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Point of Influence: What is the Role of Acupuncture in In Vitro Fertilization Outcomes?

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Abstract

Augmenting in vitro fertilization (IVF) with acupuncture is a popular adjuvant therapy in the United States, but its influence on IVF birth outcomes remains controversial. Recent meta-analyses found acupuncture is effective to increase the risk of live births by 30% when acupuncture was compared with no treatment in nine trials of 1,980 women. The efficacy of acupuncture is unclear, however, and confounded by the need for an adequate, inert control. Acupuncture does not increase the risk of miscarriage. Additionally, acupuncture was 42% more effective to increase live births when women had previously failed a cycle, and baseline pregnancy rate continues to mediate acupuncture's effects. The characteristics of treatment more favorable to improving birth outcomes included more treatments, timing treatments in the period before and on the day of embryo transfer (ET), and using a modified Paulus protocol on the day of ET. These findings should inform the dosage, timing, and components of acupuncture therapy and type of comparator in future trials investigating the effects of acupuncture on IVF outcomes.
COMMENTARY
Point of Influence:
What is the Role of Acupuncture in In Vitro
Fertilization Outcomes?
Lee E. Hullender Rubin, DAOM, MS, LAc, FABORM
ABSTRACT
Augmenting in vitro fertilization (IVF) with acupuncture is a popular adjuvant therapy in the United States, but
its influence on IVF birth outcomes remains controversial. Recent meta-analyses found acupuncture is effective
to increase the risk of live births by 30% when acupuncture was compared with no treatment in nine trials of
1,980 women. The efficacy of acupuncture is unclear, however, and confounded by the need for an adequate,
inert control. Acupuncture does not increase the risk of miscarriage. Additionally, acupuncture was 42% more
effective to increase live births when women had previously failed a cycle, and baseline pregnancy rate
continues to mediate acupuncture’s effects. The characteristics of treatment more favorable to improving birth
outcomes included more treatments, timing treatments in the period before and on the day of embryo transfer
(ET), and using a modified Paulus protocol on the day of ET. These findings should inform the dosage, timing,
and components of acupuncture therapy and type of comparator in future trials investigating the effects of
acupuncture on IVF outcomes.
INTRODUCTION
Infertility is a public health issue,affecting1in8
people in the United States—a substantial proportion of
Americans hoping to build their families.
1,2
In women ages
35–44, 7.3 million will pursue some type of fertility
treatment
1
in which in vitro fertilization (IVF) is one op-
tion. There are several IVF cycle types, including fresh or
frozen cycles with nondonor or donor eggs. In general, IVF
procedures require a woman or a person whose gender was
assigned female at birth, to take medications to stimulate
her ovaries and induce multiple follicular development.
When the follicles are mature, they are retrieved and fer-
tilized in a laboratory. Usually no more than 1 viable fresh
embryo can be transferred to the womb of the intended
mother in a fresh, nondonor cycle; or, they can be tested for
genetic abnormalities and then frozen. After genetic testing
identifies euploid embryos, the frozen embryo is thawed
and transferred as part of a frozen embryo transfer (FET)
cycle. It is important to note that embryos can be autolo-
gous or donated, and oocytes can be fertilized in a petri dish
or via intracytoplasmic sperm injection. Alternatively, any
mature eggs retrieved can also be cryopreserved un-
fertilized until needed, a procedure also known as egg
banking. In 2016, there were 65,840 egg banking cycles
reported in the United States.
3
All cycle outcomes are reported to the Centers for Dis-
ease Control and Prevention (CDC).
3
According to the
pooled data from the CDC, pregnancy rates vary widely
among clinics and regions within the United States, and the
prevalence of frozen cycles and egg-freezing cycles is
growing.
3
Multiple variables modulate an outcome, in-
cluding age of the mother, her infertility diagnosis, and the
type of cycle performed.
3
In 2016, there were 52,686 em-
bryo transfers (ETs) with fresh, autologous embryos in the
United States that resulted in 19,137 live births—a 36.3%
success rate across all ages of women.
3
There is no guar-
antee of success, and patients endure invasive physical
Osher Center for Integrative Medicine, University of California, San Francisco, San Francisco, CA.
MEDICAL ACUPUNCTURE
Volume 31, Number 6, 2019
#Mary Ann Liebert, Inc.
