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38 ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3
In Vitro Fertilization and Acupuncture
IN VITRO FERTILIZATION AND ACUPUNCTURE:
CLINICAL EFFICACY AND MECHANISTIC BASIS
Belinda J. Anderson, PhD, LAc; Florina Haimovici, MD; Elizabeth S. Ginsburg, MD; Danny J. Schust, MD; Peter M. Wayne, PhD
months but had not conceived. More recent estimates suggest
that 10%-15% of couples experience infertility, with a higher
prevalence in women over age 34.
2
In vitro fertilization (IVF) is the most successful of the infer-
tility treatments, and for many people is the last possibility for
achieving pregnancy. In 2001 (the most recent year for which
national data were published), there were 29,344 deliveries from
IVF, which resulted in the birth of 40,687 infants. This represents
1% of all US births in that year.
2
IVF is the only infertility therapy that can successfully
bypass severe pelvic adhesions and male-factor infertility and
simultaneously elucidate causes of infertility for which no other
tests exist, such as poor oocyte maturation or failure of embryo
cleavage. As a result of recent improvements in ovulation induc-
tion protocols and adjustments in treatment regimens, 3-6 cycles
of standard IVF can result in more than 65% of patients ultimate-
ly delivering a baby.
3,4
The average delivery rate resulting from
IVF per single initiated cycle using fresh, non-donor oocyte, how-
ever, was still only 33%.
5
Therefore, the majority of IVF cycles do
not result in pregnancy, and there is generally a need for multiple
IVF cycles for pregnancy to be achieved.
For many, the cost of IVF is so high that it is difficult to
undergo even a single attempt. Estimates of the direct cost to the
patient of a single cycle of IVF range from $7,000 to $11,000.
6,7
This figure excludes the cost of medications, which averages over
$1,500 per cycle. Only 4 states in the United States mandate full
Belinda J. Anderson, PhD, LAc, is the academic dean at Pacific
College of Oriental Medicine, New York. Florina Haimovici,
MD, is the director of Education in Medical Psychiatry at
Faulkner Hospital and an instructor in Psychiatry at Brigham
and Women’s and Faulkner Hospitals, Harvard Medical
School, Boston, Mass. Elizabeth S. Ginsburg, MD, is medical
director of the In Vitro Fertilization Program at Brigham and
Women’s Hospital, Harvard Medical School. Danny J.
Schust, MD, is an associate professor of Obstetrics,
Gynecology and Women’s Health and division head,
Reproductive Endocrinology and Infertility at Columbia
School of Medicine, University of Missouri, Columbia, Mo.
Peter M. Wayne, PhD, is a director of research in the
Research Department at the New England School of
Acupuncture, Watertown, Mass.
I
nfertility is a significant public health issue with high med-
ical and social costs. In the most recent survey by the
Centers for Disease Control and Prevention (CDC) investi-
gating impaired fecundity and infertility in the United
States, 1.2 million participants (2% of those surveyed) had
an infertility-related medical appointment during the past year.
1
An additional 13% received infertility services at some point in
their lives, and 7% of married couples in which the woman was of
reproductive age reported they had not used contraception for 12
Objective • To provide an overview of the use of acupuncture
as an adjunct therapy for in vitro fertilization (IVF), including
an evidence-based evaluation of its efficacy and safety and an
examination of possible mechanisms of action.
Design • Literature review using PubMed, the Science Citation
Index®, The Cochrane Library (Database of Systematic
Reviews and Central Register of Controlled Trials), the New
England School of Acupuncture library databases, and a cross-
referencing of published data, personal libraries, and Chinese
medicine textbooks.
Results • Limited but supportive evidence from clinical trials
and case series suggests that acupuncture may improve the suc-
cess rate of IVF and the quality of life of patients undergoing IVF
and that it is a safe adjunct therapy. However, this conclusion
should be interpreted with caution because most studies
reviewed had design limitations, and the acupuncture interven-
tions employed often were not consistent with traditional
Chinese medical principles. The reviewed literature suggests 4
possible mechanisms by which acupuncture could improve the
outcome of IVF: modulating neuroendocrinological factors;
increasing blood flow to the uterus and ovaries; modulating
cytokines; and reducing stress, anxiety, and depression.
Conclusions • More high-quality randomized, controlled trials
incorporating placebo acupuncture controls, authentic acupunc-
ture interventions, and a range of outcome measures representa-
tive of both clinical outcomes and putative mechanistic processes
are required to better assess the efficacy of acupuncture as an
adjunct for IVF. (Altern Ther Health Med. 2007;13(3):38-48.)
original researchoriginal research
In Vitro Fertilization and Acupuncture
ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3 39
insurance coverage for IVF, and 8 mandate partial coverage.
8
Stress, anxiety, and depression are common among patients
undergoing IVF treatment. Potential reasons for this include the
invasive nature of the therapy itself, the knowledge that IVF is
often the last hope for a biological child, and the high cost of
treatment.
9,10
A significant body of literature supports the con-
tention that stress, anxiety, and depression contribute to lower
pregnancy rates among women undergoing IVF.
11,12
Due to the relatively low success rate of IVF per cycle, as well
as the high emotional and financial costs associated with IVF,
many patients have turned to complementary and alternative
medicine (CAM) to enhance the success of IVF treatment.
13
Among CAM treatments, acupuncture is a frequently used
adjunctive therapy. However, whether acupuncture is safe and
effective for IVF has not yet been established. This paper evaluates
the evidence regarding the efficacy and safety of acupuncture for
improving the success rate of IVF. We briefly review the biomed-
ical and traditional Chinese medicine (TCM) explanations for
infertility and then critically summarize and evaluate the studies
conducted to date that include data on the efficacy and safety of
acupuncture for improving the success rate of IVF. Finally, we
summarize published research exploring the mechanisms that
may underlie acupuncture’s impact on IVF success and propose 4
possible (interrelated) mechanisms for how acupuncture could
improve IVF success rates.
