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ARTICLE
Impact of whole systems traditional Chinese
medicine on in-vitro fertilization outcomes
Lee E Hullender Rubin a,b,c,*, Michael S Opsahl d, Klaus E Wiemer d,
Scott D Mist b, Aaron B Caughey b
aOregon College of Oriental Medicine, 75 NW Couch St, Portland, OR, 97210, USA; bOregon Health and Science University,
Portland, OR, USA; cPortland Acupuncture Studio, Portland, OR, USA; dPoma Fertility, Northwest Center for
Reproductive Sciences, Kirkland, WA, USA
* Corresponding author. E-mail address: lrubin@ocom.edu (LE Hullender Rubin).
Lee Hullender Rubin, DAOM, MS, LAc, FABORM, is a clinician and researcher specializing in reproductive medi-
cine, women’s health and vulvar pain. She graduated with her master’s degree from Bastyr University in 2001,
and her doctorate from the Oregon College of Oriental Medicine (OCOM) in 2009. Dr Hullender Rubin was OCOM’s
first postdoctoral research fellow funded by a National Institutes of Health educational grant. She teaches the
doctoral infertility module and is Adjunct Research Faculty at OCOM, and Visiting Research Faculty at Oregon
Health and Science University. She currently practices at her clinic, the Portland Acupuncture Studio, in Port-
land, Oregon.
Abstract Patients undergoing IVF may receive either acupuncture or whole-systems traditional Chinese medicine (WS-TCM) as an
adjuvant IVF treatment. WS-TCM is a complex intervention that can include acupuncture, Chinese herbal medicine, dietary, life-
style recommendations. In this retrospective cohort study, 1231 IVF patient records were reviewed to assess the effect of adjuvant
WS-TCM on IVF outcomes compared among three groups: IVF with no additional treatment; IVF and elective acupuncture on day of
embryo transfer; or IVF and elective WS-TCM. The primary outcome was live birth. Of 1069 non-donor cycles, WS-TCM was associ-
ated with greater odds of live birth compared with IVF alone (adjusted odds ratio [AOR] 2.09; 95% confidence interval [CI] 1.36 to
3.21), or embryo transfer with acupuncture only (AOR 1.62; 95% CI 1.04 to 2.52). Of 162 donor cycles, WS-TCM was associated with
increased live births compared with all groups (odds Ratio [OR] 3.72; 95% CI 1.05 to 13.24, unadjusted) or embryo transfer with acu-
puncture only (OR 4.09; 95% CI: 1.02 to 16.38, unadjusted). Overall, IVF with adjuvant WS-TCM was associated with greater odds of
live birth in donor and non-donor cycles. These results should be taken cautiously as more rigorous research is needed.
© 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: acupuncture, Chinese herbal medicine, embryo transfer, in-vitro fertilization, live births, traditional Chinese medicine
http://dx.doi.org/10.1016/j.rbmo.2015.02.005
1472-6483/© 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
Reproductive BioMedicine Online (2015) 30, 602
–
612
www.sciencedirect.com
www.rbmonline.com
Introduction
Women undergoing IVF commonly pursue adjuvant comple-
mentary and alternative health approaches to support their
cycles. Given that early studies have found that acupunc-
ture significantly improves IVF pregnancy rates, patients in-
creasingly choose adjuvant acupuncture to optimize their
chances of pregnancy and live birth (De Lacey et al., 2009).
Utilization rates are unclear. In a survey of 428 Northern Cali-
fornian couples, 22% reported using acupuncture (Smith et al.,
2010), but of 118 Boston-area women surveyed, 47% women
reported using acupuncture and 17% used herbs during their
assisted reproduction technique cycle (Domar et al., 2012).
Another survey of 77 patients found that 92% reported using
acupuncture to support their IVF cycle (Aelion et al., 2009).
A patient may seek an acupuncturist’s support by self-
referral, or her IVF physician may refer her, but it is also pos-
sible that IVF physicians may not be aware of patient use of
these additional therapies (Boivin and Schmidt, 2009).
Investigations into the effect of acupuncture on IVF out-
comes largely focus on a limited number of standardized treat-
ments, usually two, on or around embryo transfer compared
with no acupuncture, sham acupuncture or a placebo needle.
Initial studies suggested that acupuncture on or around embryo
transer improved IVF outcomes (Dieterle et al., 2006; Paulus
et al., 2002; Smith et al., 2006; Westergaard et al., 2006),
and, in a meta-analysis of seven trials, acupuncture in-
creased the odds of clinical pregnancy by 65% (Manheimer
et al., 2008). As more trials were completed, the equivocal
effects were found when this narrow dose of only two or three
acupuncture sessions were compared to controls. In a review
of 14 trials, two to three acupuncture treatments adminis-
tered around embryo transfer did not improve clinical preg-
nancy rates compared with controls (Cheong et al., 2013b).
Another review of 16 trials confirmed these findings, but the
covariate of baseline pregnancy rate was found to be a sig-
nificant mediator of acupuncture’s effect (Manheimer et al.,
2013). Additionally, a clear need exists for an adequate acu-
puncture control, as penetrating or non-penetrating ‘sham or
placebo’ acupuncture controls are likely to be impractical and
may have physiological effects (Manheimer, 2011; Vickers
et al., 2012).
