Ultrasound Obstet Gynecol 2014; 43: 25–33

Published online 2 December 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12566

Ultrasound for monitoring controlled ovarian stimulation:

a systematic review and meta-analysis of randomized
controlled trials
W. P. MARTINS*†, C. V. R. VIEIRA*, D. M. TEIXEIRA*, M. A. P. BARBOSA*, L. A. DASSUNÇÃO*
and C. O. NASTRI*†
*Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil;
†Ultrasonography and Retraining Medical School of Ribeirao Preto (EURP), Ribeirao Preto, Brazil

K E Y W O R D S: assisted reproduction techniques; ovulation induction; ultrasonography

ABSTRACT similar or less effective than ultrasonography combined

Objective To evaluate the efficacy and safety of moni-
toring controlled ovarian stimulation (COS) using ultra-
sonography.
Methods We performed a search in April 2013 for ran-
domized controlled trials (RCTs). Studies that compared
different methods for monitoring COS, including ultra-
sound assessment of follicles (alone or combined with
hormonal assessment), in at least one group were consid-
ered eligible.
Results The search retrieved 1515 records, six of which
were eligible. Five studies were included that compared
ultrasonography alone with ultrasonography and hor-
monal assessment (estradiol and/or progesterone) and
one study compared 2D and 3D ultrasound monitoring.
None of the included studies reported on live birth. Four
of the five studies reported on clinical pregnancy (RR,
0.95; 95% CI, 0.78–1.16; n = 611); the confidence inter-
val (CI) was somewhat wide, but allowed us to conclude
that ultrasonography alone differs little from ultrasono-
graphy combined with hormonal assessment. Three stud-
ies reported on the number of oocytes retrieved (mean
difference (MD), 0.8 oocytes; 95% CI, –0.4 to 2.0;
n = 474); the CI was somewhat wide and did not per-
mit us to conclude whether ultrasonography alone is
better than or similar to ultrasonography and hormonal
assessment for this outcome. All five studies reported on
ovarian hyperstimulation syndrome (OR, 1.02; 95% CI,
0.47–2.25; n = 725) and only one study reported on mis-
carriage (RR, 0.37; 95% CI, 0.07–1.79; n = 45); for these
two outcomes, the CI was very wide and did not permit
us to conclude whether ultrasonography alone is better,
with hormonal assessment. For the study comparing 2D
and 3D ultrasound, the reported outcomes were clinical
pregnancy (RR, 1.00; 95% CI, 0.58–1.73, n = 72) and
the number of oocytes retrieved (MD, –0.4 oocytes; 95%
CI, –3.6 to 2.9; n = 72); for both, the CI was very wide
and did not permit us to conclude whether use of 3D ultra-
sound is better, similar or less effective than use of 2D
ultrasound.
Conclusions Current evidence suggests that monitoring
COS only with ultrasonography is unlikely to substan-
tially alter the chances of achieving a clinical pregnancy
and the number of oocytes retrieved is similar to that
when monitoring with ultrasonography and hormonal
assessment. For the other outcomes and comparisons,
the available data are inconclusive. We believe that more
studies evaluating the optimal procedure for monitoring
COS are needed. Copyright  2013 ISUOG. Published
by John Wiley & Sons Ltd.
INTRODUCTION
Assisted reproductive techniques (ART) are widely
used for treatment of infertility/subfertility1,2 . These
procedures include in-vitro handling of both human
oocytes and sperm or of embryos, with the objective of
achieving pregnancy and live birth3 . In order to optimize
the results of ART, recruitment of multiple follicles
is often necessary and this is achieved by controlled
ovarian stimulation (COS)4,5 . The estimated pregnancy
rate per cycle using standard COS is approximately
30%6 , but when using minimal ovarian stimulation, the
pregnancy rate per cycle is lower, approximately 10%7 .

Correspondence to: Dr W. P. Martins, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao
Paulo (FMRP-USP), Av. Bandeirantes, 3900 - 8 andar - HCRP - Campus Universitario, Ribeirao Preto, Sao Paulo 14048-900, Brazil
(e-mail: wpmartins@gmail.com)
Accepted: 8 July 2013

Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd. SYSTEMATIC REVIEW
26
Such a difference highlights the relevance of COS for
the success of ART. However, using standard COS to
obtain more follicles, there is an increased risk of ovarian
hyperstimulation syndrome (OHSS)8,9 .
Counting ovarian follicles and measurement by ultra-
sonography, and/or hormonal assessment, particularly
of serum estradiol concentration, are frequently used
for monitoring COS. When monitoring COS, clinicians
are able to make decisions on: (1) early cancellation of
cycles without proper ovarian response, thus avoiding
unnecessary waste of resources; (2) the most appropriate
time to trigger final follicular maturation, to maximize the
number of retrieved mature oocytes; and (3) assessment
of the risk of OHSS, which is useful when considering
some recent strategies, e.g. using cabergoline10 or
replacement of human chorionic gonadotropin (hCG)
by a gonadotropin-releasing hormone (GnRH) agonist
to trigger final follicular maturation8,11 . Combining
ultrasonography and hormonal assessment can poten-
tially provide the clinician with more information,
thereby reducing poor decision-making that can arise
from errors using a single method. However, the
need for intensive monitoring of COS is controversial;
the combination of methods is more time-consuming
and expensive and associated with a greater level
of discomfort for the patient.
Three-dimensional (3D) ultrasonography is also being
used to monitor COS. The assessment of follicle dimen-
sions was described in the mid-1990s12 . More recently,
the semiautomated measurement of follicle volume or
diameter by 3D ultrasound (sonography-based automated
volume count (SonoAVC)) has been investigated13 . This
method was shown to have good agreement with con-
ventional ultrasonography and requires less time14 , thus
being particularly advantageous when there are several
follicles15 . Two other potential advantages are: first, using
the volume-based diameter instead of an average of differ-
ent diameters, thus reducing variability of measurements
in non-spherical follicles, and second, reducing the chance
of missing or double-counting follicles.
Given that the benefits of monitoring COS are well
established in the literature and vigilant monitoring is
practiced worldwide, the most appropriate method should
be sought. So far, recommendations are ambiguous. In the
last published systematic review and meta-analysis16 the
authors did not find evidence that combined monitoring
for COS is better than monitoring by ultrasonography
alone for live birth and clinical pregnancy; however,
they suggested using combined monitoring for COS as
precautionary good practice, since evidence of prevention
of OHSS was not properly evaluated by the included
randomized controlled trials (RCTs). An update of the
previous systematic review would be interesting also
because new studies on this subject have been published.
The objective of this review is to evaluate the efficacy
and safety of monitoring COS by ultrasonography, with
or without inclusion of hormonal assessment, for women
undergoing ART and to compare different ultrasound
methods.
Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.
Martins et al.
METHODS
The study protocol was registered at PROSPERO
(http://www.crd.york.ac.uk/prospero/): CRD42012003
297. The study received ethical approval from our
department’s research committee.
Only truly randomized RCTs were considered eligible;
quasi- or pseudo-randomized trials were not included17,18 .
Studies that permitted inclusion of a participant more than
once (crossover trials or ‘per cycle’ studies) were included
only if data regarding the first cycle of each participant
were available or if all consecutive cycles of each partic-
ipant were performed in the same group; in all cases, the
number of allocated women (rather than the number of
cycles) was considered the denominator. We included tri-
als that compared different methods of monitoring COS,
including ultrasound assessment of follicles (alone or com-
bined with hormonal assessment) in at least one group.
Search strategy
We searched for trials using the following elec-
tronic databases: Cochrane Central Register of
Controlled Trials (CENTRAL); Cumulative Index
to Nursing and Allied Health Literature (CINAHL);
EMBASE; Literatura Latino-Americana e do Caribe
em Ciências da Saúde (LILACS); Medical Literature
Analysis and Retrieval System Online (MEDLINE)
and PsycINFO. Trial registers were searched for in
Current Controlled Trials (www.controlled-trials.com),
ClinicalTrials.gov (http://clinicaltrials.gov/ct2/search)
and the World Health Organization International
