
10%;
the
triplet-birth
rate
was
near
7%.
Among
women
40
years
of
age
or
older,
the
risk
for
triplets
was
greatly
reduced;
both
triplet-gestation
and
triplet-birth
rates
were
less
than
2%
when
4
embryos
were
transferred
and
less
than
5%
when
5
embryos
were
transferred.
Triplet
rates
among
women
aged
35
to
39
years
were
intermediate
between
the
younger
and
older
age
groups.
The
basic
patterns
in
live-birth
and
multiple-birth
rates
apparent
in
Table
2
persisted
after
further
stratification
on
previous
pregnancies,
previous
live
births,
previous
ART
cycles,
infertility
diagnosis,
use
of
intracytoplasmic
sperm
injection,
use
of
assisted
hatch-
ing,
and
clinic-level
pregnancy
and
age-
specific
pregnancy
rates
(data
not
shown).
For
all
age
groups,
however,
trends
in
live-birth
rates
varied
mark-
edly
between
cycles
in
which
1
or
more
embryos
had
been
cryopreserved
and
cycles
in
which
no
embryos
were
cryo-
preserved
(TABLE
3).
Women
in
the
cryopreserved
group
achieved
higher
live-birth
rates
with
fewer
embryos
transferred.
Among
women
aged
20
to
29
years
and
30
to
34
years,
those
with
cryopreserved
embryos
achieved
live-
birth
rates
of
43%
and
36%,
respec-
tively,
when
2
embryos
were
trans-
ferred;
these
rates
were
more
than
double
the
rates
observed
among
women
in
these
age
groups
for
whom
2
embryos
were
transferred
and
no
em-
bryos
were
cryopreserved.
Further,
among
the
cryopreserved
group,
live-
birth
rates
were
not
significantly
greater
when
3
or
more
embryos
were
trans-
ferred
than
when
2
embryos
were
trans-
ferred.
Among
women
aged
35
to
39
years,
live-birth
rates
were
substan-
tially
increased
for
both
2
and
3
em-
bryo
transfers
(25%
and
33%,
respec-
tively)
when
additional
embryos
were
cryopreserved.
Among
women
aged
40
to
44
years,
the
cryopreserved
group
achieved
notably
higher
live-birth
rates
when
3
embryos
were
transferred
(19%)
;
additionally,
the
live-birth
rate
continued
to
increase
slightly
when
more
than
3
embryos
were
transferred
(24%
with
5
embryos).
Among
all
age
groups,
small
sample
sizes
impeded
evaluation
of
procedures
in
which
1
em-
bryo
was
transferred
and
additional
em-
bryos
were
cryopreserved;
among
women
aged
40
to
44
years,
there
were
also
too
few
procedures
in
which
2
em-
bryos
were
transferred
and
additional
embryos
were
cryopreserved.
Al-
though
whether
embryos
were
cryo-
preserved
had
a
large
impact
on
live-
birth
rates,
trends
in
multiple-birth
rates
did
not
vary
by
the
cryopreserved
vari-
able.
Within
each
age
group,
the
trends
in
multiple
birth
presented
in
Table
2
were
similar
to
both
the
trends
in
mul-
tiple
birth
among
women
with
1
or
more
embryos
cryopreserved
and
the
trends
among
women
with
no
em-
bryos
cryopreserved
(data
not
shown).
COMMENT
Since
the
first
successful
IVF
procedure
in
1978,
19
the
field
of
ART
has
grown
rap-
idly.
In
the
United
States
alone,
more
than
60
000
ART
cycles
were initiated
in
1996,
which
resulted
in
more
than
17
000
clinical
pregnancies
and
more
than
14
000
live
births.
2
°
The
majority
of
these
were
achieved
using
fresh,
non-
JAMA,
November
17,
1999—Vol
282,
No.
19
1835
Table
2.
Key
Indicators
of
Live
Birth
and
Multiple
Birth
by
Number
of
Embryos
Transferred
and
Patient
Age
Age,
y
Embryos
Transferred,
No.