With the advent of two standardized acupuncture ses-
sions as a complete investigational intervention, acupunc-
ture providers thereby question whether it is a sufficient dose
(Craig et al., 2014; Shen et al., 2015). In clinical practice, acu-
puncture treatment is not standardized and instead consid-
ers the patient singularly; treatment is individualised. A course
of treatment can range from six to 24 treatments depend-
ing on the complexity of the case. Furthermore, if an IVF
patient seeks adjuvant acupuncture treatment in the period
before the day of embryo transfer, it is possible that the
patient, her parnter, or both, will receive a complex inter-
vention at the acupuncturist’s office, such as whole-systems
traditional Chinese medicine (WS-TCM). This is a multi-
dimensional intervention that can include any combination
of modalities classified under the system of traditional Chinese
medicine. These include any combination of acupuncture (the
insertion of sterile, filiform needles in the body) (Cochrane
et al., 2014), moxibustion (the burning of processed herb,
artemesia argyi, on or near the body) (Nedeljkovic et al.,
2013), Chinese herbal medicine (Cao et al., 2013; Ried and
Stuart, 2011; Tan et al., 2012), Chinese medical massage with
a tool (guasha) or without (tuina), Chinese medicine-based
dietary recommendations, breathing exercises (Qi Gong), or
movement exercises (Tai Chi) (Noll and Wilm, 2009). It may
also include recommendations for vitamins, supplements, or
both, depending on the training and licensure of the pro-
vider. Beyond a published case study (Hullender Rubin, 2010)
and expert texts (Liang, 2003; Lyttleton, 2004; Noll and Wilm,
2009), the effectiveness of the multi-dimensional WS-TCM ap-
proach on IVF outcomes is unclear.
Given this background, we sought to compare the repro-
ductive outcomes of women who elected WS-TCM treat-
ment in addition to their usual IVF care, and compared them
with those who received the usual IVF care alone and to those
who received two standardized acupuncture treatments on
the day of embryo transfer acupuncture only. Our main ob-
jective was to compare the three groups on the primary
outcome of live birth.
Materials and methods
Study design
This was a retrospective cohort study of WS-TCM effects on
IVF reproductive outcomes compared with two groups: those
who received acupuncture treatments only on the day of
embryo transfer (ACU); and those who received IVF usual care
alone. The Oregon College of Oriental Medicine Institu-
tional Review Board approved this study on 11 January 2011
(IRB reference number 09
–
028). Reproductive outcomes data
were obtained from a single, private IVF centre, the North-
west Center for Reproductive Sciences (NCRS), Kirkland,
Washington.
Patient criteria
Of 1509 patient charts, only NCRS patients who underwent
IVF with fresh donor or non-donor embryos transferred
between August 2005 and December 2010 were included, re-
gardless of embryo quality. Additionally, women who under-
went pre-implantation genetic screening testing or
intracytoplasmic sperm injection cycles were also included.
To further reduce selection bias, all biomedical diagnoses were
included. Diminished ovarian reserve was diagnosed if FSH was
12 mIU/ml or more, antral follicle count total less than 10,
and anti-Müllerian hormone less than 1.0 ng/ml, or any com-
bination of these measures. Since the mean age of the WS-
TCM was higher than the other groups, this most likely
accounted for the increased incidence of diminshed ovarian
reserve diagnosis. All patients who underwent transfers with
frozen embryos (n=251) or embryos from frozen oocytes
(n=27, research cycles) were excluded.
All included patient data (n=1231) were reviewed to iden-
tify patients who received ACU, and then reviewed a second
time to identify and tabulate patients who received WS-
TCM, as all WS-TCM patients received ACU as part of their
treatment plans. The data were de-identified and assigned
unique identifiers. The key was only available to the primary
investigator. Visit data were then independently abstracted
603Whole-systems TCM and IVF cohort study
from acupuncture clinic financial records and confirmed via
scheduling calendars by two research assistants. A third party
was consulted to resolve any conflicts.
Interventions
Usual care
Non-donor. IVF cycle management was individualized to each
patient according to biomedical diagnosis. In general, pa-
tients were treated with either a gonadotrophin-releasing
hormone (GnRH) agonist (Cramer et al., 1999) or antagonist
(Felberbaum et al., 1995; Olivennes et al., 1998) IVF proto-
col. Oral contraceptive pills were taken on the first day of
menses and continued from 1
–
3 weeks. Once ovarian sup-
pression was confirmed, ovarian stimulation was initiated. Go-
nadotrophin medications were administered twice daily in
variable doses based on age and antral follicle count, for up
to 12 days, and included follitropin alpha (Gonal-f, EMD Serono,
Geneva, Switzerland), follitropin beta injection (Follistim;
Merck, New Jersey, US), injectable menotropins (Menopur,
Ferring, Saint-Prex, Switzerland), or a combination of go-
nadotrophins. When three to four lead follicles measured a
minimum of 17
–
18 mm on ultrasound, a patient was trig-
gered with HCG (HCG; Novarel; Ferring, Siat-Prex, Switzer-
land). Within 36 h of trigger, transvaginal ultrasound-guided
oocyte retrieval was carried out under conscious sedation.
Once recovered from retrieval, patients were administered
intramuscular progesterone in oil injections (Watson Labo-
ratories, Parsippany, NJ, USA; West-Ward Pharmaceutical,
Eatontown, NJ, USA; or Fresenius Kabi, Lake Zurich, IL, USA),
50 mg/ml twice daily until embryo transfer.