DOI: 10.1089/acu.2019.1392
329
interventions, psychosocial burdens, and risks of financial
strain while completing these treatments.
4
To help improve their odds of delivering a child, couples
may turn to complementary and integrative health ap-
proaches to supplement their fertility treatments.
5–7
Surveys
have estimates that 8%–47% of couples add acupuncture to
their IVF cycles.
5,8,9
However, the evidence on acupunc-
ture’s effects on IVF birth outcomes remains unclear.
10,11
Despite the publication of multiple trials and, subsequently,
multiple meta-analyses, the effect of acupuncture on IVF
outcomes is promising but not definitive. Cheong et al.
11
and Manheimer et al.
10
both found acupuncture on or
around ET was not superior to any control condition for
improving clinical pregnancy rates (CPRs) or live births.
More trials have been completed since those previous meta-
analyses were published.
The mechanisms for acupuncture’s effect on repro-
duction are not yet clear, but research suggests multiple
potential pathways. First, acupuncture inhibits central
sympathetic nerve tone, which can induce vasodilation
and blood flow to the uterus and ovaries, both of which are
vital to reproduction. It is theorized this might be initiated
through the A-vand C fibers of the skeletal tissue.
12
Acu-
puncture also floods the body with endorphins,
13
ultimately
mitigating the stress response associated with infertility
and infertility-related treatment. The release of neuro-
transmitters—such as dopamine, serotonin, neuropeptides,
and oxytocin—might be initiated by acupuncture, which, in
turn, could influence the hypothalamus–pituitary–ovarian
axis to promote ovulation, regulate menses, and increase
overall fertility.
12,14
In polycystic ovary syndrome, acupunc-
ture could affect glucose uptake in the skeletal tissue,
15,16
might decrease hyperinsulinemia, and might increase insulin
clearance.
17
The aim of this article is to provide an overview of the
current literature evaluating acupuncture’s effects on IVF
outcomes.
OVERVIEW OF RECENT
IVF META-ANALYSES
As of this writing, 2 rigorous systematic reviews and meta-
analyses were published in 2019 that looked specifically at
acupuncture as an adjuvant to IVF.
18,19
See Table 1. In these
meta-analyses, acupuncture was compared with sham, no
treatment, and all comparators.
CPR is an intrauterine gestational sac and/or fetal heart
motion confirmed by ultrasound (US). Overall, there was no
difference when acupuncture was compared in a systematic
review to a sham controls to improve CPR, but verum
acupuncture increased CPR by 28%
19
–32%,
18
compared to
no treatment. When acupuncture was compared to all con-
trol groups in another systematic review by Xie et al.,
19
acupuncture increased pregnancy rates by 21%.
19
Ongoing pregnancy rate (OPR) is an intrauterine preg-
nancy beyond 12 weeks and confirmed by US. Acupuncture
increased OPR by 42% in Smith et al.’s analysis,
18
and Xie
et al.
19
did not assess OPR.
The live birth of an infant resulting from conception after
IVF is measured as a live birth rate (LBR). When acupunc-
ture was compared with a sham control, the impact of acu-
puncture was equivocal on this outcome. When acupuncture
was compared with no treatment, Smith et al.
18
found that
acupuncture increased LBR by 30%, and Xie et al’s
19
anal-
ysis found no significant difference among groups, but the
LBR was trending toward significance.
Miscarriage rates are of particular interest in IVF
20
and are an adverse outcome. Smith et al.
18
found that
Table 1. Outcomes Comparison of Meta-Analyses of Acupuncture’s Influence on INVITRO
Fertilization Pregnancy Outcomes by Smith et al.
18
and Xie et al.
19
Acupuncture vs. no treatment Verum vs. sham acupuncture Acupuncture
vs. all controls
Rates Smith et al. Xie et al. Smith et al. Xie et al. Xie et al.
