A systematic review and meta-analysis of psychological predictors of successful assisted reproductive technologies
Purewal et al. BMC Res Notes
A systematic review and meta-analysis of psychological predictors of successful assisted reproductive technologies
S. Purewal 0
S. C. E. Chapman 2
O. B. A. van den Akker 1
0 Institute of Psychology, Faculty of Education , Health and Wellbeing , University of Wolverhampton , Wolverhampton WV1 1AD , UK
1 Department of Psychology, School of Science and Technology, Middlesex University , London NW4 4BT , UK
2 Department of Pharmacy & Pharmacology, University of Bath , Claverton Down Road, Bath BA2 7AY , UK
Objectives: The aim of this systematic review and meta-analysis was to perform an updated investigation of the effects of depression and anxiety on pregnancy outcomes following assisted reproductive technologies. A bibliographic search was performed using PubMed, PsycINFO, Embase, Science Direct databases. Data retrieved were analysed using a random effects model to estimate standardised mean differences. Results: Of the 22 included studies, 18 investigated depression, 15 state anxiety, and seven trait anxiety. Data from 4018 patients were included in the meta-analysis. Results indicated that women who achieved pregnancy or a live birth reported lower levels of depression pre-treatment than those who did not, although the effects were small d = − 0.177 (95% CI − 0.327 to − 0.027, z = 2.309, p = 0.021). These results were consistent under different methodological conditions and the quality of these observational were graded as satisfactory. A similar pattern was seen for state (d = − 0.096, 95% CI − 0.180 to − 0.012: z = 2.241, p = 0.025) and trait anxiety (d = − 0.188, 95% CI − 0.007 to 0.356, z = 2.181, p = 0.029). More research is needed to investigate the impact of psychological variables on assisted reproductive technologies outcomes and moderator influences during assisted reproductive technologies processes.
Infertility; Assisted reproductive technologies; Psychology; Depression; Anxiety; Meta-analysis
According to The Human Fertilisation and Embryology
Authority (HFEA), in 2014 [
], 2% of all the babies born
in the UK had been conceived through In vitro
fertilisation (IVF) treatment. Studies since the 1980s [
been reporting that some patients find IVF stressful and
psychological burden are common reasons why some
couples stop treatment . However, previous synthesis
of this research has found no or small impact of
psychological variables on assisted reproductive technologies
(ART) outcomes. Boivin et al. [
] found that emotional
distress was not related to ART outcomes. Whereas,
Matthiesen et al. [
] found a small effect size for stress,
state and trait anxiety and decreased clinical pregnancies.
Despite Boivin [
] and Matthiesen’s [
] reporting no or
little impact of psychological distress in ART outcomes,
meta-analysis/systematic reviews on the effectiveness of
psychological interventions in reducing psychological
distress and promoting pregnancy rates have reported
conflicting data. One meta-analytic review [
that psychological interventions were not effective at
reducing depression or anxiety but they did improve
pregnancy rates. Whereas, a recent critical review [
found psychosocial interventions improved
psychological and pregnancy outcomes. However, Akioyamen et al.
] found the use of antidepressants had no impact on
fertility treatment pregnancy rates.
The aims of this meta-analysis were to perform an
updated meta-analysis investigating the effects of
depression, state and trait anxiety on ART outcomes.
This paper presents part 1 of a two-part review that
investigated lifestyle and Body mass index (BMI)
predictors of ART outcomes (in press). The systematic review
and meta-analysis was performed following PRISMA and
MOOSE guidelines [
Studies were considered if they presented original data
and reported live birth rates or pregnancy outcome data.
Studies were excluded if they did not investigate baseline
(before stimulation) maternal depression, state anxiety
(transitory state) or/and trait anxiety (stable disposition
of anxiety-proneness) and ART outcomes. They were
included if they used a standardised psychological
measure (e.g., BDI—Beck’s Depression Inventory) reporting
continuous or categorical (cut-off-score) data. Studies
that assessed anxiety referencing the current time or a
recent period (such as the last 2 weeks) were classed as
‘state’ anxiety e.g., the Psychological general well-being
index (PGWB); Hospital Anxiety and Depression Scale
(HADS) and the Zung Self-Rating Anxiety Scale because
sensitivity data-analyses revealed no significant
differences between the effect size of general anxiety scores
to specific state anxiety scores (Q = 0.866, d.f. = 1,
p = 0.352). We excluded studies assessing psychological
variables after stimulation because ovarian stimulation
leads to increases in stress hormones (i.e., serum
norepinephrine and cortisol values) [
Only studies using ART techniques were included (e.g.,
IVF, intracytoplasmic sperm injection—ICSI, zygote
intrafallopian transfer—ZIFT). Other exclusion criteria
were if it was not possible to calculate unadjusted effect
sizes for predictor variables (e.g., predictor data grouped
by outcome, only adjusted data reported) and therefore
meta-analysis of unadjusted effect sizes could not be
Information sources and search
We searched for relevant publications in six
bibliographic databases—PubMed, PsycInfo, Embase,
ScienceDirect, Web of Science and Scopus. In PubMed,
the search used the following keywords and abstracts:
(“Pregnancy”[Mesh] OR “Pregnancy” OR “pregnant” OR
“live birth” OR “birth rate”) AND (“IVF” OR
“intracytoplasmic” OR “intracytoplasmic sperm injection” OR “in
vitro fertilization” OR “ICSI” OR “assisted reproductive
technology” OR “in vitro fertilisation”) AND
(“psychological stress” OR “depressive disorder” OR “anxiety” OR
“anxiety disorder” OR “adjustment disorder” OR
“emotions” OR “psychosomatic medicine” OR “psychological
adaption” OR “distress” OR “depression” OR “stress” OR
“occupation stress” OR “stressful life events” OR “major
life events” OR “stressors”). We limited the searches to
studies published after 1979/01/01 and conducted in
humans. Hand searches of references cited in previous
review papers were also conducted and the search was
updated in November 2016.