All recovered oocytes were fertilized within the embry-
ology laboratory by either conventional insemination or in-
tracytoplasmic sperm injection. Fertilization was visually
confirmed by the presence of two pronuclei 17
–
22 h after fer-
tilization. Embryos were cultured in 5% oxygen incubators and
were evaluated every 24 h before embryo transfer. All embryos
were individually cultured in 20
–
30 µl droplets of Global
Medium (IVF Online, Guildford, CT, USA), supplemented with
10% human serum albumin and covered with 5.5 ml of equili-
brated oil. Embryo culture was carried out in 35 mm Nunc
dishes (Thermo Scientific Fisher, San Rafael, CA, USA). For
blastocyst culture, embryos were moved to new culture dishes
on day 3 of development. Day of embryo transfer was based
on the cause of patient infertility, number and quality of
embryos, as well as patient age. Blastocyst culture and trans-
fer was attempted whenever possible. When pre-implantation
genetic diagnosis or screening was planned, blastomere biopsy
was carried out on cleavage-stage embryos on day 3 of de-
velopment, and embryo transfer occurred on day 5.
Day 3 embryo(s) or day 5 blastocyst(s) embryo transfer was
undertaken with all patients with a full bladder using a Wallace
catheter (Smiths Medical International, Kent, UK) with ul-
trasound guidance by one out of four physicians and accord-
ing to SART guidelines (SART and ASRM, 2006; SART and ASRM,
2008; SART and ASRM, 2009). After transfer, Prometrium (pro-
gesterone, AbbVie Inc., Chicago, IL, USA), 200 mg supposi-
tories were inserted vaginally twice daily. Serum HCG was
collected to determine pregnancy 14 days after retrieval. If
pregnant, progesterone supplementation continued to ges-
tational week 10. If not pregnant, progesterone was
discontinued.
Donor. Egg donors underwent ovarian stimulation using similar
protocols as non-donors. Donor egg recipients underwent an
endometrial development cycle timed to correspond to the
ovarian stimulation of the donor. Donor recipients began the
oral contraceptive pill on the first day of their menses and
continued from 1
–
3 weeks. Once suppression was con-
firmed, Vivelle-Dot patches (Novartis, Basel, Switzerland) and
Estrace (Bayer-Schering, Berlin, Germany) were incremen-
tally increased for up to 11
–
15 days depending on oestrogen
levels and endometrial thickness. Once the endometrial thick-
ness achieved 8 mm or thicker, and the donor eggs were re-
trieved, the donor recipient proceeded with the same
progesterone protocol and embryo transfer as non-donor
patients.
Acupuncture group
In addition to the IVF usual care, patients could elect to receive
two standardized acupuncture treatments on the day of
embryo transfer (ACU). The IVF nurse notified patients that
acupuncture treatment was available to them. All ACU treat-
ment protocols were based on previous published research
(Craig et al., 2014; Paulus et al., 2002), and the treatment
methods were previously described (Hullender Rubin et al.,
2012a,b 2013c). Patients received two standardized acupunc-
ture treatments on the same day as the embryo transfer.
Treatments were administered onsite at the IVF centre by
one of nine state-licensed acupuncturists, certified in acu-
puncture by the National Certification Commission of Acu-
puncture and Oriental Medicine (NCCAOM). The acupuncturists’
experience ranged from 1
–
9 years. All were trained to carry
out the treatments in the same manner, and a treatment
manual was provided. Refresher training to ensure continu-
ity of methods occurred annually.
The first acupuncture session took place 1 h and 15 min
before embryo transfer, and the second no more than 30 min
after the embryo transfer. The Craig acupuncture protocol
was used on both cycle types between 2005 and 2007 (Craig
et al., 2014), and the following points were needled. Before
embryo transfer: GV-20/Baihui; PC-6/Neiguan; CV-6/Qihai;
ST-29/Guilai; SP-8/Diji; LR-3/Taichong; right ear (uterus, en-
docrine); left ear (Shenmen, Brain) After embryo tranfer: LI-
4/Hegu; SP-10/Xuehai; ST-36/Zusanli; SP-6/Sanyinjiao; KI-
3/Taixi; right ear (Shenmen, Brain); and left ear (uterus,
endocrine). Between 2008 and 2009, the modified Craig pro-
tocol was used in both cycle types, with the only modifica-
tion being acupoint KI-3/Taixi was removed from the protocol
(Hullender Rubin et al., 2012a,b). In 2010, the acupuncture
protocol was adjusted according to cycle type owing to pre-
liminary retrospective analysis suggesting fresh, non-donor
cycles benefitted from the modified Craig (Hullender Rubin
et al., 2012a), and donor cycles benefitted from the Craig pro-
tocol (Hullender Rubin et al., 2012b, 2013a). Patients could
also elect to listen to soft music or a guided meditation during
the acupuncture sessions. No other recommendations were
provided.
Whole-systems traditional Chinese medicine group
In addition to the usual IVF care and acupuncture on the day
of embryo transfer as described above, patients could elect
604 LE Hullender Rubin et al.
to pursue adjuvant whole-systems traditional Chinese Medi-
cine (WS-TCM) treatment. Patients were either referred by
the IVF doctor or self-referred. Flyers describing care with
the acupuncturist were available in the IVF clinic lobby.
One of three Washington state-licensed acupuncturists with
3
–
4 years of master’s level training in acupuncture and Chinese
herbal medicine provided the WS-TCM treatment. All three
acupuncturists were nationally certified by the NCCAOM in acu-
puncture, one (LHR) was NCCAOM certified in herbs, and one
was certified in herbs by the California state licensing exam.
All pursued postgraduate continuing education in reproduc-
tive medicine and infertility, and one (LHR) was board cer-
tified in reproductive medicine by the American Board of
Oriental Reproductive Medicine.