Clinical
pregnancy
N=12, n=2230 N=17, n=3084 N=9, n=2901 N=11, n=3060 N=27, n=6116
RR: 1.32 RR: 1.28 RR: 1.07 RR: 1.14 RR: 1.21
(95% CI: 1.07, 1.62) (95% CI: 1.08, 1.52) (95% CI: 0.88, 1.30) (95% CI: 0.94, 1.39) (95% CI: 1.07, 1.38)
Ongoing
pregnancy
N=6, n=1144) — N=6, n=1884 —
RR: 1.42 RR: 0.98
(95% CI: 1.17, 1.73) (95% CI: 0.86, 1.13)
Live birth N=9, n=1980 N=9, n=1992 N=6, n=2465 N=6, n=2480 N=15, n=4472
RR: 1.30 RR: 1.26 RR: 1.01 RR: 1.01 RR: 1.14
(95% CI: 1.00, 1.68) (95% CI: 0.99, 1.60) (95% CI: 0.80, 1.28) (95% CI: 0.80, 1.27) (95% CI: 0.96, 1.35)
Miscarriage N=10, n=2042 — N=7, n=2698 N=15, n=1504
RR: 1.43 RR: 1.15 RR: 1.14
(95% CI: 1.03, 1.98) (95% CI: 0.79, 1.67) (95% CI: 0.93, 1.41)
Data are presented as N=number of trials, n=number of participants, relative risk (RR), and 95% confidence interval (CI).
—, represents no data reported.
330 COMMENTARY
acupuncture reduced the miscarriage rate by 43%, com-
pared with no treatment; however no difference emerged
between verum and sham acupuncture and. In a pooled
analysis of studies with any comparators, Xie et al.
19
found
that there was also no difference between acupuncture and
control groups on miscarriage rates.
The discordance among analyses is likely due to each re-
view’s inclusion criteria. In their analysis, Smith et al.
18
only
included studies in which the primary endpoint was a birth
outcome and excluded studies that evaluated acupuncture’s
impact on pain during oocyte retrieval. The researchers cited
the mechanisms of action as being different for analgesia
versus reproductive support as a rationale for their exclusion.
18
Those pain trials were included in Xie et al.’s
19
analysis. The
variability of included trials analyzed underscores the differ-
ences in results between the 2 meta-analyses as outcomes will
change when different studies are pooled together.
Both meta-analyses found several variables that were
significant sources of heterogeneity. Variables that mediated
outcomes included the number of acupuncture treatments
during the IVF cycles,
18,19
baseline pregnancy rates,
18
timing
of acupuncture treatment,
18
acupuncture protocols used,
18,19
and previously failed cycles.
19
When there were more than 3 acupuncture treatments
during a cycle, acupuncture improved CPR by 50%–60%.
18,19
The effects of more sessions have also been observed in
women who choose acupuncture to supplement their IVF
treatments. Nine
21
to 12
22
sessions were associated with sig-
nificant increases in the odds of live births in observational
studies. These sessions were administered prior to ET and
included day of ET acupuncture.
21,22
A significant modifier of effect is the baseline pregnancy
rate.
18
Among 11 trials in which CPR outcomes averaged
<32%, women who were randomized to day of ET acu-
puncture had an increased likelihood of pregnancy of
60%.
18
Manheimer et al.
10
also found that the effects of
acupuncture were incrementally diminished as baseline
pregnancy rates improved. Currently, the U.S. national av-
erage already exceeds the 32% threshold.
3
The effect of acupuncture therapy during IVF cycles is
also relative to the timing of sessions and protocols used.
There was a 17% increase in CPR when acupuncture was
provided solely or before ET.
18
Modifications of the Pau-
lus
23
protocol were also more effective for increase CPR
by 34% than strict reproduction of the Paulus protocol.
18
In
addition, of particular interest, when women had cycles
that had previously failed, acupuncture, when added to
IVF, increased the likelihood of CPR by 60% and of live
births by 42%.
19
DISCUSSION
Previous analyses
10,11
found similar IVF outcomes when
verum acupuncture was compared with sham acupuncture.
The use of sham needles in acupuncture investigations is
controversial, as they are not inert
24,25
and obfuscate out-
comes.
20,24
Sham-needling controls involve penetrating or
nonpenetrating needles that are inserted on or off acupuncture
points and/or channels. Sham/placebo needles confound re-
sults and encourage false rejection of acupuncture therapy.
20
Future trials should be comparative in effectiveness until a
truly inert sham or placebo is developed.