1
2
3
4
5
6
20-29
10.4
Live
Births
per
In
Vitro
Fertilization
Transfer
Procedure,
23.7*
37.7*
37.3
36.6
37.5
31.3
30-34
9.1
19.4*
35.1*
36.4
33.0t
34.6
28.61
35-39
6.3
14.0*
23.0*
33.3*
29.8*
30.1
28.3
40-44
2.1
5.0*
8.3f
14.4*
20.3*
20.2
15.1t
20-29
Multiple
Births
per
Live
Birth,
%
22.71
45.7*
48.1
47.8
54.6
50.0
30-34
19.7*
39.8*
45
.4*
44.1
48.0
50.0
35-39
11.61
29.4*
37.5*
38.4
42.4 42.4
40-44
10.8
11.3
20.0
24.6
24.1
38.6t
20-29
Triplet
or
Higher
Gestations
per
Pregnancy,
13.0*
18.1t
17.9
24.0
24.5
30-34
10.8*
15.8*
17.4
23.21
18.8
35-39
4.0*
11.5*
13.4
16.31
22.3
40-44
0
1.8
4.2
5.9
12.5
20-29
Triplet
or
Higher-Order
Births
per
Live
Birth,
%
9.9*
12.0
10.5
16.4
7.1
30-34
6.7*
10.0*
8.8
9.5
10.2
35-39
2.2t
5.4*
6.5
8.5
11.4
40-44
0
0.7
2.1
0.9
5.3
*P<.01
for
comparison
between
the
proportion
in
a
given
embryo
category
to
the
proportion
in
the
preceding
embryo
category
within
the
same
age
group.
tP<.05
for
comparison
between
the
proportion
in
a
given
embryo
category
to
the
proportion
in
the
preceding
embryo
category
within
the
same
age
group.
Table
3.
Live-Birth
Rate
by
Number
of
Embryos
Transferred,
Patient
Age,
and
Whether
Extra
Embryos
Were
Cryopreserved
for
Later
Use
Embryos
Transferred,
No.
2
3
4
5
6
Age
20-29
y
0
embryos
cryopreserved
17.9
34.3*
34.2
34.1
35.4
28.3
embryos
cryopreserved
42.7
41.1
40.3
40.5
40.0
42.9
Age
30-34
y
0
embryos
cryopreserved
17.2
30.4* 34.3*
30.31
33.3
28.5
embryos
cryopreserved
36.0
41.5
38.8
38.0
37.1
28.8
Age
35-39
y
0
embryos
cryopreserved
13.3
19.9*
30.8*
28.6
29.3
27.6
embryos
cryopreserved
24.7
33.0
37.61
33.2
31.9
32.9
Age
40-44
y
0
embryos
cryopreserved
5.1
7.7f
13.8*
19.6*
18.8
14.8
embryos
cryopreserved
18.8
17.5
24.0
25.9
18.4
*P<.01
for
comparison
between
the
proportion
in
a
given
embryo
category
to
the
proportion
in
the
preceding
embryo
category
within
the
same
age-cryopreserved
group.
tP<.05
for
comparison
between
the
proportion
in
a
given
embryo
category
to
the
proportion
in
the
preceding
embryo
category
within
the
same
age-cryopreserved
group.
BIRTH
RATES
AND
MULTIPLE-BIRTH
RISK
USING
IVF
donor
IVF
treatments.
We
examined
these
population-based
data,
and
in
keeping
with
prior
studies,
11-17
'
21-23
we
found
that
3
factors-patient
age,
num-
ber
of
embryos
transferred,
and
the
abil-
ity
to
select
embryos
for
transfer-had
a
pronounced
effect
on
the
success
of
an
IVF
procedure
and
the
risk
for
mul-
tiple
birth.
The
large
sample
size
al-
lowed
us
to
explore
the
interrelation-
ships
between
these
3
factors.
Although
we
did
not
have
specific
laboratory
data
to
classify
embryo
qual-
ity,
we
found
that
among
women
younger
than
35
years,
when
the
num-
ber
of
embryos
transferred
was
elec-
tively
limited
to
2,
as
indicated
by
1
or
more
available
embryos
being
cryopre-
served,
the
live-birth
rates
achieved
were
comparable
to
those
achieved
with
transfer
of
3
embryos;
however,
the
multiple-birth
risk
was
halved
and
the
risk
for
triplet
and
higher-order
preg-
nancies
and
births
was
virtually
elimi-
nated.
In
contrast,
women
aged
35
to
39
years
appeared
to
receive
some
ben-
efit
from
elective
transfer
of
3
rather
than
2
embryos;
although
not
statisti-
cally
significant
at
the
.05
level,
the
live-
birth
rate
increased
by
8
percentage
points.
While
multiple-birth
rates
were
also
increased
with
3
embryos
trans-
ferred
(29.4%),
these
risks
were
much
smaller
than
those
seen
in
women
aged
20
to
29
years
with
3
embryos
trans-
ferred
(45.7%).
There
were
too
few
pro-
cedures
to
compare
elective
transfer
of
2
vs
3
embryos
among
women
aged
40
to
44
years;
however,
we
observed
a
trend
of
increasing
birth
rates
with
elec-
tive
transfer
of
up
to
5
embryos.
Addi-
tionally,
the
multiple-birth
rate
among
women
aged
40
to
44
years
with
5
em-
bryos
transferred
(24.6%)
was
compa-
rable
to
the
multiple-birth
rate
seen
among
women
aged
20
to
29
years
with
only
2
embryos
transferred
(22.7%)
and
the
triplet-birth
rate
was
relatively
low
at
2.1%.