At the initial visit, the patient’s biomedical chart was re-
viewed. The patient was assessed according to TCM theory,
an accepted form of medicine (WHO, 2007). A detailed WS-
TCM treatment plan was provided outlining the dose and fre-
quency of acupuncture, electro-acupuncture, Chinese
medicine-based dietary suggestions, lifestyle recommenda-
tions, and any recommended nutritional supplements.
Patient visits were typically once a week and increased
in frequency to twice a week from the start of IVF suppres-
sion medications to oocyte retrieval. Needles sizes ranged
from 0.18 mm to 0.25 mm in diameter and 30
–
40 mm in
length for body points, and 0.16 mm x 15 mm for ears. Size
and length were selected based on patient’s tolerance,
acupoint location and body size. Needles used were Vinco
brand (China), Sierin brand (Japan), and DBC brand (Korea).
Electroacupuncture stimulator used was ES-2 (Heliomed,
China) between 2005 and 2007, and Electrostimulator 4c.Pro
(Pantheon Research, Venice, CA, USA) was used between
2007 and 2010. Treatment could also include the following
modalities: warming Far Infrared Mineral lamp (TDP CQ-27,
FIRARD II, China), Chinese medical massage (tuina) and in-
direct moxibustion stick (Hoist Wuyan Jiutiao, Smokeless
Moxa Stick, China). All customized Chinese herb formulas
were dispensed in granular form and manufactured by KPC
herbs (Taiwan). All herbal tablets were made of standard-
ized Chinese herbal formulas and manufactured by Golden
Flower Chinese Herbs (Taiwan). Recommended nutritional
supplements included prenatal vitamins, essential fatty acids,
antioxidants and probiotics.
Acupuncture and herbal treatment was based on TCM
pattern diagnosis and phase of menstrual cycle. According to
Chinese medicine, regulating the menstrual cycle is consid-
ered a central treatment approach to female reproduction
(Cochrane et al., 2014). This approach was previously de-
scribed in several case studies (Hullender, 2009; Hullender
Rubin, 2010; Hullender Rubin and Marx, 2012; Hullender Rubin
et al., 2013b), but in general, treatment was divided into four
phases: menses (cycle days 1
–
4, follicular [cycle days 5
–
11],
ovulation [cycle days 12
–
16], and luteal [cycle days 17 to onset
of menses]). During menses, treatment was directed at regu-
lating menses and reducing of dysmenorrhoea pain, if present
(Smith et al., 2011). Follicular phase treatment was di-
rected at regulating reproductive hormones (Chen, 1997;
Napadow et al., 2008), and endometrial (Stener-Victorin et al.,
1996) and follicular development (Rashidi et al., 2013). Ovu-
lation phase treatment was directed at inducing ovulation
(Jedel et al., 2011; Johansson and Stener-Victorin, 2013;
Johansson et al., 2013; Stener-Victorin et al., 2012). Luteal
phase treatment focused on regulating hormones (Cochrane
et al., 2014). Throughout the entire cycle, treatment had a
sub-aim of reducing stress (De Lacey et al., 2009; Kovarova
et al., 2010; Madaschi et al., 2010). During the IVF cycle, WS-
TCM treatments were individualized according to patient needs
and TCM pattern diagnosis, but aimed to support the goals
of the IVF phase. Treatment could also include Chinese
medicine-based dietary and lifestyle recommendations. During
down-regulation and ovarian stimulation, treatment was aimed
to improve ovarian and uterine blood flow (Magarelli et al.,
2009; Stener-Victorin et al., 1996), improve oocyte quality
(Rashidi et al., 2013) and reduce stress. Acupuncture was op-
tional on the day of oocyte retrieval to manage pain (Gejervall
et al., 2005; Humaidan et al., 2006; Stener-Victorin, 2005),
or postoperative nausea, vomiting, or both (Cheong et al.,
2013a), which was used by only six patients. One more visit
was suggested 5
–
7 days after embryo transfer to reduce stress.
Outcome measures
The primary outcome measure was live birth after 24 weeks’
gestation. Secondary outcome measures were biochemical
pregnancies, spontaneous abortions, ectopic pregnancies, ges-
tational age, singleton, twin and triplet pregnancy. Biochemi-
cal pregnancy was defined as a positive serum beta-HCG and
pregnancy that failed to develop to the clinically identifi-
able stage on ultrasound evaluation. Spontaneous abortion is
defined as the spontaneous loss of a pregnancy with an
ultrasound-confirmed gestational sac before 20 gestational
weeks.
Statistical analysis
Treatment groups were counted and differentiated by donor
or non-donor cycle type. Demographics and descriptive sta-
tistics were computed by group in the following variables for
non-donor cycles: age, FSH, primary infertility, cause of in-
fertility, cycle number, method of fertilization, pre-
implantation genetic screening, total antral follicle count,
number of days stimulated, total gonadotrophin dose, peak
oestradiol, endometrial thickness, number of mature oocytes
obtained, number of embryos transferred, day of embryo
transfer (day 3 or 5), ovarian hyperstimulation syndrome
(OHSS) and gestational age. For donor cycles, the same
covariates were compared with the exception of age, FSH,
total antral follicle count, number of days stimulated, total
gonadotrophin dose and OHSS.
Outcomes of live birth, biochemical pregnancy, sponta-
neous abortion, singleton, twins and triplet pregnancy were
tabulated by group and cycle type. Differences in outcomes
were calculated using logistic regression and adjusted by
covariates associated with outcomes.