INFERTILITY FROM A WESTERN BIOMEDICAL
PERSPECTIVE
A growing body of research has begun to identify a number
of physiological and psychological mechanisms that may underlie
female infertility and explain the limited success of IVF treat-
ments. The causes of female infertility can be grouped into 4
major categories:
14
(1) abnormalities in oocyte production; (2)
anatomic abnormalities leading to obstruction of transport of the
sperm, oocyte, and/or embryo through the reproductive tract (eg,
tubal, uterine, cervical, peritoneal factors); (3) abnormalities in
the implantation process, including early defects in embryo devel-
opment, and embryo-endometrial interaction; and (4) numerous
other factors that are probably most important in women with
unexplained infertility (eg, age, body weight, cigarette smoking,
alcohol and caffeine intake, psychological and emotional factors,
immunological abnormalities, borderline hormonal imbalances).
The IVF procedure can overcome many of the conditions
that cause infertility by artificially modifying oocyte production,
fertilizing oocytes in vitro, and ensuring delivery of 1 or more
embryos into a hormonally-stimulated endometrium. For these
reasons, combined with the superior success of IVF compared to
other assisted reproductive technologies, IVF is widely used for
the treatment of infertility of known and unexplained etiology.
INFERTILITY FROM A TRADITIONAL CHINESE MEDICINE
PERSPECTIVE
The application of Chinese medicine to women’s health has
been practiced for thousands of years, and some of the earliest
written records contain rich and detailed descriptions of gyneco-
logical and reproductive disorders and their treatment.
15
The
most commonly practiced form of Chinese medicine today, both
in the West and in China, is TCM.
16
TCM developed at the turn of
the last century and represents a systemization of various
Chinese medicine practices into a unified medical system that
could best be integrated with Western medicine.
There are several fundamental theoretical constructs that
form the foundation of the TCM view of the body and its dysfunc-
tions. Used together, these underlie a complex system of diagno-
sis. In this system, signs and symptoms are analyzed to allow the
choice of one or more TCM patterns that characterize a person’s
illness. A treatment strategy is tailored around the TCM pattern
diagnoses. Acupuncture, exercise, diet, massage, and the use of
herbs comprise the fundamental TCM treatment modalities.
Acupuncture is based on the notion that there are pathways
(meridians) within the body where qi (Chi) flows. Along these
meridians are specific regions (acupuncture points, acupoints)
that are used to treat specific conditions. Fundamental to the
Chinese medicine understanding of the mechanism of acupunc-
ture is the idea that stimulation of these points alters the flow of
qi in the meridian system. Scientific studies have shown that
acupuncture points and meridians have unique electrical proper-
ties and connective tissue characteristics.
17,18
The most common way that the effect of an inserted
acupuncture needle is enhanced is through either manual manip-
ulation or electrical stimulation. Simple manual insertion of
acupuncture needles with brief manipulation was the most com-
mon form of practice until the middle of the 20th century, when
mild electrical stimulation (10-100 Hz) of inserted needles, elec-
tro-acupuncture (EA), was developed. The majority of research
investigating the efficacy and mechanistic basis of acupuncture
(especially when used for pain suppression) has focused on EA,
but the most common clinically practiced form of acupuncture in
the United States is manual acupuncture.
16
Thus far, there has
been only limited investigation into the clinical and mechanistic
similarities and differences between EA and manual acupuncture.
When considered from a TCM perspective, infertility is
almost always associated with some type of Kidney deficiency,
although additional secondary imbalances are often also pre-
sent.
19,20
The Kidney in TCM does not refer to the organ and associ-
ated functions from a biomedical perspective (and the “K” is
capitalized). Rather, the TCM concept of Kidney encompasses the
organ and a range of functions and physiological processes, some
of which bear no relationship to kidney function in a biomedical
sense. In TCM, the Kidney underlies the fundamental constitu-
tion of a person and in women directly relates to a 7-year cycle
corresponding with developmental changes from birth through
childhood, puberty, the reproductive years, and old age. Within
this framework, infertility often reflects an earlier-than-normal
decline of Kidney-related functions that results from either consti-
tutional factors (eg, genetic) or lifestyle and dietary issues.
19
Common causes of infertility within the TCM framework are qi
imbalances and deficiencies, blood-level imbalances (insufficiency
40 ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3
and blocked circulation), blockages due to the buildup of fluids,
and inflammatory processes.
19-21
Treatment of infertility in TCM begins with the diagnosis of
primary and secondary patterns, based on the grouping of signs
and symptoms assessed using standard examination techniques
(eg, pulse and tongue analysis, interview).
19
According to Liang,
the various western medical infertility diagnoses can be viewed
within the context of the various TCM patterns.
21
TCM pattern
diagnoses of Kidney yin deficiency, Kidney yang deficiency, blood
deficiency, and qi deficiency include the Western medical diag-
noses of anovulation, small or misshapen uterus, poor follicle
and/or egg quality, low estradiol, low progesterone, and high fol-
licle-stimulating hormone (FSH). TCM pattern diagnoses of qi
stagnation, blood stasis, and phlegm damp obstruction include
the Western medical diagnoses of blocked fallopian tubes, uterine
fibroids, ovarian cysts, endometriosis, adhesions, and stress. The
TCM pattern diagnosis of damp heat includes the Western med-
ical diagnoses of infections of the cervix, vagina, pelvis, urinary
tract, and fallopian tubes.
Based on the patterns diagnosed, a specific acupuncture pro-
tocol (treatment strategy) is developed to address imbalances.
The treatment strategy dictates the number and location of
acupuncture points (eg, specific body and ear acupoints), type of
needle stimulation (eg, manual or electrical), and number and fre-
quency of treatments.
19
Though the tailoring of treatment strate-
gies to individual primary and secondary diagnostic patterns is
standard in clinical practice and increasingly appreciated in
acupuncture research,
22
this approach is not reflected in the
research on the use of acupuncture in conjunction with IVF that is
summarized below.