When
embryos
were
not
cryopre-
served,
we
observed
increases
in
the
live-birth
rate
when
up
to
3
embryos
were
transferred
for
women
aged
20
to
29
years
and
30
to
34
years,
when
up
to
4
embryos
were
transferred
for
women
aged
35
to
39
years,
and
when
up
to
5
embryos
were
transferred
for
women
aged
40
to
44
years.
The
in-
creased
embryo
number
needed
to
maximize
success
rates
for
women
younger
than
40
years
also
presented
important
drawbacks,
however,
as
com-
mensurate
increases
in
multiple-
and
triplet-birth
rates
were
noted.
Our
findings
for
patients
younger
than
35
years
are
supported
by
prior
studies,
11
'
12
'
14
'
15
'
17
most
notably
the
analysis
of
the
British
IVF
registry
by
Templeton
and
Morris."
This
popula-
tion-based
study
of
British
IVF
cycles
found
that
when
more
than
4
eggs
had
1836
JAMA,
November
17,
1999-Vol
282,
No.
19
BIRTH
RATES
AND
MULTIPLE-BIRTH
RISK
USING
IVF
been
fertilized,
the
odds
of
a
live
birth
were
no
different
with
elective
trans-
fer
of
2
embryos
compared
with
elec-
tive
transfer
of
3
embryos;
however,
the
multiple-birth
risk
was
increased
when
3
embryos
were
transferred.
Although
our
findings
among
patients
older
than
35
years
are
supported
by
a
previous
clinical
study,'
our
results
for
this
age
group
are
not
consistent
with
the
Brit-
ish
data.
While
we
noted
an
improve-
ment
in
the
birth
rate
among
women
aged
35
to
39
years
with
elective
trans-
fer
of
3
embryos,
the
British
study
showed
no
difference
in
live-birth
rates
between
elective
transfer
of
2
and
elec-
tive
transfer
of
3
embryos.
Differences
in
IVF
practice
between
the
United
Kingdom
and
the
United
States
might
partially
explain
the
dis-
parity
between
our
results
and
the
Brit-
ish
data.
The
United
Kingdom
limits
the
number
of
embryos
transferred
to
3,
6
while
in
the
United
States
it
is
not
un-
common
to
transfer
4,
5,
or
even
6
em-
bryos,
particularly
in
women
aged
35
years
or
older.
Thus,
even
in
the
elec-
tive
transfer
group,
differential
deci-
sion
making
by
US
and
UK
practition-
ers
about
whether
to
transfer
2,
3,
or
more
embryos
in
women
35
years
of
age
or
older
may
have
affected
comparabil-
ity
between
patients
included
in
vari-
ous
embryo-number
groups.
In
fact,
in
the
United
States,
there
were
very
few
cycles
among
women
aged
40
years
or
older
in
which
embryo
transfer
had
been
electively
limited
to
2.
Although
this
ren-
dered
us
unable
to
compare
elective
transfer
of
2
and
elective
transfer
of
3
em-
bryos
for
this
oldest
age
group,
we
were
able
to
examine
elective
transfer
of
higher
numbers
of
embryos
and
found
that
live-birth
rates
improved
when
more
than
3
embryos
were
transferred,
whether
or
not
additional
embryos
had
been
cryopreserved.
Embryo
transfers
beyond
3
could
not
be
evaluated
with
the
British
data.
A
further
difference
between
the
2
studies
is
the
definition
of
elective
trans-
fer.
We
defined
elective
transfer
on
the
basis
of
whether
embryos
had
been
cryo-
preserved,
whereas
the
comparable
cat-
egory
in
the
British
study
was
based
on
the
number
of
embryos
fertilized.
Our
definition
may
have
been
a
more
spe-
cific
indicator
of
embryo
quality
as
not
only
did
an
excess
of
fertilized
em-
bryos
need
to
be
available,
but
1
or
more
of
them
had
to
be
deemed
acceptable
for
cryopreservation.
Thus,
our
cryopre-
served
group
may
have
represented
a
more
select
group
of
cycles.
If
this
is
true,
it
also
follows
that our
group
of
cycles
for
which
no
embryos
were
cryopre-
served
included
a
heterogeneous
mix
of
cycles.
That
is,
our
"nonelective
trans-
fer"
group
included
cycles
for
which
em-
bryo
transfer
was
truly
limited
because
additional
embryos
were
not
available,
as
well
as
cycles
in
which
additional
em-
bryos
that
were
available
for
transfer
were
neither
transferred
nor
cryopre-
served
for
any
number
of
reasons
re-
lated
to
clinical
assessment
and
prac-
tice
or
patient
choice.
We
do
not
have
data
on
the
number
of
embryos
fertil-
ized
and
therefore
cannot
subdivide
this
group
further.