Data were analysed in the following ways: (i) compara-
bility of demographics between group; (ii) differences in out-
comes with chi-squared (when groups numbered 10 or greater)
or Fisher’s exact (when groups numbered less than 10). Means
were compared via analysis of variance and proportions were
compared by chi-squared; and (iii) in order to control for po-
tential confounding, the magnitude of effects on pregnancy
605Whole-systems TCM and IVF cohort study
outcomes was assessed using multivariable logistic regres-
sion analyses and presented as adjusted odds ratios (AOR) with
95% confidence intervals (CI). Results were considered sta-
tistically significantly different if P <0.05. Stata. (StataCorp,
2011, USA) was used to carry out all tests.
Results
A total of 1231 fresh cycles took place, in which an embryo
transfer occurred. Non-donor cycles numbered 1069 and donor
cycles numbered 162 (Table 1). In the non-donor cycles, 580
patients were in the usual care group, 370 in the ACU group
and 119 in the WS-TCM group. The mean (±SD) number of WS-
TCM visits was 12.0 (±12.4). The three groups were compa-
rable on all reproductive variables at the start of the cycle,
except diagnosis of diminished ovarian reserve (P=0.01), di-
agnosis of cause of infertility as ‘other’ (P=0.03); cycle
number (P=0.004) and total antral follicle count (P=0.0497).
Significant differences were found in cycle characteristics:
number of mature oocytes obtained (P=0.02); number of
embryos transferred (P=0.003) (Table 2).
The proportion of live births was significantly higher in the
WS-TCM group (61.3%) compared with either the usual care
Table 1 Demographic characteristics.
Non-donor cycles WS-TCM Usual care ACU P-value
Group N 119 580 370
Age a,b 35.0 ±4.0 34.3 ±4.3 34.9 ±4.3 NS
FSHa,b 10.9 ±3.4 10.7 ±3.1 11.2 ±3.9 NS
Total antral follicle counta,b,f 8.0 ±2.4 8.3 ±2.5 7.9 ±2.6 0.0497
Primary infertilityc,d 48.0 51.4 52.7 NS
Cause of infertilityc,d
Male 40.0 36.6 35.4 NS
Diminished ovarian reservef31.1 20.9 27.3 0.01
Endometriosis 10.1 11.9 12.7 NS
Ovulatory dysfunction 17.7 20.7 21.6 NS
Tubal 15.1 15.9 13.0 NS
Uterine 6.7 5.9 5.2 NS
Otherf13.5 7.8 6.0 0.03
Unknown 8.4 14.5 14.3 NS
Multiple diagnoses 34.5 31.4 30.8 NS
Cycle number c,d
First cyclef57.4 72.6 70.0 0.004
Repeated cyclef42.6 27.4 30.0 0.004
Donor cycles WS-TCM Usual care ACU P-value
Group N 21 104 37
Primary infertilityc,d 47.6 34.6 45.9 NS
Cause of infertility
Malec,e 19.0 16.3 10.8 NS
Diminished ovarian reservec,d 81.0 92.3 89.2 NS
Endometriosisc,e 0.0 16.3 10.8 NS
Ovulatory dysfunctionc,e 9.5 1.0 2.7 NS
Tubalc,e 9.5 6.7 5.4 NS
Uterinec,e 9.5 7.6 5.4 NS
Otherc,e 4.8 9.6 8.1 NS
Unknownc,e 0.0 0.0 0.0 NS
Multiple diagnosesc,e,f 28.6 42.3 24.3 0.02
Cycle number
First cyclec,e 57.1 51.0 67.6 NS
Repeated cyclec,e 42.9 49.0 32.4 NS
aData are mean ±SD.
bAnalysis of variance.
cData are proportion.
dChi-squared.
eFisher’s exact.
fSignificant findings (P<0.05).
ACU =women receiving acupuncture on day of embryo transfer; NS =not statistically signifi-
cant; WS-TCM =Whole-systems traditional Chinese medicine.
606 LE Hullender Rubin et al.
(48.2%) or ACU groups (50.8%, P=0.03 (Table 3). Fewer spon-
taneous abortions (P=0.02) occurred in the WS-TCM group
compared with the other groups. On the outcome of bio-
chemical pregnancies, there was no difference between
groups, but WS-TCM trended toward significantly fewer than
the other groups (P=0.05). No ectopic pregnancies occurred
in the WS-TCM group, but this was not a significant differ-
ence than compared with the usual care or ACU groups. Mean
gestational age, and the proportions of live birth on or after
37 gestational weeks, singleton, twin and triplet pregnan-
cies were not different between groups.
The WS-TCM group was associated with more live births
compared with both groups when adjusted for the covariates
of previous IVF cycle, age, and gonadotrophin dosage (AOR
1.93; 95% CI 1.27 to 2.92) (Table 4). More live births were
associated with WS-TCM compared with embryo transfer acu-
puncture only, adjusted for age and gonadotrophin dosage
(AOR 1.62; 95% CI 1.04 to 2.52), and when compared with IVF
alone, adjusted for previous IVF and gonadotrophin dosage
(AOR 2.09; 95% CI 1.36 to 3.21). Live births were not signifi-
cantly affected in patients who received acupuncture only
on the day of embryo transfer compared with IVF usual
care.
When compared with both groups, WS-TCM was associ-
ated with fewer biochemical pregnancies (odds ratio [OR] 0.27;
95% CI 0.08 to 0.86). Decreased biochemical pregnancies were
also associated with WS-TCM compared with embryo trans-
fer acupuncture alone unadjusted (OR 0.25; 95% CI 0.07 to
Table 2 Cycle characteristics.