EVALUATING THE EFFICACY OF ACUPUNCTURE AS AN
ADJUNCT THERAPY FOR IN VITRO FERTILIZATION
Methods
To review the existing research regarding acupuncture as an
adjunct therapy for IVF, we conducted a literature search using
PubMed, the Science Citation Index, the Cochrane Database of
Systematic Reviews, the Cochrane Central Register of Controlled
Trials, and the New England School of Acupuncture library data-
bases. Additional manual searches of retrieved articles, personal
libraries, and TCM textbooks were conducted. Search terms
included acupuncture or electroacupuncture and in vitro fertilization
or IVF or fertility or embryo transfer or ovulation. Only full-length
studies (studies reported as abstracts were excluded) that used
either acupuncture and/or electroacupuncture (acupressure was
excluded) in conjunction with IVF were included in this review.
Studies using Chinese herbs in conjunction with acupuncture also
were included.
Results
The table summarizes the 11 studies that resulted from the
literature searches in conjunction with the exclusion and inclu-
sion criteria. The table separates the studies according to study
aims and experimental design. The first 4 studies were prospec-
tive randomized controlled trials (RCTs)
23-26
specifically designed
to address the hypothesis that acupuncture improves the out-
come of IVF. The fifth and sixth studies were prospective RCTs
primarily investigating the use of electroacupuncture as an alter-
native to conventional analgesic methods for oocyte retrieval and
also collected data on IVF outcome.
27,28
The seventh study was
prospective with no randomization,
29
and the eighth through
eleventh studies were case series
30,31
and narrative descriptions of
case studies in TCM texts.
20,21
Randomized, Controlled Trials to Determine Whether Acupuncture
Improves In Vitro Fertilization Outcomes
Of the 4 RCTs specifically addressing the hypothesis that
acupuncture could increase the success rate of IVF, 2 had sham
acupuncture controls.
24,25
Of these 4 studies, 3 present evidence
suggesting acupuncture can significantly improve the success of
IVF. The first study, by Paulus et al, included 160 women (average
age 32.5 years) undergoing IVF with or without intracytoplasmic
sperm injection (ICSI).
23
Two groups were compared (n=80 each).
One group received EA 25 minutes before and 25 minutes after
embryo transfer (ET), and the other underwent a standard IVF
procedure without acupuncture. The clinical pregnancy rate in
the non-acupuncture group was 21/80 (26%) compared to 34/80
(42.5%) in the EA group.
The Paulus et al study
23
published in 2002 provided the
impetus for further studies, 3 of which were published in 2006.
24-26
In a study involving 225 women (average age 34.9 years), Dieterle
et al investigated the effect of real (n=116) and sham (n=109)
acupuncture on the outcome of IVF with and without ICSI.
24
Sham acupuncture was undertaken by the use of points that were
not appropriate for fertility-related conditions. Two manual
acupuncture treatments were given 30 minutes and 3 days after
ET. The group that received real acupuncture compared with the
sham group had significantly higher implantation rates (14.2% vs
5.9%, respectively), clinical pregnancy rates (33.6% vs 15.6%), bio-
chemical pregnancy rates (35.3% vs 16.5%), and ongoing pregnan-
cy rates (28.4% vs 13.8%).
Smith et al compared real acupuncture to sham acupunc-
ture.
25
The sham intervention involved the use of non-acupunc-
ture points and the non-insertive Streitberger needle (the shaft of
the needle collapses into the needle handle) in women undergo-
ing IVF with and without ICSI. All subjects (average age 36 years,
randomized into 2 groups) received 3 acupuncture treatments on
day 9 of stimulating injections and immediately before and after
ET (similar to Paulus et al’s methods). Subjects in the real
acupuncture group (n=110) as compared with the sham group
(n=118) exhibited statistically non-significant trends toward high-
er pregnancy rates (31% vs 23%, respectively) and ongoing preg-
nancy rates at 18 weeks (28% vs 18%).
In a study of women (average age 37 years) undergoing IVF
with and without ICSI, Westergaard et al compared subjects who
had not received acupuncture (n=87) with those who had
received acupuncture immediately before and after ET (ACU 1
group, n=95), and with an additional acupuncture treatment 2
In Vitro Fertilization and Acupuncture
In Vitro Fertilization and Acupuncture
ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3 41
Author, Year
(Reference)
1. Paulus et al,
2002 (23)
2. Dieterle et al,
2006 (24)
3. Smith et al,
2006 (25)
4. Westergaard
et al, 2006
(26)
5. Stener-
Victorin et al,
1999 (27)
6. Stener-
Victorin et al,
2003 (28)
Study
Design
RCT
RCT
RCT
RCT
RCT
RCT
Study
Population
• 160 women
• Age 32.5 y; range
28.5-36.5 y
• 225 women
• Avg age 34.9 y;
range 31.3-38.9 y
• 128 women
• Avg age 36 y;
range 31.2-40.9 y
• 273 women
• Avg age 37 y;
range 24-45 y
• 150 women
• Avg age 34.4 y;
range 25-46 y
• 286 women
• Avg age 32.9 y,
range 22-38 y
Intervention
(Sample Size)
• Acu (n=80)
• Control: No Acu
(n=80)
• Acu (n=116)
• Control: placebo
Acu (sham pts)
(n=109)
• Acu (n=110)
• Control: Placebo
(sham pts,
Streitberger)
(n=118)
• Acu-1 tx (n=95)
• Acu -2 tx (n=91)
• Control: no Acu
(n=87)
• Acu + PCB
(n=75)
• Control:
alfentanil + PCB
(n=75)
• Acu + PCB
(n=141)
• Control:
alfentanil + PCB
(n=145)
Acupuncture
Treatment
• MA
• 25 min before and after ET
• Fixed protocol
• MA
• Two txs 30 min and 3 days
after ET
• Fixed protocol
• MA
• 3 txs: Day 9 of stimulating
injections, before and
after ET
• Used Paulus and TCM to
determine pt selection
(pts not specified)
• MA
• 25 min before and after ET
(Acu-1); plus 2 days post ET
(Acu-2)
• EA and MA
• One tx, 30 min before and
until the end of OA
• Fixed protocol
• EA and MA
• One tx, 30 min before and
until the end of OA
• Fixed protocol
Relevant Outcomes
Measured
• Clinical pregnancy—
presence of a fetal sac
(by ultrasound) 6 wks
post ET
• Uterine artery
pulsatility index
• Clinical pregnancy rate