Published IVF acupuncture studies have largely included
fresh autologous embryos with only 1 study investigating
acupuncture’s effects on frozen embryo cycles. In addition,
nearly all studies excluded donor embryos (fresh or frozen) as
the baseline pregnancy rates with autologous embryos are
generally better than with fresh or frozen cycles. Does acu-
puncture affect these cycles differently? It has been estimated
that FETs are associated with a 49% increase in the odds of
live births, compared with fresh ETs.
26
In a small sample of
fresh, donor cycles (N=58), *11 sessions of acupuncture
therapy were associated with a robust increase in the odds of
live birth, compared with acupuncture on the day of ET alone
(odds ratio =4.09; 95% confidence interval: 1.02–16.38).
22
Limiting the generalizability of these findings is that the
current state of evidence is lagging behind usual care in the
United States. All published studies occurred prior to the
widespread implementation of preimplantation genetic test-
ing (PGT) in IVF usual care in the United States. Many
patients add PGT to their IVF cycles to ensure only euploid
embryos are transferred, and thereby increase their chances of
delivering a healthy baby and reduce the number of cycles
needed.
27
In the 2 systematic reviews,
18,19
an analysis on acupunc-
ture’s impact on relevant psychosocial outcomes was absent,
yet, IVF patients are significantly burdened by infertility-
related stress,
28,29
and insured IVF patients have cited stress
as the primary reason they discontinued treatment despite not
conceiving.
4
Because acupuncture is widely known to mod-
ulate stress, it could be an important way to support patients
during their treatment. There is a gap in knowledge of the
magnitude of acupuncture’s effects for reducing the emotional
burden of IVF treatment. Several studies have assessed pa-
tients’ psychosocial outcomes as secondary endpoints; there-
fore, a formal systematic review and meta-analysis is needed
to assess the magnitude of acupuncture’s effect on this im-
portant outcome and these are currently underway.
CONCLUSIONS
Acupuncture has been effective for increasing CPR by
28%–32%, OPR by 42%, and LBR by 30%, compared to no
treatment. However, the efficacy of acupuncture was still
unclear and confounded by sham controls that were not inert.
Acupuncture was more effective for increasing live births
when women had previous cycles that failed, compared with
COMMENTARY 331
a control condition. Baseline pregnancy rate is also a medi-
ator of acupuncture’s effects. The characteristics of treat-
ment that were more favorable for improving outcomes were
more treatments, focusing treatment before and on the day of
ET, and using a modified Paulus protocol on the day of ET.
See Box 1.
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Box 1. Summary of the Current Evidence
on Acupuncture’s Influence on INVITRO
Fertilization Birth Outcomes
1. Acupuncture, compared to no treatment, is effective for
increasing:
Clinical pregnancy rate by 28%–32%
Ongoing pregnancy rate by 42%
Live birth rate by 30%.
2. The efficacy of acupuncture is still unclear and confounded
by the need for an adequate, inert control.
3. Acupuncture was more effective for increasing live births:
In patients with previously failed cycles
Clinics with a baseline pregnancy rate <32%.
4. Characteristics more-favorable for improving outcomes
were:
More acupuncture treatments,
Acupuncture treatment focused before and on the day
of embryo transfer
Using a modified Paulus protocol on the day of embryo
transfer.
332 COMMENTARY
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Address correspondence to:
Lee E. Hullender Rubin, DAOM, MS, LAc, FABORM
Osher Center for Integrative Medicine
University of California, San Francisco
Box 1726
1545 Divisadero Street, 4th Floor
San Francisco, CA 94115
E-mail: lee.hullenderrubin@ucsf.edu
COMMENTARY 333
Article
Introduction : Polycystic ovary syndrome (PCOS) is a complex lifelong disorder. While previous research reported on the effectiveness of acupuncture for PCOS symptoms, robust information on how PCOS is treated in community clinical practice remains sparse. This study explores how practitioners with training and certification in biomedicine and acupuncture for menstrual and reproductive health, American Board of Oriental Reproductive Medicine (ABORM) Fellows, approach the treatment of people with PCOS within the acupuncture clinic setting. Methods : Between February and March 2020, ABORM Fellows (n=346) received a link to an online survey collecting characteristics of point selection, rationale, treatment frequency, and outcome measures used. Quantitative data was analysed using descriptive statistics. Qualitative data was coded, checked for interrater reliability, and analysed using a qualitative descriptive approach. Results : One hundred and twenty-seven ABORM Fellows responded (36.7%). Practitioners reported a pragmatic approach to the treatment of PCOS in their acupuncture clinics, consistent with practising using a partnership model, especially with respect to treatment timings and frequency, often dictated by their patients’ practical and financial considerations. Acupuncture points SP6 (Sanyinjiao), SP9 (Yinlingquan), LR3 (Taichong), EX-CA-1 (Zigong), and CV4 (Guanyuan) were commonly used, following a combination of rationales provided including Drain Damp, Tonify the Spleen, and both Qi and blood movement. Local anatomy, timing of ovulation, and knowledge from research literature on acupuncture for PCOS also influenced point selection rationale. Conclusions : When treating PCOS in clinical practice, ABORM Fellows rely on both traditional and modern aspects of acupuncture and biomedicine to inform diagnosis, treatment, and outcome measures.
