Clinical Efficacy and Safety Evaluation of Thumbtack Needle in Nausea and Vomiting in Pregnancy: a Randomized Controlled Clinical Trial
Phase: NA
Conditions: Nausea and Vomiting in Pregnancy (NVP)
Sponsor: Dongmei Huang

Study Protocol
Clinical efficacy and safety evaluation of thumbtack needle
in nausea and vomiting in pregnancy: a randomized
controlled clinical trial
Protocol edition: 3.0
Edition date: 2024.9.15
Main study unit: Tongji Hospital affiliated to Tongji Medical College
of Huazhong University of Science and Technology (Department of
integrated Chinese and western medicine)
Main researcher:
Huang Dongmei
Other researcher: Huang Guangying, Wang Zhi, Hongying Xu,
Chuanxiang Yuan, Lin Nie, Yuanyuan She, Yuhong Zhang, Jia Liu,
Xiaoyan Li, Li Yang, Qiaoyun Bao, Lei Zhang, Linlin Xi, Xuezhou
Yang, Longlong Fan
Tongji Hospital affiliated to Tongji Medical College of Huazhong University of
Science and Technology
Sep, 2024

1. Study background
Nausea and vomiting in pregnancy (NVP) is symptoms of nausea and/or vomiting that
occur during pregnancy before 16 weeks' gestation and exclude other causes of
nausea and vomiting. NVP affects up to 90% of pregnant women, usually starting at
the 4th ~ 7th week of pregnancy, peaking around the 9th week, and the symptoms of
90% patients resolving naturally at the 20th week. NVP has become the most common
and intractable problem in the first trimester and is the second most common cause of
presentation during pregnancy
whereas threatened
miscarriage is the first[1].
According to a large-scale survey in China [2], the incidence of NVP in the first
trimester population (n=3337) was 62.51%, and 47.2% in the second trimester
population (n=2915) still had NVP. Combined with the first and second trimesters,
NVP occurred in 73% of pregnant women (2129 people, including those that occurred
in the first or second trimester). Among the 2129 patients who developed NVP during
pregnancy, 1832 (86.05%) had symptoms that began in the first trimester.
Symptoms and severity of NVP vary widely, ranging from simple nausea to the most
severe form of hyperemesis gravidarum (HG). HG is the most severe stage of nausea
and vomiting during pregnancy, accounting for 0.5~2% of all pregnant women[3].
Although NVP is very common during pregnancy, it is generally considered normal
and self-limiting, and its adverse effects on pregnancy are largely underestimated.
However, there is evidence that all types of NVP affect the quality of life of pregnant
women, and that the magnitude of the impact increases with the frequency of
symptoms[4]. In addition, NVP increases the risk of postpartum depression, and the
risk increases with the severity of NVP[2]. Due to the lack of awareness of NVP and
concerns about the teratogenicity of drugs to embryos, NVP treatment is always
insufficient, and the choice of medication regimen is conservative, and symptomatic
supportive therapy is generally used. The survey found that only 3.64% of patients in
China were treated for NVP in the first trimester, which was much lower than the
level of the United States (18%) and other countries[2]. Therefore, pregnant women in
China have to endure more discomfort caused by NVP during pregnancy.