• Biochemical
pregnancy rate
• Implantation rate
• Ongoing pregnancy rate
• Miscarriages
• Clinical pregnancy rate
• Implantation
• Ongoing pregnancy
• Adverse events
• Health status
• Clinical pregnancy
• Ongoing pregnancy
• Pain before/after OA
• No. of ICSI cycles
• No. of standard
IVF cycles
• No. of oocytes retrieved
• Fertilization rate
• No. of ET
• No. of pregnancy, and
miscarriages before
16th wk
• Implantation rate
• Take-home baby per ET
• Pain before/after OA
• No. of oocytes retrieved
• Fertilization rate
• No. of ET procedures
• No. of ET
• No. of pregnancy, and
miscarriages before
16th wk
Results
• Women receiving Acu had a higher clini-
cal pregnancy rate (42.5% vs 26.3%)*
• No difference between the Acu and
no-Acu groups in the uterine artery
pulsatility index
• Acu group compared to the placebo group
had significantly higher clinical pregnancy
rate (33.6% vs 15.6%)*, biochemical preg-
nancy rate (35.3% vs 16.5%)*, implanta-
tion rate (14.2% vs 5.9%)*, and ongoing
pregnancy rate (28.4% v 13.8%)*
• No difference in miscarriages
• No significant differences in any outcomes
• Clinical pregnancy rate: Acupuncture vs
placebo – 34% vs 27%
• Acu-1 group compared to control had sig-
nificantly higher clinical and ongoing
pregnancy rates (39% vs 26% and 36%
vs 22%)*
• Acu-2 group not significantly different
from control
• Acu-2 had a higher, but not significantly,
early pregnancy loss compared to Acu-1
and control (33% vs 15% vs 21)
• Acu equal to alfentanil in pain
management
• Acu had significantly higher implantation
rate (27.2% vs 16.3%)*, pregnancy rate
(45.9% vs 28.3%)*, and take-home baby
rate (41% vs 19.4%)* per ET
• Acu greater stress before OA and longer
period of discomfort
• Acu equal to alfentanil in pain
manangement
• No significant differences between
Acu and alfentanil groups in any IVF
outcome measures
• Neuropeptide Y in FF were significantly
higher in the Acu group
TABLE Summary of Studies Evaluating Acupuncture as an Adjunct Therapy for IVF
42 ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3
In Vitro Fertilization and Acupuncture
days after ET (ACU 2 group, n=91).
26
Clinical and ongoing preg-
nancy rates were significantly higher in the ACU 1 group com-
pared with controls (39% vs 26% and 36% vs 22%, respectively).
The ACU 2 group, compared with the control group, exhibited
statistically non-significant trends toward higher clinical and
ongoing pregnancy rates (36% vs 26%, respectively).
Trials Investigating the Use of Acupuncture as an Alternative to
Conventional Analgesic Methods for Oocyte Retrieval
Two prospective, randomized studies were aimed primarily
at investigating the efficacy of acupuncture as an alternative to
pharmacological analgesia for ooctye aspiration.
27,28
These studies
also assessed differences in pregnancy rates between those receiv-
ing acupuncture and those receiving conventional analgesia. Each
of these studies used a single acupuncture treatment (consisting
of EA and manual acupuncture) performed 30 minutes before
oocyte aspiration and lasting until just after aspiration was com-
pleted. The first study showed that women who received acupunc-
ture had significantly higher implantation rates (27.2% vs 16.3%),
pregnancy rates (45.9% vs 28.3%), and take-home baby rates (41%
7. Balk et al,
2003 (31)
8. Emmons
and Patton,
2000 (32)
9. Johnson
2006 (33)
10. Liang
2003 (21)
11. Lyttleton
2004 (20)
CT
Case
series
Case
series
Case
study
Case
study
• 10 women
• Avg age 36 y,
range 31-41 y
• 6 women
• Avg age 35.8 y;
range 29-41 y
• 22 women
• Avg age 36.2 y;
range 31.5-43.2
• 11 women
• Ages 32-48 y
• 2 women
• Ages 39 and 40 y
• Acu (n=10)
• Control: No-Acu
group were other
women at the clinic
• Acu (n=6)
• Acu (n=22)
• Control: No acu
group were women
at the clinic during
2003
• Acu and Chinese
herbs (n=10)
• Acu only (n=1)
• Acu and Chinese
herbs (n=2)
• EA
• 2 tx/wk for 4 wk prior to ET
• Fixed protocol
• MA
• 3-4 twice weekly tx on days
1-3, 4-6, 7-9, and 9-11 + tx on
day of or prior to egg retrieval
• Fixed protocol + individual
points
• MA
• Introductory and 3 full tx
prior to ET, 2 tx 25 min
before and after ET
• MA
• Individual protocol
• MA
• Individual protocol
• No. gestational sacs
• Pregnancy and
implantation rates
• No. of on-going
pregnancy
• Neuropeptide
Y in FF
• Amount of addi-
tional analgesic
• Uterine artery
pulsatility index
• Endometrial lining
• Eggs retrieved
• Eggs fertilized
• Embryos
transferred
• No of follicles
retrieved
• Pregnancy rate
• Pregnancy rate past
first trimester
• Fetal heart beat 4
weeks after ET
• Take-home baby
• Take-home baby
• Acu group reported significant-
ly lower amounts of additional
alfentanil
• 2 hr after OA Acu group
reported significantly less
abdominal pain, other pain,
nausea and stress and were
significantly more calm
• No significant differences
between Acu and no-Acu group
in any outcome measures
• No pregnancy in non-Acu cycles
• 3 women produced more folli-
cles following Acu tx (11.3 vs
3.9), all 3 women conceived,
but only 1 pregnancy lasted
past the first trimester
• Acu group had greater
pregnancy rate than control
(57.7% vs 45.3%), but not
statistically significant
• Tx resulted in take-home baby
for all subjects
• Tx resulted in take-home baby
for both subjects
TABLE Summary of Studies Evaluating Acupuncture as an Adjunct Therapy for IVF (continued)
Author, Year
(Reference)
Study
Design
Study
Population
Intervention
(Sample Size)
Acupuncture
Treatment
Relevant Outcomes
Measured Results
Acu=acupuncture; Avg=average; CT=controlled trial; EA=electroacupuncture; ET=embryo transfer; FF=follicular fluid; ICSI=intracytoplasmic sperm injection;
IVF=in vitro fertilization; MA=manual acupuncture; OA=oocyte aspiration; PCB=paracervical block; Preg=pregnancy; Pts=points; RCT=randomized controlled trial;
Y=years; STAI=State Trait Anxiety Inventory; TCM=traditional Chinese medicine; Tx=treatment
*Significant to at least P<.05
In Vitro Fertilization and Acupuncture
ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3 43
vs 19.4%) per embryo transfer.