Trials Registry Platform search portal (http://apps.
who.int/trialsearch/Default.aspx). In addition, authors
manually searched the reference lists of the included
articles and similar reviews to find additional records.
The following search terms were used: ‘ultrasono-
graphy’ OR ‘ultrasound’ AND ‘ovarian stimulation’
OR ‘ovarian hyperstimulation’ OR ‘ovulation induction’
OR ‘controlled ovarian’ OR ‘IVF’ OR ‘ICSI’ OR ‘in
vitro fertilization’ OR ‘intracytoplasmic sperm injection’
OR ‘assisted reproduction’ OR ‘embryo transfer’ OR
‘embryo deposition’ OR ‘embryo replacement’ OR
‘blastocyst’, using filters for randomized controlled trials
and adjusting for each database as necessary. We did
not impose a publication date or language limitations for
the searches.
Titles and abstracts were reviewed independently by
two authors (C.V.R.V. and L.A.D.) who checked for
duplicates and used the pre-established criteria for
inclusion. In cases of disagreement, a third author
(W.P.M.) was consulted. These authors retrieved the full-
text manuscripts of trials considered to be potentially
eligible for inclusion. Two authors (W.P.M. and C.O.N.)
independently evaluated eligibility and disagreements
were resolved by consensus. We corresponded with study
investigators as required to clarify study eligibility. We
placed no limitation on language, publication date or
publication status.
Ultrasound Obstet Gynecol 2014; 43: 25–33.
Monitoring controlled ovarian stimulation
Data collection
Two authors (C.O.N. and W.P.M.) independently
extracted data from the included studies using a data
extraction form planned and piloted by the authors and
another author (D.M.T.) checked the data. Disagreements
were resolved by consensus. Authors corresponded
with study investigators as required to resolve queries
concerning the data. In order to analyze data according to
the intention-to-treat principle, the number of allocated
women was used as the denominator when possible. The
names of authors and titles of the included studies were
juxtaposed to identify duplicate publications, which were
considered by the authors as being part of a unique
study.
The following data were extracted from included
studies: (1) methods (aim of trial, recruitment of partici-
pants, inclusion/exclusion criteria and status of informed
consent and ethical approval); (2) participant character-
istics (number, age, cause of infertility); (3) intervention
(use of ultrasonography and/or hormonal assessment to
monitor COS); (4) primary outcomes (effectiveness (live
births per allocated woman), adverse events and OHSS
per allocated woman); (5) secondary outcomes (clinical
pregnancy per allocated woman, miscarriage per clinical
pregnancy and number of retrieved oocytes (mature
or total)). Implantation rate was not included in the
meta-analysis because the denominator for this outcome
(number of embryos transferred) was not randomized;
however, we planned to include this information in the
characteristics of included studies.
Two authors (C.O.N. and W.P.M.) independently
assessed the risk of selection bias (random sequence
generation and allocation concealment), performance bias
(blinding of participants and personnel), detection bias
(blinding of outcome assessors), attrition bias (incom-
plete outcome data), reporting bias (selective outcome
reporting) and other potential sources of bias (number
of embryos transferred). The Cochrane Collaboration
criteria for judging risk of bias19 were used and studies
were classified as being at ‘low’, ‘high’ or ‘unclear’ risk of
bias.
Summary measures
All results were combined for meta-analysis with Review
Manager 5.1 (Copenhagen: The Nordic Cochrane Centre,
Cochrane Collaboration, 2011). The number of events
in the control and intervention groups of each study
were used to calculate a Mantel–Haenszel risk ratio
(RR). We prefer to use the RR because the odds ratio
(OR) is more difficult to interpret and to apply in
practice. Additionally, there is some concern that the
OR might be interpreted as a RR, which will tend
to overestimate the intervention effect, especially when
events are common19 . However, when a zero cell count
or prevalence < 1% was observed, the Peto fixed-effect
OR was used because this method is considered to be
the least biased, providing the best confidence interval
Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.
27
coverage in these situations19 . The resulting OR value is
very similar to the RR, thus avoiding misinterpretation.
The precision of estimates was evaluated using the 95%
confidence interval. We considered the clinical relevance
of any statistically significant findings.
Synthesis of results
The following comparisons were planned: (1) ultrasono-