Study selection, data collection process and data items
SP, OvdA and SC independently screened titles, abstracts
and full-text reports [
]. Any disagreements were
resolved by discussion. Data extracted included all
independent (depression; state anxiety; trait anxiety) and
dependent variables (live birth or pregnancy) and
sample sizes. When two or more dependent variables were
reported (e.g., serum pregnancy, clinical pregnancy and
live birth), the data which was considered ‘gold standard’
and most relevant to patients was recorded (in this case,
live birth) [
]. We also extracted patient, treatment and
Risk of bias
SP and OvdA independently assessed the quality of each
study using Newcastle–Ottawa Scale (NOS) [
cross checked with each other to reach 100%
consensus. The scale awarded a maximum of nine stars to each
study: four stars for the adequate selection of cases and
controls, two stars for comparability of cases and
controls, and three stars for the adequate ascertainment of
the exposure in both the case and control groups. We
defined high quality as scoring at least seven stars the on
the NOS; medium quality as scoring five or six stars and
low quality as four or fewer stars.
Summary measures and synthesis of results
Comprehensive meta-analysis [
] was used to
calculate overall weighted effect sizes using a random effects
model. Extracted data (e.g., events, means) were
converted into standardised mean differences and used to
compare women with live birth/pregnancy outcomes and
women without. Outliers were identified as studies with
residuals greater than 1.96 and they were removed from
the analysis as recommended.
We quantified heterogeneity in study effect sizes using
the I2 statistic. We intended to conduct moderator
analyses to investigate significant heterogeneity where more
than 10 studies provided data on potential
moderators (as recommended by guidelines; [
]). However, as
shown below, insufficient studies were available, so
moderator analyses were not performed.
Sensitivity analyses were conducted to examine whether
effects were robust under different methodological
assumptions: (1) when only live birth and only pregnancy
data are included; (2) when only pregnancy ultrasound
scan results and only pregnancy test results are used; (3)
when only first time ART users data is included; (4) when
results from a single cycle are used (not multiple cycles);
(5) when only IVF, only ICSI and a combination of IVF and
ICSI treatments are used: (6) when only high quality were
included; and (7) when studies were recent (studies
published from 2010 onwards were considered to be recent).
We tested for publication bias for by examining funnel
plots for evidence of asymmetry, and using Duval and
Tweedie’s trim and fill method to impute studies where
evidence of asymmetry was present. We also tested for
the significance of these effects using Egger’s t test.
The screening process is summarised in the study
PRISMA flow chart (Additional file 1: Figure S1). Where
papers provided insufficient data for the meta-analysis,
authors were contacted for additional data and three
corresponding authors (D. Lancastle, K. Sanders and R.
Türk) responded with additional, unpublished data.
Of the 22 included studies, 18 studies investigated
depression, 15 state anxiety, and seven trait anxiety. Data
from 4018 patients were included in the meta-analysis.
An overview of study characteristics is presented in
Additional file 2: Table S1.
Synthesis of results
Eighteen studies reported on depression [
], 2 were
removed from these analyses as outliers [
]. In the
remaining studies there was a small, negative and
significant effect of depression in women who achieved a
pregnancy or live birth than in women who did not − 0.101
(95% CI − 0.193 to − 0.009, z = 2.152, p = 0.031).
This estimate was not significantly heterogeneous
(I2 = 24.956%, p = 0.176) see Additional file 3: Figure S2.
Sensitivity analysis The effects of depression remained
consistent in the sensitivity analyses (see Table 1), with the
exception that when the analysis was conducted in studies
examining first time ART and in studies reporting IVF
outcomes (not ICSI), effects became smaller and nonsignificant.
Fifteen studies reported baseline state anxiety [
23–25, 27, 28, 30–33, 35–38
]. Initial data analyses
revealed one study was an outlier and their data was
removed  from the analyses, there was a small,
significant and negative effect of state anxiety between women
who achieved live birth or pregnancy and women who
did not − 0.096 (95% CI − 0.180 to − 0.012: z = − 2.241,
p = 0.025) and no evidence of heterogeneity (I2 = 0.00%,
p < 0.454) see Additional file 4: Figure S3.