27
The similarly designed subse-
quent study
28
and others
29,30
failed to confirm these results.
Prospective Non-randomized Study, Case Series, and Narrative
Descriptions of Case Studies in Traditional Chinese Medicine Texts
In a study by Balk et al, 10 women (average age 36 years)
were given EA twice a week for 4 weeks prior to embryo transfer
and compared with an unknown number of women in the same
clinic who did not receive EA.
31
No significant difference was seen
between the women who received EA and those who did not in
any of the outcome measures.
Emmons and Patton undertook a case series involving 6
women (average age 35.8 years) who had previously responded
poorly to gonadotropin therapy and who were undergoing IVF
with ICSI.
32
These women received twice-weekly manual
acupuncture for 3 or 4 weeks. There were no pregnancies in non-
acupuncture cycles. Of the 6 women, 3 produced more follicles
after acupuncture treatment and all 3 conceived; only 1 woman’s
pregnancy lasted past the first trimester. Johnson undertook a
case series of 22 women (average age 36.2 years) who received an
introductory treatment followed by 3 full treatments prior to ET
and 2 treatments 25 minutes before and after ET.
33
These women
were compared to other women in the clinic who had not
received acupuncture and exhibited statistically non-significant
trends toward higher pregnancy rates (57.7% in the acupuncture
group vs 45.3% in the no-acupuncture group). A couple of narra-
tive case studies involving 13 women who were treated with
acupuncture and Chinese herbs reported that all women gave
birth to healthy babies.
20,21
Collectively, the studies summarized in the table suggest the
following.
Acupuncture may improve the success rate of IVF. Four of
6 RCTs (including 3 of the 4 specifically designed to test improved
pregnancy rates),
23-27
1 case series,
32
and 13 narrative case stud-
ies
20,21
suggest that acupuncture may improve IVF outcome.
Acupuncture may improve the quality of life (QOL) of
patients undergoing IVF. Two RCTs demonstrated that acupunc-
ture was equivalent to conventional analgesia for managing pain
associated with oocyte aspiration.
27,28
Stener-Victorin et al also
reported that women receiving acupuncture reported significantly
less abdominal pain, other pain, nausea, and stress 2 hours after
oocyte aspiration compared to women receiving conventional
analgesia.
28
Another RCT reported that women who had received
acupuncture for pain management associated with oocyte aspira-
tion had less postoperative tiredness and confusion when com-
pared with women receiving conventional analgesia.
29
In 2 of these
studies, however, patients who had received acupuncture were
reported to have experienced greater stress, discomfort, and/or
pain.
27,29
Smith et al reported that the most frequently reported side
effects of the acupuncture treatments were relaxation, feeling calm
and peaceful, and feeling energized.
25
Acupuncture may be a safe adjunct therapy for IVF
patients. No adverse events were reported in any of the studies
presented in the table. This coincides with the excellent general
safety profile of acupuncture.
34,35
Although the studies summarized in the table suggest
acupuncture may improve pregnancy rates and QOL among
patients undergoing IVF, these results must be considered incon-
clusive and interpreted with caution for the following reasons.
The majority of available studies have significant design
limitations. Of the 6 RCTs, only 4 were specifically designed to
address the hypothesis that acupuncture could increase the success
rate of IVF, and only 2 of these included sham acupuncture con-
trols. Though case series and non-randomized studies provide
additional support, the absence of randomization and control
groups in these studies results in great potential for bias. In studies
that did not include a sham acupuncture control, it is difficult to
distinguish the effects of acupuncture needling from placebogenic,
non-specific effects associated with treatments.
36,37
In many studies,
details of procedures related to eligibility screening, randomiza-
tion, blinding, and statistical analyses were absent. Other reviews
of this literature highlight these and additional limitations of the
studies, especially in relation to the choice of the primary outcome
measure (pregnancy rate) and a range of issues related to sample
size calculation and statistical analysis of outcome data.
38-40
The majority of the acupuncture protocols employed in
studies to date do not reflect clinical practice. First, the dosages
of acupuncture employed in most of the trials were very low (1-9
treatments). In standard clinical practice, acupuncture treatment
protocols occur over a period of weeks or months, especially for
conditions such as infertility, which often are associated with
long-standing deficiencies and imbalances.
19
Second, TCM diag-
noses were assessed in only 1 of the trials presented in the table
and even in that study were not used to determine all acupunc-
ture treatments.
25
Consequently, in all other studies, treatment
protocols were not tailored to address TCM-specific imbalances
and symptoms. Rather, the same treatment protocol was given to
all subjects regardless of the basis of their infertility from a TCM
perspective. This potentially creates a fixed-protocol bias and
reduces the likelihood that the treatment will be appropriate and
effective for individual subjects.
41
Several studies used EA, a form of treatment that is not com-
monly used in a clinical setting for the treatment of infertility.
27,28,31
The choice of acupuncture points was often difficult to under-
stand and justify and without a high degree of similarity to sug-
gested protocols in Chinese medicine texts.
19-21
Furthermore, some
points (Sp6 and LI4) are contraindicated in pregnancy and may
therefore be unsuitable after ET. This may explain the outcome
reported by Westergaard et al of a greater early pregnancy loss in
subjects who were given acupuncture 2 days after ET, as com-
pared with those not receiving acupuncture and those only receiv-
ing acupuncture immediately before and after ET (33% vs 21% vs
15% respectively).