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Lifestyle habits of women undergoing in vitro fertilization (IVF) treatment are largely unknown. Therefore, this prospective study aimed to determine the prevalence of negative lifestyle habits in women undergoing IVF and determine if habits are related to the region in the United States and/or by mandated insurance coverage. A total of 12,811 ART patients were surveyed in infertility clinics throughout the US. They took an online questionnaire added to the patient portal of electronic medical record eIVF, a fertility-specific electronic health record. Of the women surveyed, 17-23% of patients drank alcohol, 2-7% smoked, 62-68% drank caffeine, < 1% used recreational drugs, and 47-62% exercised during their IVF treatment. There were a few statistically significant regional differences in health habits (p < 0.001) but there were no differences in health habits between women who resided in a state with mandated insurance coverage versus those without insurance coverage. This is the first prospective assessment of lifestyle habits across regions in the USA and by insurance coverage. The study concluded that women undergoing IVF engage in behaviors which may negatively impact their cycle. Women in certain parts of the US had significantly worse habits than other regions, but the availability of mandated insurance coverage did not impact health habits.
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This was a systematic review and meta-analysis to examine the efficacy, effectiveness and safety of acupuncture as an adjunct to embryo transfer compared with controls to improve reproductive outcomes. The primary outcome was clinical pregnancy. Twenty trials and 5130 women were included in the review. The meta-analysis found increased pregnancies (risk ratio [RR] 1.32, 95% confidence interval [CI] 1.07–1.62, 12 trials, 2230 women), live births (RR 1.30, 95% CI 1.00–1.68, 9 trials, 1980 women) and reduced miscarriage (RR 1.43, 95% CI 1.03–1.98, 10 trials, 2042 women) when acupuncture was compared with no adjunctive control. There was significant heterogeneity, but no significant differences between acupuncture and sham controls. Acupuncture may have a significant effect on clinical pregnancy rates, independent of comparator group, when used in women who have had multiple previous IVF cycles, or where there was a low baseline pregnancy rate. The findings suggest acupuncture may be effective when compared with no adjunctive treatment with increased clinical pregnancies, but is not an efficacious treatment when compared with sham controls, although non-specific effects may be active in both acupuncture and sham controls. Future research examining the effects of acupuncture for women with poorer IVF outcomes is warranted.
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Objective: To determine if preimplantation genetic testing for aneuploidy (PGT-A) is cost-effective for patients undergoing in vitro fertilization (IVF). Design: Decision analytic model comparing costs and clinical outcomes of two strategies: IVF with and without PGT-A. Setting: Genetics laboratory. Patients: Women ≤ 42 years of age undergoing IVF. Intervention(s): Decision analytic model applied to the above patient population utilizing a combination of actual clinical data and assumptions from the literature regarding the outcomes of IVF with and without PGT-A. Main outcome measure(s): The primary outcome was cumulative IVF-related costs to achieve a live birth or exhaust the embryo cohort from a single oocyte retrieval. The secondary outcomes were time from retrieval to the embryo transfer resulting in live birth or completion of treatment, cumulative live birth rate, failed embryo transfers, and clinical losses. Results: 8,998 patients from 74 IVF centers were included. For patients with greater than one embryo, the cost differential favored the use of PGT-A, ranging from $931-2411 and depending upon number of embryos screened. As expected, the cumulative live birth rate was equivalent for both groups once all embryos were exhausted. However, PGT-A reduced time in treatment by up to four months. In addition, patients undergoing PGT-A experienced fewer failed embryo transfers and clinical miscarriages. Conclusion: For patients with > 1 embryo, IVF with PGT-A reduces healthcare costs, shortens treatment time, and reduces the risk of failed embryo transfer and clinical miscarriage when compared to IVF alone.