Sensitivity analysis In subsequent state anxiety
analyses, the evidence for state anxiety varies slightly under
different methodological conditions. See Table 2 for all
Across the seven studies reporting data on trait
27, 32, 33, 35–38
] there was a significant difference
between women who achieved a live birth or pregnancy
and women who did not − 0.188 (95% CI − 0.007 to
0.356, z = − 2.181, p = 0.029) and no evidence of
heterogeneity (I2 < 0.001%, p < 0.965) see Additional file 5:
Sensitivity analysis Analysis revealed that the evidence
for trait anxiety was not robust under different
methodological conditions. There were not enough studies to
measure trait anxiety effect in high quality studies. See
Table 3 for all results.
< 0.001%, p = 0.647
< 0.001%, p = 0.775
< 0.001%, p = 0.488
18.128%, p = 0.287
< 0.001%, p = 0.600
< 0.001%, p = 0.674)
< 0.001%, p = 0.747
All sensitivity data analyses are presented for the combined LB and pregnancy outcome except when separate pregnancy or livebirth outcomes are reported
Data indicated low levels of publication bias risk. For the
depression dataset, trim and fill data analyses revealed
only 2 additional studies would be needed to ensure
the funnel plot was generally symmetrical and Egger’s
regression intercept was not significant t(14) = 0.352,
p = 0.730. Trim and fill data analyses for state anxiety
revealed no additional studies were needed, the funnel
plot was symmetrical, but Egger’s meta regression
intercept was also significant (− 1.08, 95% CI − 2.44, 0.281,
p = 0.05). Trim and fill data analyses for trait anxiety
revealed no additional studies were needed, the funnel
plot was symmetrical and Egger’s meta regression
intercept was not significant (− 0.169, 95% CI − 1.658, 1.319
p = 0.391).
Findings from this updated meta-analysis report that
depression, state and trait anxiety have a small, significant
and negative effect on ART outcomes, which were
generally robust under different methodological assumptions.
These results provide an updated review of the
literature from Boivin et al. [
] and Matthiesen et al. [
reported little impact of psychological variables on ART
outcomes. Cumulatively, these findings provide some
encouragement to patients and clinicians, that baseline
anxiety and depression will only have a small impact on
their ART outcomes. However, for some patients this
small impact could result in negative outcomes. Our
results indicate that clinics could provide psychological
support to minimise any psychological distress to help
improve ART outcomes.
However, the research literature on the effects of
depression and anxiety on ART outcomes is narrowly
focused. That is, the studies included in this review often
only measured whether depression and anxiety predict
ART outcomes and did not acknowledge other factors
that could impact the relationship between
psychological variables and ART outcomes. For example, depressed
patients are more likely to smoke or have a poor diet but
the relationship is complex [
]. Smoking has
consistently been found to be detrimental to ART outcomes
] and the effect of obesity on ART outcome is
inconsistent with some reviews reporting a negative
], and other reviews finding only a small
effect of obesity  or insufficient evidence to support
an effect [
]. To the author’s knowledge, no review has
examined whether psychological variables are moderated
by lifestyle factors and BMI that could affect ART
outcomes. The relationship between psychological variables
and lifestyle factors such as smoking, alcohol and obesity
is inter-related. Depression and anxiety are often
comorbid with obesity and binge-eating [
depression and anxiety are known to be comorbid with alcohol
consumption  and smoking [
]. We confirm a
substantial effect for BMI and smoking and ART outcomes
independently [Authors, in press]. However, unlike BMI
and smoking reviews, the numbers of studies and sample
sizes included in psychological ART meta-analyses are
To conclude, depression and anxiety have a small,
significant and negative effect on ART outcomes. The
clinical implications of this study are that some patients
experiencing depression or anxiety may need
psychological support before they start treatment, to help improve
There is a gap in the literature examining the effect of
psychological variables on live birth outcomes, the gold
standard for ART outcomes [
]. New research using
large, representative samples examining the link between
psychological variables and lifestyles should be carried
out to fully understand the psychological mechanisms
that affect infertility and to obtain clinically relevant
effect size data.
Additional file 1: Figure S1. Prisma flowchart.
Additional file 2: Table S1. Study characteristic.
Additional file 3: Figure S2. A forest plot of depression data.
Additional file 4: Figure S3. A forest plot of state anxiety data.
Additional file 5: Figure S4. A forest plot of trait anxiety data.
ART: assisted reproductive technologies; IVF: in vitro fertilisation; HFEA: The
Human Fertilisation and Embryology Authority; BMI: body mass index; ICSI:
intracytoplasmic sperm injection; ZIFT: zygote intrafallopian transfer.
SP: contributed towards all aspect of this research project starting from
conception of the work, searching databases and retrieving papers, analysing/
interpreting data and writing up. SCEC: contributed to searching databases,
analysing data and writing up. OBAA contributed to the conception of the
work, searching databases and retrieving papers and writing up. All authors
read and approved the final manuscript.
The authors would like to acknowledge the help of Subarna Roy for retrieving
The authors declare that they have no competing interests.
Availability of data and materials
The data sets generated and analysed during the current study are available
from the corresponding author on reasonable request.
Consent for publication
Ethics approval and consent to participate
This research was funded by the British Academy small grant award
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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