graphy only vs ultrasonography and hormonal assess-
ment; (2) ultrasonography and hormonal assessment
vs hormonal assessment only; (3) ultrasonography only
vs hormonal assessment only; (4) 3D ultrasonography
(including semi-automated method) with or without hor-
monal assessment vs 2D ultrasonography with or without
hormonal assessment. An increase in the risk of a partic-
ular outcome associated with the use of ultrasonography,
which may be either beneficial (e.g. clinical pregnancy)
or detrimental (e.g. OHSS) was displayed graphically in
the meta-analyses to the right of the centerline, while a
decrease in the risk of an outcome was displayed to the
left of the centerline. We assessed heterogeneity using the
I2 statistic. Substantial heterogeneity (I2 > 50%) among
studies was addressed, firstly by rechecking that data
were correct and, secondly, by using a random-effects
model.
In view of the difficulty of detecting and correcting
for publication bias and other reporting biases, we
aimed to minimize their potential impact by ensuring a
comprehensive search for eligible studies and by remaining
alert for duplication of data. If there were 10 or more
studies in an analysis, we had planned to use a funnel
plot to explore the possibility of small-study effects (a
tendency for estimates of the intervention effect to be
more beneficial in smaller studies).
No subgroup analysis was undertaken. We planned
to perform a sensitivity analysis to verify whether
conclusions would differ if eligibility was restricted to
studies judged not to be at high risk of bias.
A table was generated using GRADEPRO software
to summarize findings. The quality of evidence for the
main review outcomes was evaluated using the following
GRADE criteria:
High quality. Further research is very unlikely to change
our confidence in the estimate of effect.
Moderate quality. Further research is likely to have an
important impact on our confidence in the estimate of
effect and may change the estimate.
Low quality. Further research is very likely to have an
important impact on our confidence in the estimate of
effect and is likely to change the estimate.
Very low quality. We are very uncertain about the
estimate.
We considered the limitations of included studies (e.g.
high risk of bias), inconsistency of effect, imprecision,
indirectness and publication bias. Judgments about
evidence quality (high, moderate, low or very low) were
justified, documented and incorporated into the reporting
of results for each outcome20 .
Ultrasound Obstet Gynecol 2014; 43: 25–33.
28
RESULTS
Study selection and characteristics
The electronic search was run on 15 April 2013 and
a total of 1515 records were retrieved (Figure 1). One
additional record was retrieved by manual search of
reference lists of potentially eligible studies and related
reviews. After removing duplicates, 1126 records were
screened on the basis of title and abstract; 11 records
were considered potentially eligible and were evaluated
further. From these records, four were excluded for the
following reasons: two studies were not randomized21,22 ,
one study was pseudorandomized15 and one record was
related to an ongoing trial for which participants are still
being recruited23 ; six studies from seven records were
included in the quantitative meta-analysis.
The six studies included in the quantitative analysis and
their characteristics are reported in Table 1. All studies
were parallel-design RCTs. Five studies were single-center
studies (two based in Israel24,25 , one in Spain26 , one in the
UK27 and one in France)28 . The other study was a multi-
center (four) study conducted in the UK29 . We contacted
corresponding authors to obtain further information for
two of the studies25,29 .
A total of 797 women from six studies were included;
in five studies, 359 women were monitored using 2D
ultrasound alone while 366 were monitored using 2D
ultrasound combined with hormonal assessment. In one of
these studies, women were allowed to undergo additional
cycles in the same assigned group26 : 42 cycles in 31
women (average, 1.35 cycles per woman) in one group
Electronic search (n = 1515)
CENTRAL (n = 302)
CINAHL (n = 120)
EMBASE (n = 343)
LILACS (n = 4)
MEDLINE (n = 612)
PsycINFO (n = 8)
Clinical trials (n = 65)
Controlled trials (n = 27)
WHO International Trials Registry Platform (n = 34)
Screened after removal of duplicates
(n = 1126)
Full-text articles assessed for eligibility
(n = 11)
Included in quantitative meta-analysis
(n = 6, from 7 records)
Figure 1 Flowchart of selection of studies comparing methods for monitoring controlled ovarian stimulation.
Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.