26
Several of the recent study critiques commented on prob-
lems associated with the choice of acupuncture points and ear
treatments that were used in some of these studies. This touches
on a much larger issue of the authentic use of acupuncture in a
conventional medical setting within the confines of a clinical trial.
44 ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3
In Vitro Fertilization and Acupuncture
TCM diagnosis and point selection are complex issues based on
an in-depth understanding of a large body of theoretical informa-
tion. Clinical trials need to involve properly trained acupunctur-
ists who are knowledgeable in the discipline, preferably with
nationally recognized qualifications, certifications, and appropri-
ate licenses. This would negate the readers’ need to try and under-
stand, validate, and justify the acupuncture protocols when the
majority of them are not qualified to do so.
Important details of the experimental protocol are not
provided. The qualifications and experience of the acupunctur-
ists involved in the design and administration of the treatment
protocols are poorly described, making it difficult to assess the
validity of the intervention. Additionally, many other details of
the experimental protocol, as suggested by the standards for
reporting interventions in controlled trials of acupuncture
(STRICTA),
42
were not reported, making the quality of the these
trials’ outcomes difficult to evaluate.
In summary, although methodological problems with the
existing clinical research limit conclusions, there is some evidence
to suggest that acupuncture may be a safe and effective adjunct
therapy for women undergoing IVF. There is a definite need for
more thorough and carefully designed clinical trials to evaluate
the effect of acupuncture on IVF success rates.
POTENTIAL MECHANISMS UNDERLYING ACUPUNCTURE’S
IMPACT ON FERTILITY AND IN VITRO FERTILIZATION
SUCCESS RATES
Understanding the mechanism by which acupuncture
improves IVF success rates is important because it defines appro-
priate outcome measures that should be evaluated in future clini-
cal trials assessing the use of acupuncture with IVF. It also
furthers our understanding of how acupuncture modulates specif-
ic physiological processes, which could lead to a more targeted
approach to identifying women who would specifically benefit
from acupuncture while undergoing IVF.
Drawing on a broad body of literature evaluating the mech-
anistic basis of acupuncture as well as our understanding of the
physiological basis of female fertility, we propose 4 interrelated
mechanisms by which acupuncture could improve the outcome
of IVF: (1) modulating neuroendocrinological factors; (2)
increasing blood flow to the uterus and ovaries; (3) modulating
immune factors, especially cytokines; and (4) reducing stress,
anxiety, and depression.
Acupuncture and the Hypothalamus-Pituitary-Gonadal
and -Adrenal Axes
The hypothalamus releases a range of hypophysiotrophic
hormones, several of which are directly or indirectly important
for fertility: gonadotropin-releasing hormone (GnRH), corti-
cotrophin-releasing hormone (CRH), growth hormone-releasing
hormone (GHRH), and thyroid-releasing hormone (TRH). These
hormones act on the pituitary gland to regulate its own hormone
production.
14
GnRH regulates the production of FSH and luteiniz-
ing hormone (LH), which in turn regulates the activity of the
ovaries and their production of estrogen and progesterone. The
ovarian steroid hormones then provide a feedback mechanism to
regulate the hypothalamus. The connection of the hypothalamus-
pituitary-gonads is called the HPG axis. Likewise, CRH regulates
the production of adrenocorticotrophic hormone (ACTH), which
in turn regulates the secretion of cortisol by the adrenal gland.
Cortisol can then negatively feed back on the hypothalamus and
pituitary gland to control the further production of both ACTH
and CRH. The connection of the hypothalamus-pituitary-adrenal
gland is called the HPA axis. Both of these axes play important
roles in reproductive function.
14
The production of GHRH and
TRH and the physiological functions that they regulate also can
play an important role in fertility.
14
Many reproductive problems are related to abnormalities in
hypothalamic and pituitary function. These can be caused by
structural abnormalities such as tumors; genetic mutations
(either acquired or congenital); lifestyle factors (such as poor
nutrition, excessive exercise, smoking, obesity, and chronic
stress); and psychological factors (such as eating disorders and
depression). The HPA axis is intimately involved in the negative
effects that stress has upon fertility. Stress elevates cortisol levels.
Cortisol enhances vascular reactivity, activates the catabolism of
protein and fat to provide energy, and inhibits insulin activity.
Chronic exposure to stress and elevated cortisol levels inhibit
nonessential processes such as reproduction.
Precisely how acupuncture can affect neuroendocrinological
factors is not known. It is well established, however, that EA
inhibits pain perception by elevating several classes of neuro-
chemicals,
43
including β-endorphin.
44
The ability of acupuncture
to affect a range of cellular and physiological functions is attrib-
uted to this modulation of neurochemicals. These substances
then influence a range of hypothalamic functions and affect
reproduction, autonomic function, and even the immune sys-
tem.
14,45,46
It has been suggested that acupuncture acts to modulate
both the HPG
28,47,48
and HPA
49,50
axes.
Recent studies have demonstrated that EA can alter several
different neuroendocrinological factors that are important deter-
minants of female fertility. Stener-Victorin et al showed that low-
frequency (2 Hz) EA treatment induced regular ovulation in one
third of women with anovulation associated with polycystic ovary
syndrome (PCOS).
51
Using a rat model of steroid-induced PCOS,
low-frequency EA has been shown to reduce elevated ovarian
nerve growth factor, corticotrophin-releasing factor, and endothe-
lian concentrations
47,50
and to increase concentrations of hypothal-
amic β-endorphin.
52
This appears to result from a modulation of
the sympathetic nerve activity in the ovary
53
and allows EA to nor-
malize most of the steroid-induced changes in ovarian adrenocep-
tors and to prevent steroid-induced up-regulation of the
low-affinity p75 neurotrophin receptor.
54
Acupuncture and Uterine and Ovarian Blood Flow
Adequate blood flow to the developing ovarian follicle and
decidualized endometrium is essential to the initiation and main-
tenance of normal human pregnancy. Doppler ultrasound evalua-
In Vitro Fertilization and Acupuncture
ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3 45
tion of uterine and ovarian blood flow has demonstrated that
improved blood flow in either vascular system is associated with
improved fertility outcomes, although follicular flow measure-
ments are more closely correlated with improved fertility out-
comes.