Non-donor cycles WS-TCM Usual care ACU P-value
Group, n119 580 370
Number of days stimulateda,b 9.8 ±1.2 9.9 ±1.2 9.9 ±1.3 NS
Total gonadotrophin dose, IUa,b 3959.3 ±1503.6 3721.6 ±1515.6 3932.1 ±1580.1 NS
Peak oestradiol, pg/mla,b 3153.7 ±1781.8 3211.0 ±1644.0 3017.0 ±1634.0 NS
Endometrial thickness, mma,b 10.9 ±2.4 11.2 ±2.4 11.2 ±2.2 NS
Number of mature oocytes obtaineda,b,f 14.0 ±8.7 15.7 ±9.1 14.2 ±8.0 0.02
OHSS c,d 8.4 9.5 7.1 NS
Fertilization methodc,d
Conventional 47.1 51.0 46.3 NS
ICSI 48.7 46.2 49.3 NS
Mixed 4.2 2.8 4.3 NS
Pre-implantation genetic screeningc,d 13.5 9.3 6.5 NS
Number of embryos transferreda,b,f 2.9 ±1.2 2.6 ±1.1 2.8 ±1.1 0.003
Day of embryo transferc,d
Day 3 64.7 59.7 65.7 NS
Day 5 35.3 40.3 34.3 NS
Mean number of acupuncture visitsa12.0 ±12.4
Donor cycles
Group, N 21 104 37
Peak oestradiol, pg/mla,b 4303.9 ±2130.5 4250.3 ±2035.4 4428.4 ±2660.4 NS
Endometrial thickness, mma,b 9.7 ±2.0 10.5 ±2.1 10.0 ±2.0 NS
Number of mature oocytes obtained from donora,b,f 18.6 ±8.0 21.7 ±8.7 26.4 ±11.2 0.005
Fertilization method
Conventionalc,d 57.1 60.6 67.6 NS
ICSIc,e 38.1 33.7 27.0 NS
Mixedc,e 4.8 5.8 5.4 NS
Pre-implantation genetic diagnosis Testingc,e 4.8 10.6 8.3 NS
Number of embryos transferred a,b 2.2 ±0.7 2.2 ±0.7 1.9 ±0.6 NS
Day of embryo transfer
Day 3c,e 23.8 38.5 24.3 NS
Day 5c,d 76.2 61.5 76.7 NS
Mean number of acupuncture visitsa10.6 ±13.6
aData are mean ±SD.
bAnalysis of variance.
cData are proportions.
dChi-squared.
eFisher exact.
fSignificant findings (P<0.05).
ACU =day of embryo transfer acupuncture only; ICSI =intracytoplasmic injection; NS =not significant; OHSS =ovarian hyperstimulation syndrome;
WS-TCM =whole-systems traditional Chinese medicine.
607Whole-systems TCM and IVF cohort study
0.82), or standard IVF when adjusted for FSH and gonado-
trophin dosage, (AOR 0.28; 95% CI 0.09 to 0.91). No differ-
ence was observed between the ACU and usual care groups
on this outcome.
No differences were detected between groups on the
outcomes of spontaneous abortion, ectopic pregnancies,
singleton, twin, triplet pregnancies or gestational
age.
Table 3 Reproductive outcomes.
Non-donor cycles WS-TCM Usual care ACU P-value
Group, n119 580 370
Live birtha,b,f 61.3 48.2 50.8 0.03
Biochemical pregnancya,c,f 2.5 8.4 9.5 NS
Spontaneous abortiona,c,f 5.8 10.7 7.3 0.02
Ectopica,c 0 1.0 0.8 NS
Singletona,b 60.3 63.2 57.0 NS
Twinsa,b 38.4 33.2 40.3 NS
Tripletsa,b 1.4 3.2 2.2 NS
Gestational aged,e 37.8 ±2.7 37.8 ±2.8 37.4 ±3.3 NS
Live birth on or after 37.0 weeksa,b 64.4 72.9 67.6 NS
Donor cycles
Group, n21 104 37
Live birthc,d 85.7 62.5 59.5 NS
Biochemical pregnancy a,c 4.8 8.7 8.1 NS
Spontaneous abortiona,c 4.8 11.5 16.2 NS
Ectopica,c 0.0 1.0 0.0 NS
Singleton a,b 55.6 54.0 54.6 NS
Twinsa,c 38.9 45.3 45.5 NS
Tripletsa,c 4.8 1.6 0.0 NS
Gestational aged,e 37.7 ±3.3 36.9 ±3.1 36.8 ±3.7 NS
Live birth on or after 37.0 weeksa,b 72.2 60.0 63.6 NS
aData are proportions.
bChi-squared.
cFisher’s exact.
dData are mean ±SD.
eAnalysis of variance.
fSignificant findings (P<0.05).
ACU =day of embryo transfer acupuncture only; NS =not significant; WS-TCM =whole-
systems traditional Chinese medicine.
Table 4 Reproductive outcomes logistic regression analysis (odds ratio and 95% confidence interval).