Martins et al.
and 48 cycles in 35 women (average, 1.37 cycles per
woman) in the other. In the sixth study, 36 women were
monitored using 2D ultrasound and compared with 36
women monitored by 3D ultrasound.
Five studies compared ultrasonography only with
ultrasonography and hormonal assessment for monitoring
COS24 – 26,28,29 . One study27 compared 3D ultrasono-
graphy with 2D ultrasonography for monitoring COS;
hormones were not assessed in any group. In three
studies, in women monitored only by ultrasonography
blood estradiol was determined just before inducing the
final follicular maturation with hCG24 – 26 .
Regarding examined outcomes, none of the six studies
reported on live birth, five reported on OHSS, all six
reported on clinical pregnancy, one reported on miscar-
riage and four reported on oocytes retrieved. Concerning
clinical pregnancy, although all six studies reported on
this outcome, the data from one study24 were not included
in the meta-analysis because we were unable to estimate
how many women achieved clinical pregnancy in each
group: authors reported clinical pregnancy rate per oocyte
retrieval (25.0% vs 22.2%, ultrasound alone vs ultra-
sound and hormonal assessment) and per embryo transfer
(26.5% vs 27.2%), but we were not able to extract the
number of women who underwent oocyte retrieval or
embryo transfer. No study reported on implantation rate.
Five studies described adequate methods of random-
ization, and in one the method of randomization was
not described24 . In four studies, the method of allocation
concealment was not clear; these studies were deemed
to be at unclear risk of selection bias24,26 – 28 . We did
Manual search
(n = 1)
Excluded: clearly did not meet
inclusion criteria (n = 1115)
Full-text articles excluded (n = 4):
Not randomized (n = 3)
Ongoing trial without results (n = 1)
Ultrasound Obstet Gynecol 2014; 43: 25–33.
 Table 1 Characteristics of included randomized controlled trials comparing methods for monitoring controlled ovarian stimulation
Study
26
Aguirre et al. (2010)
Golan et al. (1994)24
Lass (2003)29
Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd.
Rongieres (2006)28
Wiser et al. (2012)25
Raine-Fenning et al. (2010)27
*Only provided pregnancy rate per oocyte retrieval and embryo transfer, not per woman allocated. 2D, two-dimensional; 3D, three-dimensional; COS, controlled ovarian stimulation;
GnRH, gonadotropin-releasing hormone; H, hormonal monitoring; hCG, human chorionic gonadotropin; IVF, in-vitro fertilization; OHSS, ovarian hyperstimulation syndrome; SonoAVC,
3D sonography-based automated volume count; US, ultrasound.
Ultrasound Obstet Gynecol 2014; 43: 25–33.
Comparison n Objective Group Outcome
US vs US + H 66 To verify necessity of estradiol serum Group A (n = 35; 42 IVF cycles), Clinical pregnancy, number of oocytes
measurement in IVF cycles COS followed with US and estradiol retrieved, OHSS, miscarriage
monitoring
Group B (n = 35, four excluded; 48 IVF
cycles), COS followed with 2D US alone;
estradiol quantified on day of hCG
administration
US vs US + H 114 To verify safety of cycle monitoring with Group A (n = 57), COS followed with US Number of oocytes retrieved, OHSS*
US alone in cycles using GnRH analog in and estradiol monitoring
Monitoring controlled ovarian stimulation
long protocol Group B (n = 57), COS followed with 2D
US alone
US vs US + H 297 To test whether strict adherence to Group A (n = 148), COS followed with Clinical pregnancy, number of oocytes
hormonal plus US criteria has an daily US and estradiol monitoring retrieved, OHSS
advantage over monitoring cycle by US Group B (n = 149), COS followed with 2D
criteria alone US alone
US vs US + H 185 To compare reproductive outcomes Group A (n = 97), COS followed with 2D Clinical pregnancy, OHSS
between two types of COS monitoring: US and estradiol monitoring
US with or without serum hormonal Group B (n = 88), COS followed with 2D
assessment US alone
US vs US + H 63 To evaluate safety of monitoring IVF cycles Group A (n = 31; 1 excluded, 30 included), Clinical pregnancy, OHSS, number of
by US alone COS followed with 2D US and serum oocytes retrieved
estradiol and progesterone monitoring at
each visit
Group B (n = 34; 1 excluded, 33 included),
COS followed with 2D US alone,
estradiol assessed on day of hCG
administration
3D US vs 2D US 72 To evaluate effect of a new automated Group A (n = 36), COS followed with 2D Number of oocytes retrieved, clinical
technique of follicle measurement US, 3D US used for assessing oocyte pregnancy
(SonoAVC) on timing of oocyte volume with SonoAVC
maturation and subsequent oocyte Group B (n = 36), COS followed with 2D
retrieval US alone
29
30 Martins et al.