The
unit
of
analysis
for
this
study
was
the
IVF
transfer
procedure.
Women
who
underwent
more
than
1
transfer
procedure
in
1996
are
therefore
repre-
sented
in
multiple
procedures.
Al-
though
we
did
not
have
the
necessary
data
to
link
cycles
from
the
same
woman,
we
did
have
medical
history
data
for
each
procedure,
including
whether
a
woman
had
undergone
pre-
vious
ART
cycles
(in
1996
or
earlier).
Therefore,
we
repeated
our
analysis
af-
ter
limiting
the
sample
to
women
who
were
undergoing
their
first
cycle
and
found
no
difference
in
comparison
to
our
original
findings
(data
not
shown).
We
focused
this
presentation
on
the
most
relevant
outcomes,
live
birth
and
multiple
birth.
We
also
examined
the
more
proximal
outcomes,
pregnancy
and
multiple-gestation
pregnancy.
Be-
cause
the
trends
observed
for
live-
birth
rates
and
multiple-birth
rates
were
parallel
to
the
trends
for
pregnancy
rates
and
multiple-gestation
rates,
respec-
tively,
we
presented
only
the
former
here.
However,
because
trends
for
trip-
let-gestation
rates
were
in
some
in-
stances
more
pronounced
than
triplet-
birth
rates,
we
presented
both.
The
differences
in
the
pattern
of
results
for
triplet
gestation
and
birth
rates
may
re-
flect
an
effect
due
to
spontaneous
or
therapeutic
fetal
reduction.
Patients
and
health
care
professionals
may
con-
sider
being
faced
with
the
choice
of
therapeutic
fetal
reduction
as
an
addi-
tional
undesirable
consequence
of
a
triplet
or
greater
gestation.
The
trends
in
triplet-gestation
rates
provide
an
in-
dication
of
the
total
triplet
risk—the
po-
tential
for
having
a
triplet
birth
with
as-
sociated
infant
and
maternal
health
risks
and
the
potential
of
being
faced
with
the
decision
for
a
therapeutic
re-
duction.
The
trends
in
triplet-birth
rates
provide
a
sense
of
the
realized
public
health
impact
of
triplets
in
1996.
This
study
was
based
on
observa-
tional
data.
Although
we
were
able
to
stratify
on
age
and
availability
of
em-
bryos
for
transfer,
we
cannot
com-
pletely
discount
the
possibility
that
women
who
had
3
embryos
trans-
ferred
had
poorer
quality
embryos
than
those
who
had
2
embryos
transferred
or
differed
on
some
other
unmea-
sured
determinant
of
success.
Given
the
limitations
of
current
embryo
grading
methods,
only
a
large
randomized
trial
would
ensure
complete
comparability
between
women
with
different
num-
bers
of
embryos
transferred.
Although
these
findings
are
based
on
observational
data,
they
strongly
sug-
gest
that
embryo
transfer
can
be
lim-
ited
in
many
women
undergoing
IVF,
thereby
reducing
the
risk
of
multiple
birth
without
reducing
the
chance
of
pregnancy
and
live
birth.
Adverse
fe-
tal
and
infant
outcomes
associated
with
multiple
pregnancy
and
birth
have
been
identified
as
the
greatest
potential
haz-
ard
associated
with
IVF
therapies.
As
technology
advances,
we
look
to
de-
velopments
in
embryo
culture
tech-
niques,
such
as
blastocyst
culture,
to
eliminate
the
need
for
high-order
em-
bryo
transfers
for
all
age
groups.
24
Un-
til
then,
however,
persons
undergoing
IVF
and
their
physicians
need
to
care-
fully
consider
the
trade-offs
between
benefit
and
risk
in
deciding
how
many
embryos
to
transfer.
This
is
particu-
larly
critical
for
younger
patients.
JAMA,
November
17,
1999—Vol
282,
No.
19
1837
BIRTH
RATES
AND
MULTIPLE-BIRTH
RISK
USING
IVF
Funding/Support:
The
data
used
for
this
study
were
collected
as
part
of
the
Assisted
Reproductive
Tech-
nology
reporting
system.
This
system
is
jointly
sup-
ported
by
the
Centers
for
Disease
Control
and
Pre-
vention,
Atlanta,
Ga;
the
Society
for
Assisted
Reproductive
Technology
(SART),
Birmingham,
Ala;
the
American
Society
for
Reproductive
Medicine
(ASRM),
Birmingham,
Ala;
and
RESOLVE,
the
Na-
tional
Infertility
Association,
Somerville,
Mass.
Acknowledgment:
We
are
grateful
to
SART,
ASRM,
and
RESOLVE,
without
whose
contribution
this
work
would
not
have
been
possible.
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November
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1999-Vol
282,
No.
19