Outcome Cycle type WS-TCM versus all WS-TCM versus usual care WS-TCM versus ACU ACU versus usual care
Live birth Non-donor 1.93, 1.27 to 2.92a,h 2.09, 1.36 to 3.21b,h 1.62, 1.04 to 2.52c,h 1.24, 0.94 to 1.64d
Donor 3.72, 1.05 to 13.24e,h 3.6, 1.00 to 13.01e4.09, 1.02 to 16.38e,h 0.74, 0.35 to 1.58e
Biochemical
pregnancy
Non-donor 0.27, 0.08 to 0.86e,h 0.28, 0.09 to 0.91f,h 0.25, 0.07 to 0.82e,h 1.30, 0.83 to 2.03e
Donor 0.54, 0.07 to 4.36e0.55, 0.06 to 4.74g0.57, 0.06 to 5.82e1.01, 0.26 to 3.90e
Spontaneous
abortion
Non-donor 0.60, 0.27 to 1.34e0.50, 0.22 to 1.13e0.79, 0.34 to 1.87e0.72, 0.45 to 1.14e
Donor 0.34, 0.04 to 2.70e0.38, 0.05 to 3.12e0.26, 0.03 to 2.31e1.67, 0.59 to 4.75e
aAdjusted odds ratio comparing WS-TCM with all groups with previous IVF, age and gonadotrophin dosage as covariates.
bAdjusted odds ratio comparing WS-TCM with usual care, with previous IVF and gonadotrophin dosage as covariates.
cAdjusted odds ratio comparing WS-TCM with ACU with age and gonadotrophin dosage as covariates.
dAdjusted odds ratio comparing usual care with ACU with prior IVF, age, and gonadotrophin dosage as covariates.
eUnadjusted odds ratio.
fAdjusted odds ratio comparing WS-TCM with usual care, with FSH, and gonadotrophin dosage as covariates.
gAdjusted odds ratio comparing WS-TCM with usual care, with number of embryos transferred as covariate.
hSignificant outcomes.
ACU =day of embryo transfer acupuncture only; usual care, usual IVF care; WS-TCM =whole-systems traditional Chinese medicine.
608 LE Hullender Rubin et al.
Of the donor cycles, 104 recipients usual care group re-
ceived an embryo transfer, 37 in the ACU group and 21 in the
WS-TCM group. The mean (±SD) number of WS-TCM visits was
10.6 (±13.6). The three groups were comparable on the vari-
ables of incidence of primary infertility; cause of infertility
due to male factors; diagnosis of diminished ovarian reserve;
endometriosis; ovulatory dysfunction; tubal issues; uterine
issues; unknown reasons; other diagnosis; male only factors;
female only factors; male and female factors; cycle number;
incidence of pre-implantation genetic screening; fertiliza-
tion method; number of days stimulated; peak oestradiol; en-
dometrial thickness; day 3 or day 5 embryo transfer (Tables 1
and 2). Groups were different for the following variables:
multiple diagnoses (P=0.02) and number of mature oocytes
obtained (P=0.005).
On the outcome of live births, 85.7% of the WS-TCM group,
62.5% of the usual care and 59.5% of the ACU group had a live
birth (Table 3). No differences were observed between groups
for biochemical pregnancies or spontaneous abortions. No
ectopic pregnancies occurred in the WS-TCM group for this
cycle type, but this was not significantly fewer than usual care
or ACU groups. Gestational age, singleton, twin, and triplet
pregnancies were also not different between groups.
Significantly greater odds of live birth was associated with
adjuvant WS-TCM compared with all groups (OR 3.72; 95% CI
1.05 to 13.24), and when compared with the ACU group (OR
4.09; 95% CI 1.02 to 16.38). When WS-TCM was compared with
usual care, an association of increased odds trended towards
significance (OR 3.6; 95% CI 1.00 to 13.01, unadjusted). The
small sample size and exceedingly broad confidence inter-
vals, however, indicate the weaknesses of these associa-
tions. No difference was found between the ACU and usual
care groups on this outcome.
Outcomes of biochemical pregnancy or spontaneous abor-
tion was not significantly affected by WS-TCM, regardless of
comparison group in the donor cycles.
Discussion
To the best of our knowledge, this is the first adequately
powered study of the effect of adjuvant WS-TCM on IVF re-
productive outcomes. This is meaningful for its public health
impact on infertility treatment and management, prelimi-
nary evidence of the need for an optimized acupuncture dose
and demonstration that WS-TCM, a multidisciplinary inter-
vention that includes acupuncture, was associated with more
live births than two standardized acupuncture treatments on
the day of embryo transfer or usual IVF care alone. These find-
ings suggest WS-TCM could make significant contributions to
the public health issue of infertility ( Macaluso et al., 2010;
CDC, 2010; CDC, 2014), if provided in an effective dose. Al-
though IVF live births increase with advances in patient man-
agement and laboratory procedures, success is not guaranteed.
Couples often must undergo several IVF cycles engendering
extensive emotional distress and economic costs (Cousineau
and Domar, 2007).
Acupuncture on or around day of embryo transfer does sig-
nificantly reduce stress in IVF patients in both randomized con-
trolled trials (RCTs) (Domar et al., 2009; Isoyama et al., 2012;
Smith et al., 2006) and observational studies (Balk et al., 2010;
De Lacey et al., 2009). Initial RCTs found that acupuncture
improved IVF pregnancy rates (Dieterle et al., 2006; Paulus
et al., 2002; Westergaard et al., 2006). As more studies were
conducted, the effect became less clear as subsequent studies
failed to reproduce those outcomes, with one RCT finding live
births were lower in the acupuncture group compared with
control (Craig et al., 2014). Craig et al. (2014) suspected the
location of treatment offsite from the IVF centre and study
population of acupuncture naïve women may have contrib-
uted to this finding (2014). Further, two standardized acu-
puncture sessions administered on day of embryo transfer
alone were an insufficient acupuncture dose to improve IVF
birth outcomes in two of the most recent systematic reviews
(Cheong et al., 2013b; Manheimer et al., 2013).