better, similar or less effective than ultrasonography and

Blinding of participants and personnel (performance bias)

hormonal assessment for this outcome (OR, 1.02; 95%
CI, 0.47–2.25, P = 0.95; five RCTs, 725 women; I2 = 0,

Blinding of outcome assessment (detection bias)

low-quality evidence) (Figure 3). When performing the

Random sequence generation (selection bias)

sensitivity analysis, restricting eligibility criteria to only
studies judged not to be at high risk of bias, the CI

Incomplete outcome data (attrition bias)

Allocation concealment (selection bias)
continued to be very wide (OR, 0.78; 95% CI, 0.27–2.28;

Selective reporting (reporting bias)

P = 0.65; two RCTs, 299 women).
Among studies included in our analysis, none reported
on live births per allocated woman.
For clinical pregnancy per allocated woman, the CI
was somewhat wide and by examining the precision
we concluded that ultrasonography alone differed little
from ultrasonography and hormonal assessment for this

Other bias
outcome (RR, 0.95; 95% CI, 0.78–1.16; P = 0.61; four
RCTs, 611 women; I2 = 10%, low-quality evidence)
(Figure 4). The CI was very wide when sensitivity
analysis involved restriction of eligibility criteria to
Aguirre et al. (2010)26 + + + − + +
studies judged not to be at high risk of bias and we were
Golan et al. (1994)24 + + + + not able to conclude whether ultrasonography alone is
better, similar or less effective than ultrasonography and
Lass (2003)29 + + + + + + −
hormonal assessment for this outcome (RR, 0.96; 95%
Raine-Fenning et al. (2010)27 + + + + + + CI, 0.62–1.48; P = 0.84; one RCT, 185 women).
Only one study reported on miscarriage per clinical
Rongieres (2006)28 + + + + + + pregnancy, and the CI was very wide; we were not
+ + + + − + +
able to conclude whether ultrasonography alone is
Wiser et al. (2012)25
better, similar or less effective than ultrasonography
and hormonal assessment for this outcome (RR, 0.37;
Figure 2 Risk of bias summary: review of authors’ judgements 95% CI, 0.07–1.79; P = 0.21; 45 pregnant women,
about each risk of bias for each included study. very-low-quality evidence). Sensitivity analysis was
not consider that blinding was likely to influence the risk not undertaken because the only study that reported
of performance bias for the present review. Two studies miscarriage was considered to be at high risk of bias.
were deemed at high risk of attrition bias because some For total number of oocytes retrieved, the CI was
participants were excluded from analysis25,26 : in one, four somewhat wide and we were not able to conclude
women were excluded from analysis because they did not whether ultrasonography alone is better or similar
follow the study protocol26 ; in the other, two women were to ultrasonography and hormonal assessment for this
excluded after allocation25 (one became pregnant before outcome (mean difference (MD), 0.77 oocytes; 95% CI,
COS and the other left the clinic before treatment). One –0.42 to 1.96; P = 0.20; three RCTs, 474 women; I2 = 10,
study was considered at unclear risk of reporting bias24 ; moderate-quality evidence) (Figure 5). When performing
the authors reported the proportion of clinical pregnan- the sensitivity analysis, the CI was wide and we were not
cies per oocyte retrieval and per embryo transfer but did able to conclude whether ultrasonography alone is better,
not report the number of women submitted to oocyte similar or slightly less effective than ultrasonography and
retrieval and/or embryo transfer in each group; thus, the hormonal assessment for this outcome (MD, 1.70 oocytes;
total number of clinical pregnancies in each group could 95% CI, –1.22 to 4.62; P = 0.25; 1 RCT, 114 women).
not be determined. One study was deemed at high risk
of other bias because the initial intervention proposed Comparison of 3D and 2D ultrasound monitoring
for the ultrasonography/hormonal assessment group was There was only one study included in this comparison,
modified during the trial: 40/148 women did not match which did not report live birth, OHSS or miscarriage. CIs
the criteria for hCG administration using the initial pro- were very wide for the two reported outcomes (clinical
posed criteria but still received hCG according to criteria pregnancy and total number of oocytes retrieved) and we
proposed for the ultrasonography only group29 . No study were not able to conclude whether use of 3D ultrasound is
reported significant differences in baseline age, body mass better, similar, or less effective than use of 2D ultrasound;
index or follicle-stimulating hormone level between the considering the values for clinical pregnancy (RR, 1.00;
groups. The risk of bias summary is presented in Figure 2. 95% CI, 0.58–1.73; P = 1.00; 72 women) and total
Monitoring with ultrasonography only vs number of oocytes retrieved (MD, –0.37 oocytes; 95%
ultrasonography and hormonal assessment CI, –3.63 to 2.89; P = 0.82; 72 women), this study was
not judged to be at high risk of bias.
For OHSS, the CI was very wide and we were not We did not identify any evidence of publication bias
able to conclude whether ultrasonography alone is or selective reporting within studies. Since fewer than

Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2014; 43: 25–33.
Monitoring controlled ovarian stimulation 31

US alone US + Hormones
Study or Subgroup Events Total Events Total Weight (%) Peto odds ratio Peto odds ratio

Aguirre et al. (2010)26 0 35 0 31 Not estimable

Golan et al.(1994)24 4 57 3 57 26.6 1.35 (0.29, 6.20)
Lass (2003)29 7 149 5 148 46.3 1.40 (0.44, 4.45)
Rongieres (2006)28 2 88 5 97 27.1 0.46 (0.10, 2.06)
Wiser et al. (2012)25 0 30 0 33 Not estimable

Total (95% CI) 359 366 100.0 1.02 (0.47, 2.25)

Total events 13 13
Heterogeneity: χ2 = 1.53, 2 d.f., P = 0.47; I2 = 0%
0.1 0.2 0.5 1 2 5 10
Test for overall effect: Z = 0.06, P = 0.95
Favors US alone Favors US + Hormones

Figure 3 Forest plot for ovarian hyperstimulation syndrome: comparison of ultrasound (US) monitoring alone vs US and hormonal
monitoring.