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Objective: To study the reason(s) why insured patients discontinue in vitro fertilization (IVF) before achieving a live birth. Design: Cross-sectional study. Setting: Private academically affiliated infertility center. Patient(s): A total of 893 insured women who had completed one IVF cycle but did not return for treatment for at least 1 year and who had not achieved a live birth were identified; 312 eligible women completed the survey. Intervention(s): None. Main outcome measure(s): Reasons for treatment termination. Result(s): Two-thirds of the participants (65.2%) did not seek care elsewhere and discontinued treatment. When asked why they discontinued treatment, these women indicated that further treatment was too stressful (40.2%), they could not afford out-of-pocket costs (25.1%), they had lost insurance coverage (24.6%), or they had conceived spontaneously (24.1%). Among those citing stress as a reason for discontinuing treatment (n = 80), the top sources of stress included already having given IVF their best chance (65.0%), feeling too stressed to continue (47.5%), and infertility taking too much of a toll on their relationship (36.3%). When participants were asked what could have made their experience better, the most common suggestions were evening/weekend office hours (47.4%) and easy access to a mental health professional (39.4%). Of the 34.8% of women who sought care elsewhere, the most common reason given was wanting a second opinion (55.7%). Conclusion(s): Psychologic burden was the most common reason why insured patients reported discontinuing IVF treatment. Stress reduction strategies are desired by patients and could affect the decision to terminate treatment.
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Objective: To investigate whether there is a difference in obstetrical and perinatal outcomes in blastocyst frozen-thawed embryo transfers (FETs) compared with cleavage-stage FET. Design: A retrospective cohort study. Setting: Not applicable. Patient(s): Women undergoing autologous FETs at either the blastocyst stage (n = 118,572) or the cleavage stage (n = 117,619) reported to the Society for Assisted Reproductive Technology in the years 2004-2013. Intervention(s): None. Main outcome measure(s): Live birth, gestational age, birth weight, miscarriage. Result(s): After controlling for confounders, there were a 49% increased odds of live birth after blastocyst-stage FET compared with cleavage-stage FET (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.44, 1.54). Additionally, blastocyst FET was associated with a 68% (OR = 1.68; 95% CI, 1.63, 1.74) increased odds of clinical pregnancy and an 7% (OR = 0.93; 95% CI, 0.88, 0.92) decreased odds of miscarriage. There was also a 16% increased odds of preterm delivery (OR = 1.16; 95% CI, 1.06, 1.27) after blastocyst FET but no difference in birth weights. Conclusion(s): In patients undergoing FET, blastocyst-stage transfer is associated with higher live-birth rates when compared with cleavage-stage transfers. Furthermore, perinatal outcomes are similar between the groups.
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Background: Acupuncture is a common adjuvant treatment to support patients undergoing in vitro fertilisation (IVF). However, the impact of acupuncture and the different roles it can play in IVF remain unclear. Objective: In this paper, we present an overview and critique of the current evidence on acupuncture's impact on IVF-related stress, describe harms, and propose future directions for investigation. Conclusion: Two to three acupuncture sessions performed on or around the day of embryo transfer are insufficient interventions to improve IVF birth outcomes but provide significant IVF-related stress reduction. Research investigating acupuncture to support IVF is heterogeneous and confounded by the lack of an appropriate comparator. However, evidence suggests several acupuncture sessions improve endometrial thickness, reduce stress, and improve patient satisfaction. Observational studies suggest more sessions are associated with increases in clinical pregnancy and live birth rates. An optimised acupuncture intervention with a reasonable comparator is necessary for future studies, with evidence-based guidance on technique and number of sessions. Acupuncture should not be rejected as an adjuvant therapy for IVF, but more studies are needed to clarify acupuncture's role in supporting IVF cycles.
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Perspective: Acupuncture is effective for the treatment of chronic musculosketal, headache and osteoarthritis pain. Treatment effects of acupuncture persist over time and cannot be explained solely in terms of placebo effects. Referral for a course of acupuncture treatment is a reasonable option for a patient with chronic pain.