We observed that, in addition to embryo transfer acu-
puncture, an average of 12 WS-TCM visits for non-donor cycles
and 11 visits for donor cycles were associated with greater
odds of live birth. The combined approach of WS-TCM treat-
ment before starting IVF with the two treatments on the day
of embryo transfer acupuncture may be an optimal interven-
tion to improve IVF birth outcomes in addition to stress re-
duction. An increased acupuncture dose, ie. more acupuncture
sessions, is consistent with the effectiveness reported in other
studies. Uterine blood flow was improved with eight electro-
acupuncture sessions (Stener-Victorin et al., 1996). Nine
electro-acupuncture sessions plus embryo transfer day acu-
puncture were correlated with an increase in serum cortisol
and prolactin and improved IVF outcomes in prospective clini-
cal trial (Magarelli et al., 2009). Fourteen sessions of low-
frequency electro-acupuncture significantly reduced androgens
and improved menstrual frequency over physical exercise or
no treatment in women with polycystic ovary syndrome in an
RCT (Jedel et al., 2011). Ovulation was induced in another
RCT with 24 visits over 3 months in women with polycystic
ovary syndrome (Johansson et al., 2013) using the same in-
tervention described by Jedel et al. (2011).
In our study, every patient undergoing WS-TCM received
a multidisciplinary intervention, of which all patients re-
ceived acupuncture, electro-acupuncture, or both, in addi-
tion to lifestyle and dietary recommendations. Prenatal
vitamins, essential fatty acids, antioxidants, probiotics, and
Chinese herbs were also commonly suggested. Because of the
nature of individualized care, recommendations were tai-
lored to the patient’s need and varied considerably within the
group. Further, some patients elected to only pursue acu-
puncture to support their cycles. This is representative of TCM
treatment in the real world. An objective of whole-systems
research is to evaluate the combined effects of a complex in-
tervention (Elder et al., 2006; Ritenbaugh et al., 2003). It is
not intended to evaluate the single ingredients of a complex
intervention, as it may over or underestimate the single in-
gredient’s influence and cannot account for the confound-
ing or mediating effects of the other component(s).
This retrospective study has three limitations. First, owing
to the nature of a retrospective cohort study, there is limited
internal validity. Study groups were not randomly allo-
cated, so the groups differed on several variables. We at-
tempted to minimize potential bias from these differences
by adjusting for covariates associated with pregnancy out-
comes through multivariable logistic regression analysis. We
also acknowledge the difference in the number of embryos
transferred between groups may influence our findings. During
dataset analysis, however, this covariate did not signifi-
609Whole-systems TCM and IVF cohort study
cantly impact outcomes. We therefore question the bio-
logic plausibility that the difference contributed, in part, to
our results. Further, women elected which treatment to
pursue. Women who elected WS-TCM, ACU, or both, could
differ in unknown ways that may affect outcomes.
Secondly, it was also possible that women in the usual care
groups received WS-TCM or day of embryo transfer acupunc-
ture at another site, or patients in the ACU group received
WS-TCM elsewhere leading to misclassification bias. Comple-
mentary and alternative medicine use is common in IVF pa-
tients (Smith et al., 2010) and not always reported to their
IVF practitioners (Boivin and Schmidt, 2009). Such bias,
however, would have been towards the null suggesting that
our estimates of effect would only underestimate the actual
effect of WS-TCM.
Finally, embryo quality may have differed between groups.
Although embryo quality is a known predictor of IVF success
(Heitmann et al., 2013; Vernon et al., 2011), only the highest
quality embryos available were selected for transfer. As more
women in the WS-TCM group were diagnosed with dimin-
ished ovarian reserve, it is more likely that the WS-TCM group
would have had lower quality embryos, which may mean the
effect of WS-TCM is underestimated by our study.
In conclusion, despite these potential limitations, this study
provides evidence that the addition of WS-TCM to non-
donor IVF cycles may increase the odds of achieving a live birth
over usual IVF care alone or two standardized treatments ad-
ministered around embryo transfer. The effects of WS-TCM
were less clear compared with usual donor IVF care alone but
showed a non-significant trend towards increased odds of a
live birth in this cycle type. This retrospective cohort study
suggests that WS-TCM as an adjuvant IVF treatment may be
associated with improved live birth rates. More rigorous, com-
parative effectiveness research is needed to substantiate these
findings and determine an optimal number of WS-TCM visits
compared with an adequate and validated time-attention
control, such as a mind
–
body programme to confirm these
findings.
Acknowledgements
Sincere thanks to the NCRS patients, doctors, embryology, and
nursing staff. LHR formerly owned the acupuncture prac-
tice. Whole-systems traditional Chinese medicine was pro-
vided by primary investigator (LHR); Roxane Geller, MS, LAc;
and Holly Fritz, LAc. Day of embryo transfer acupuncture was
provided by the primary investigator (LHR), HF; Melissa
Rosenberger MS, MAcOM, LAc; Janci Karp, ND, LAc, LMP;
Heather Stadler, MAc, LAc; Nicole Hidaka, MS, LAc; Lindsay
A. Staker, MS, LAc; and Elaina Greenberg, MS, LAc. Chart data
abstraction completed by Patrick Allen, MAcOM, LAc, and
Angela Humphrey, MAcOM, LAc.
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Declaration: Support provided by NIH/NCCAM grant R25 AT002879
(Suppl) and 1K23AT006392. LHR owned the acupuncture practice. The
authors report no financial or commercial conflicts of interest.
Received 11 November 2014; refereed 6 February 2015; accepted 10
February 2015.
612 LE Hullender Rubin et al.