US alone US + Hormones
Study or Subgroup Events Total Events Total Weight (%) Risk ratio Risk ratio
26
Aguirre et al. (2010) 26 35 19 31 17.4 1.21 (0.86, 1.70)
Lass (2003)29 46 149 49 148 42.4 0.93 (0.67, 1.30)
Rongieres (2006)28 26 88 30 97 24.6 0.96 (0.62, 1.48)
Wiser et al. (2012)25 12 30 19 33 15.6 0.69 (0.41, 1.18)

Total (95% CI) 302 309 100.0 0.95 (0.78, 1.16)

Total events 110 117
Heterogeneity: χ2 = 3.33, 3 d.f., P = 0.34; I2 = 10%
0.1 0.2 0.5 1 2 5 10
Test for overall effect: Z = 0.50, P = 0.61
Favors US + Hormones Favors US alone

Figure 4 Forest plot for clinical pregnancy: comparison of ultrasound (US) monitoring alone vs US and hormonal monitoring.

10 studies were included, we did not perform funnel
plot analysis. Sensitivity analysis, restricting the inclusion
criteria to studies judged not to be at high risk of bias
was the only additional analysis performed, and this was
reported along with the main results.
DISCUSSION
Five studies were included for comparison of ultra-
sonography only with ultrasonography and hormonal
assessment (Table 2). No study evaluated live birth. We
observed moderate-quality evidence that monitoring COS
by ultrasonography alone is unlikely to cause substantial
reduction in the number of oocytes retrieved as compared
with that with ultrasonography and hormonal assessment.
There is low-quality evidence that monitoring COS only
by ultrasonography probably does not substantially alter
the chance of achieving a clinical pregnancy. We are still
uncertain of its effect on OHSS and miscarriage.
Only one study was included for comparison of 3D and
2D ultrasound monitoring. This study provided data on
the number of oocytes retrieved and on clinical pregnancy;
however, the estimates were not sufficiently precise to rule
out appreciable harm or benefit.
In the comparison of ultrasonography only with
ultrasonography and hormonal assessment (Table 2), the
quality of evidence for OHSS was considered to be low; it
was downgraded one level because of imprecision (wide
95% CI) and another level because of the high risk of bias
in the included studies. The quality of evidence for clinical
pregnancy was also considered to be low; it was also
downgraded one level because of imprecision and another
level because of the high risk of bias. The quality of
evidence for miscarriage was considered to be very low; it
was downgraded two levels because of serious imprecision
(very wide 95% CI) and another level because of the high
risk of bias. The quality of evidence for the number of
oocytes retrieved was considered to be moderate; it was
downgraded one level because of the high risk of bias
observed in the included studies.
In the comparison of 3D and 2D ultrasound (Table 2),
the quality of evidence for the two reported outcomes
(clinical pregnancy and number of oocytes retrieved) was
considered to be low; it was downgraded two levels
because of serious imprecision (very wide 95% CI).
Another systematic review published in 200816
addressed this issue; at that time only two studies were
included, and both are included also in the present
review24,29 . Those authors concluded that evidence was
too scarce at that point to draw any conclusion. We
included four more studies: one from 200628 and three
studies that were published after the former review25 – 27 .
In addition to the six studies included in the quan-
titative review, three other studies addressed the same
question but were excluded because they were not
randomized15,21,22 . Two of these studies21,22 evaluated

Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2014; 43: 25–33.
32 Martins et al.

US alone US + Hormones
Study or Subgroup Mean SD Total Mean SD Total Weight (%) Mean difference Mean difference
Golan et al., (1994)24 13.4 7.5 57 11.7 8.4 57 16.6 1.70 (−1.22, 4.62)
Lass (2003)29 11.4 6.1 149 11 6.3 148 71.3 0.40 (−1.01, 1.81)
Wiser et al., (2012)25 11.7 8 30 10 5.5 33 12.1 1.70 (−1.72, 5.12)

Total (95% CI) 236 238 100.0 0.77 (−0.42, 1.96)

Heterogeneity: χ = 0.94, 2 d.f., P = 0.63;
2 I2 = 10% −10 −5 0 5 10
Test for overall effect: Z = 1.27, P = 0.20 Favors US + Hormones Favors US alone

Figure 5 Forest plot for oocytes retrieved: comparison of ultrasound (US) monitoring alone vs US and hormonal monitoring.