55-57
Blood flow impedance in the uterine arteries expressed
as a resistance index, the pulsatility index (PI), is considered valu-
able in assessing endometrial receptivity. A high uterine artery PI
is associated with a decreased pregnancy rate following IVF-
embryo transfer.
58,59
The use of ultrasound guidance for the retrieval of oocytes
during IVF cycles has demonstrated that the systolic velocity of
blood flow to a particular ovarian follicle was directly associated
with the ability to retrieve an oocyte from that follicle.
60
Women
who respond poorly to ovarian stimulation for IVF have compro-
mised blood flow to their ovarian follicles (and uteri) when com-
pared to women with normal ovarian responses.
57
The levels of
the vasoactive protein vascular endothelial growth factor (VEGF)
in the follicular fluid of poor responders is higher than that of
normal responders, and levels are inversely related to the subse-
quent quality of the embryo that is produced by the retrieved egg.
VEGF promotes angiogenesis and is produced and secreted in
response to hypoxia. High levels of VEGF in the follicular fluid
can be used to identify poor follicular development.
61
Acupuncture has been shown to modulate the circulation of
blood in many different parts of the body. Studies have shown
that acupuncture can alter cerebral blood flow
62-64
and peripheral
blood flow.
65-68
The efficacy of acupuncture in the treatment of
several disorders, including migraine headaches,
69
cerebral
ischemia,
70,71
and fibromyalgia,
66
has been proposed to be mediat-
ed by its effects on blood flow.
In a study by Stener-Victorin et al, repeated EA treatments in
10 infertile women resulted in a significantly decreased PI of the
uterine arteries.
72
This decrease was sustained for 10-14 days after
the EA treatment period. Latter studies in rats by the same group
showed that low-frequency EA increased ovarian blood flow as a
reflex response via the ovarian sympathetic nerves.
53,73
In contrast,
high-frequency EA decreased ovarian blood flow following sys-
temic circulatory changes in both normal rats and rats with PCOS.
Acupuncture also has been shown to modulate the production of
several angiogenic factors, such as endothelin-150 and VEGF.
74
Acupuncture and Cytokines
A growing body of literature supports a role between certain
soluble mediators of immune responses and the achievement and
maintenance of pregnancy. A brief description of the classifica-
tion of these factors is presented, followed by a discussion of their
putative role in fertility.
T helper cell phenotypes have been subcategorized based on
the cytokine secretory profiles of CD4+ cells. Th1 cells promote
inflammation via the secretion of inflammatory cytokines (eg,
interferon [IFN] gamma, interleukin [IL]-2, IL-12, IL-18), whereas
Th2 cells promote allergic-type responses, including mast cell and
eosinophil activation and antibody production. Cytokine secretion
associated with Th2 responses involves IL-4, IL-6, IL-10, and IL-13.
Th3 responses are characterized by the secretion of transforming
growth factor beta (TGFβ). Development of these phenotypes
begins with the naïve T helper progenitor (Thp) cell. Cytokines
and chemokines in the environment where Thp cells encounter
major histocompatibility complex (MHC) class II-presented anti-
gen direct the development of Th1, Th2, or Th3 phenotypes.
With the exception of a brief and immediate pro-inflammatory
response at the site of implantation, successful human pregnancy
appears to be characterized by a local and systemic Th2 dominance;
women with repeated pregnancy failure may be unable to modulate
their T helper responses appropriately upon becoming pregnant.
75,76
T helper cytokine profiles and their modulation in pregnancy and
upon exposure to pregnancy-related hormones have been studied
extensively. This includes their relationship with fertility,
77
repeated
implantation failure after IVF,
78
and recurrent clinical pregnancy
loss.
79
T helper cell dysregulation that adversely affects pregnancy
outcomes could be occurring systemically, at the level of the
endometrium/implantation, within the microenvironment of the
developing ovarian follicle, or at all sites.
Several studies have demonstrated acupuncture’s ability to
modulate cytokine production. It has been proposed that in the
brain, acupuncture may modulate cytokine levels via its ability to
increase the release of β-endorphin.
45,80
Investigators have demon-
strated that acupuncture normalizes Th1- and/or Th2-type
cytokines in the ventral midbrains of healthy rats,
81
in the hypo-
thalami of rats with lipopolysaccharide-induced fever,
82
and in the
ischemic cortices of rats with middle cerebral artery occlusion.
83
Chen et al showed that EA stimulation significantly up-regulated
IL-6 mRNA levels in rat cortex and striatum following cerebral
ischemia/reperfusion.
84
This may explain the neuroprotective
effect of acupuncture in cerebral ischemic injury. Other investiga-
tors have shown similar protective peripheral cytokine modula-
tion when acupuncture was used in rats with induced ulcerative
colitis
85
and in rats that had experienced operative trauma.
86
Yu e t
al showed that rats receiving acupuncture had elevated levels of
IL-2 in aqueous spleen extracts.
87
In humans, Jeong et al investigated the effect of acupuncture
on the production of inflammatory cytokines in patients with
chronic headaches and found that acupuncture resulted in
decreased levels of IL-1β and IL-6.
88
Petti et al showed that
acupuncture treatment reduced the plasma levels of IL-2 and IL-
10 in subjects with chronic allergic rhinitis when compared to
subjects receiving no treatment or those receiving sham acupunc-
ture.
89
Joos et al conducted an RCT to assess the effects of
acupuncture in the treatment of allergic asthma and found that
there was a significant reduction in the plasma levels of IL-6 and
IL-10 in subjects receiving acupuncture.
90
In contrast, IL-8 levels
rose significantly. Others have demonstrated similar cytokine nor-
malization in patients with malignant tumors
91
or rheumatoid
arthritis
92
who were treated with acupuncture.
Acupuncture and Stress, Anxiety, and Depression
A significant amount of literature supports the contention
that women who experience depression while undergoing IVF
46 ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3
In Vitro Fertilization and Acupuncture
have lower pregnancy rates than women who are not
depressed.
11,93
Depressive symptoms are common among
patients who undergo IVF, and the severity and prevalence of
depression increase as the number of IVF treatment failures
increases.
93
Anxiety is also correlated with pregnancy rates in
IVF. Women with significant concerns about the financial cost
associated with IVF were at much higher risk of not achieving a
successful delivery.
12
A prospective study of 291 women found
that anxiety had a stronger negative correlation with IVF out-
come than did depression.
94
Another study found that women
with episodic anxiety, but not those with trait or acute anxiety,
were less likely to conceive in the second IVF attempt if the first
was not successful.
95
Stress reduction appears to enhance fertility. A randomized,
controlled study of 184 women undergoing a combination of
infertility treatments evaluated the impact of cognitive behavioral
therapy (including relaxation and yoga) on pregnancy rates.
96
Women undergoing cognitive behavioral therapy were compared
to those attending a standard support group and routine care
controls. Patients with depression were excluded from the study.
Pregnancy rates were significantly higher in women undergoing
cognitive behavioral therapy and in those attending support
groups when compared to the control group; treatment groups
did not differ from one another. In a smaller study of couples
undergoing IVF,
60
couples were randomized to either counseling
or a control group during IVF.
97
The group who underwent coun-
seling experienced significantly lower anxiety and depression
scores, higher life satisfaction scores, and significantly higher
pregnancy rates than control couples. These data make a strong
case for the use of therapies that can reduce stress and negative
emotional states in women undergoing IVF.
Studies have shown that acupuncture may be effective in the
treatment of depression,
98-100
anxiety,
101,102
and stress.
103-106
Gallagher
et al conducted an RCT with 38 participants and concluded that
compared to other empirically validated treatments (eg, medica-
tion, talk therapy), acupuncture designed specifically to treat
major depression produces results that are comparable in terms of
rates of response and of relapse or recurrence.
98
In a clinical trial
involving 30 subjects receiving acupuncture compared with 31
subjects receiving drug therapy, Han et al concluded that EA can
produce the same clinical therapeutic effect as that produced by
the tetracyclic antidepressant maprotiline, with fewer side effects
and better symptom improvement.
99
Spence et al conducted a clin-
ical trial involving 18 anxious adult subjects who complained of
insomnia.
102
Five weeks of acupuncture treatment was associated
with a significant nocturnal increase in endogenous melatonin
secretion and significant improvements in polysomnographic
measures of sleep onset latency, arousal index, total sleep time,
and sleep efficiency. Additionally, state and trait anxiety scores
were lowered significantly. Middlekauff et al tested the hypothesis
that acupuncture is sympathoinhibitory in humans with heart fail-
ure.
103
Fifteen advanced heart failure patients underwent acute
mental stress testing before and during “real” acupuncture (n=10),
non-acupoint acupuncture (n=10), or no-needle acupuncture
(n=10). During the pretreatment mental stress testing, sympathet-
ic nerve activity increased significantly. This increase was eliminat-
ed after real acupuncture but not after non-acupoint or no-needle
acupuncture control treatments.
With regard to the use of acupuncture during the IVF proce-
dure, Gejervall et al demonstrated that acupuncture significantly
reduced postoperative tiredness and confusion in women under-
going oocyte aspiration for IVF.
29
Stener-Victorin et al showed
that 2 hours after oocyte aspiration, the group of women receiv-
ing acupuncture (at the time of oocyte aspiration) experienced
significantly less abdominal pain, other pain, nausea, and stress
and were significantly calmer than those in the control group,
who had received conventional analgesia.
28
The mechanistic basis for the effects of acupuncture on
depression, anxiety, and stress are not well understood. A num-
ber of possibilities have been suggested, however, including
modulation of neuropeptide Y levels in the amygdala,
28
increased
production of opioid peptides,
44,106
attenuation of the sympathet-
ic nervous system,
103,104
enhanced vagal nervous activity,
104
and
restoration of hippocampal brain-derived neurotrophic factor
levels.
105
It also has been proposed that acupuncture may influ-
ence the HPA axis and thereby alter many of the physiological
responses to stress.
49,50
CONCLUSION
There is a growing body of literature to support an under-
standing of how acupuncture may alter several physiological and
psychological processes. This literature helps to define the most
probable mechanistic pathways that are relevant to understanding
the use of acupuncture for IVF. However, many of the mechanistic
studies presented here were not designed to directly investigate
acupuncture mechanisms as they relate to female infertility or IVF.
Therefore, an important next step in understanding the mechanis-
tic basis of acupuncture as an adjunct therapy for IVF is a targeted
investigation of the effects of acupuncture therapy during IVF.
Although methodological problems with the existing clini-
cal research significantly limit their conclusions, the studies
reviewed in this article suggest that acupuncture may be a safe
and effective adjunct therapy for women undergoing IVF. Given
that many women use acupuncture during IVF therapy, there is a
highly justified need for more definitive clinical trials investigat-
ing the use of acupuncture for improving IVF outcomes. A quali-
ty clinical trial investigating this issue would have the following
characteristics: randomization, blinding, sham acupuncture con-
trol, an acupuncture treatment protocol that is consistent with
TCM principles, a range of outcome measures representative of
both clinical outcomes and putative mechanistic processes, and
compliance with rigorous statistical standards and other guide-
lines specified by STRICTA.
Such studies will provide a greater understanding of the clin-
ical applicability of acupuncture, may allow more specialized
usage for specific infertility conditions, and will enhance the cred-
ibility and integration of acupuncture in conventional Western
medical settings.
In Vitro Fertilization and Acupuncture
ALTERNATIVE THERAPIES, may/june 2007, VOL. 13, NO. 3 47
Acknowledgments
The research described in this paper was supported by Grant Number 5 U19 AT002022 from
the National Institutes of Health (NIH), National Center for Complementary and Alternative
Medicine (NCCAM). This grant was awarded to the New England School of Acupuncture, 40
Belmont St, Watertown, MA 02472, USA. Its contents are solely the responsibility of the
authors and do not necessarily represent the official views of the NCCAM or the NIH.
The authors thank Drs Linda Graziadei Schust and Steve Schachter for their careful reading of
this manuscript and their helpful comments and suggestions. Gratitude is also extended to
Monica Shields and Jennifer Lewin for their assistance with compiling the reference list.
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