Table 2 Summary of findings

Number of
participants Quality
Variable Absolute risk (95% CI) Difference (95% CI) (studies) of evidence

Comparison US + H vs US alone US + H US alone

OHSS 4% 4 (2 to 8)% OR 1.02 (0.47 to 2.25) 725 (5) Low*
Clinical pregnancy per allocated woman 38% 36 (30 to 44)% RR 0.95 (0.78 to 1.16) 611 (4) Low†
Miscarriage per clinical pregnancy 21% 8 (1 to 38)% RR 0.37 (0.07 to 1.79) 45 (1) Very low‡
Number of oocytes retrieved 11 11.8 (10.6 to 13.0) MD 0.8 ( −0.4 to 2.0) 474 (3) Moderate§
Comparison 2D US vs 3D US 2D US 3D US
Clinical pregnancy per allocated woman 42% 42 (24 to 72)% RR 1.00 (0.58 to 1.73) 72 (1) Low¶
Number of oocytes retrieved 13 12.6 (9.4 to 15.9) MD −0.4 ( −3.6 to 2.9) 72 (1) Low¶

*Downgraded one level because of imprecision and an additional level because of the quality of the included studies (3/5 studies were at high
risk of bias). †Downgraded one level because of imprecision and an additional level because of the quality of the included studies (3/4 studies
were at high risk of bias). ‡Downgraded two levels because of serious imprecision and an additional level because of the quality of the
included studies (the only included study was at high risk of bias). §Downgraded one level because of the quality of the included studies (2/3
studies were at high risk of bias). ¶Downgraded two levels because of serious imprecision. H, hormonal assessment; MD, mean difference;
OHSS, ovarian hyperstimulation syndrome; OR, odds ratio; RR, risk ratio; US, ultrasonography.

the comparison of ultrasonography alone with ultra-
sonography and hormonal assessment. One study includ-
ing 206 women22 reported live birth (RR, 1.05; 95%
CI, 0.47–2.32; P = 0.91), OHSS (OR, 0.87; 95% CI,
0.05–14.12; P = 0.92) and clinical pregnancy per woman
allocated (RR, 1.04; 95% CI, 0.57–1.90; P = 0.91). The
other study21 included 120 women and reported clin-
ical pregnancy per allocated woman (RR, 0.83; 95%
CI, 0.25–2.80; P = 0.77) and total number of oocytes
retrieved (MD, –0.30; 95% CI, –1.63 to 1.03; P = 0.66).
The third study15 evaluated use of the software SonoAVC
for comparison of 3D and 2D ultrasound in 40 women
and reported on clinical pregnancy per allocated woman
(RR, 0.90; 95% CI, 0.47–1.73; P = 0.75) and total num-
ber of oocytes retrieved (MD, 3.20 oocytes; 95% CI,
–0.89 to 7.29; P = 0.12). None of these three studies
reported a significant difference between groups, which is
in agreement with the meta-analysis of studies included in
the quantitative review.
Monitoring COS by both ultrasonography and hor-
monal assessment leads to increased costs as well as
discomfort and stress related to the process of blood col-
lection. Although the effect on other important outcomes
is uncertain, monitoring COS by ultrasonography alone
is not likely to reduce the number of oocytes retrieved
or to alter substantially the chance of achieving a clinical
pregnancy. Therefore, we believe that ultrasonography
alone should be considered a reasonable alternative for
monitoring COS.
Although the included studies were consistent in their
estimate of effect, the quality of evidence compiled in this
review was impaired by the quality of the studies. Three
out of six studies were deemed to be at high risk of bias.
Beyond the core reasons for eliminating the monitoring
of some hormones and inclusion of semiautomated
techniques, the reduction in costs and/or stress and
the improvement of logistics should be considered; no
trial has addressed cost-effectiveness or quality of life
as related to these interventions. Additionally, the small
number of RCTs makes the assessment of publication and
reporting bias suboptimal, because of the impossibility of
performing a funnel plot analysis.
Current evidence suggests that monitoring COS by
ultrasound alone is unlikely to alter substantially the
chance of achieving a clinical pregnancy and the number
of oocytes retrieved is at least similar when compared
to that retrieved using ultrasonography and hormonal
assessment. For the other outcomes and comparisons, the
available data remain inconclusive. We believe that more
studies evaluating the optimal procedure for monitoring
COS are needed; these studies should report on both live
birth and OHSS and should include at least 300 women
per group to ensure sufficient power to detect an absolute
difference greater than 10% for live birth.

Copyright  2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2014; 43: 25–33.
Monitoring controlled ovarian stimulation
ACKNOWLEDGMENTS
The authors of this study received financial sup-
port from: CAPES, Brazil (C.O.N.); CNPq, Brazil
(W.P.M.); FAPESP, Brazil (D.M.T.); HC-FMRP-USP,
Brazil (W.P.M.); EURP, Brazil (C.O.N., W.P.M.).
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