The treatment of NVP is generally focused on symptomatic supportive treatment,
such
as
antinausea,
rehydration,
and
correction
of
acid-base
balance.
Doxylamine-pyridoxine)
(Xonvea®,
the
first-line
drug
recommended
in
the
guidelines of the United States and the United Kingdom [5-6], considering that it may
be related to birth defects, has not been approved for its use in pregnancy in many
countries, including China. Due to its special taste, traditional Chinese medicine is
difficult for pregnant women to swallow, thus limiting its application in NVP.
Acupuncture has good efficacy in the treatment of NVP. In a recent large-sample,
multicenter RCT study [7], 352 pregnant patients with moderate or severe NVP were
recruited in 13 tertiary hospitals in China (the severity of NVP was determined by the
pregnancy-unique quantification of emesis and nausea (PUQE) score, which ranged
from 3~15, <6 is mild, 6~12 is moderate, and ≥13 is severe), and was treated with
acupuncture combined with doxylamine-pyridoxine for 2 weeks. It was found that
acupuncture or drugs (docemin-pyridoxine) alone were effective in both moderate and
severe NVP, and that the effect of acupuncture was comparable to that of
doxymine-pyridoxine,
and
that
the
combination
of
acupuncture
and
doxymine-pyridoxine may be more effective than their alone. The research results
won the top ten academic advances in traditional Chinese medicine in 2023.
Although acupuncture using traditional millineedle has a good effect on NVP, it is
inevitably painful when the millineedle is inserted, and the needle sensation of
soreness, numbness, swelling and pain during acupuncture is sometimes so strong to
cause fear and discomfort in pregnant women, which would produce an adverse effect
on pregnancy. Moreover, acupuncture with millineedle needs to be conducted once a
day, and pregnant women need to go to the hospital frequently every day, and
pregnant women are already inconvenient, which increases the difficulty of pregnant
women's medical treatment. Pregnant women, especially in the early stages of
pregnancy, should not be stimulated, should recuperate, and maintain physical and
mental peace. Therefore, although acupuncture with millineedle has a good effect on
NVP, it is still difficult to promote its application in clinical practice.
As a kind of intradermal needle, thumbtack needle (TN) is a method of shallow

puncture and long-term needle. Although the amount of stimulation of TN is weaker
than that of millineedle, it has a much longer effect and can produce continuous and
stable stimulation, and therefore, the cumulative effect is often better than that of
traditional millineedle acupuncture. Moreover, due to the small needle body of TN
(the diameter of the needle body is only 0.15 ~ 0.25mm, and the length of the needle
body is only 1.2 ~ 2.5mm), it will not hurt the subcutaneous nerves, blood vessels,
viscera and other tissues, which is very comfortable and safe to treat, and overcomes
the needle sting pain of traditional millineedles. Therefore, TN is especially suitable
for some patients who are afraid of needles [8]. In addition, the TN can be retented for
3~5 days after one treatment, which greatly reduces the duration and frequency of
patient’s visits. In recent years, some small-sample, non-randomized controlled
clinical studies have shown that TN is effective in the treatment of hyperemesis
gravidarum [9-11].
For the treatment of VNP, acupoints such as Zhongwan (CV12), Neiguan (PC6), and
Zusanli (ST36) are often used. CV12 is the recruitment point of the stomach, which
has the effect of strengthening the spleen and stomach, promoting gastrointestinal
peristalsis and emptying. PC6 is the key point for relieving vomiting, rationalizing qi
and widening the chest, calming the heart and calming the nerves, and reducing
stomach inversion and relieving nausea; Acupuncture ST36 can strengthen the spleen
and stomach, nourish qi and nourish blood. Those with disharmony in the liver and
stomach are added BL17 or BL18 to relieve the liver and regulate qi, and reconcile
the liver and stomach. Those with obstruction of phlegm and dampness are added
Fenglong (ST40) to dissolve phlegm and dampness, and those with spleen deficiency
and dampness are added to Yinlingquan (SP9) to strengthen the spleen and dispel the
dampness.
Since the effect of acupuncture is accumulated over time, the effect is no less than that
of traditional milli-needle acupuncture, and the treatment is comfortable, safe and
painless, and it can be treated once in 3~5 days, which is simple and easy. Although
there are several small, non-randomized clinical trials that suggest that acupuncture
has good clinical efficacy in the treatment of VNP, multi-center and large-sample

RCTs are still needed to provide high-quality evidence-based evidence. This project
intends to use multi-center, large-sample, randomized, controlled, double-blind
clinical trials to observe the effects of nausea and vomiting, quality of life, anxiety
and depression, weight change, blood electrolyte levels, liver and kidney function,
thyroid function, intravenous infusion therapy, use of additional drugs, hospitalization,
pregnancy complications (gestational diabetes and hypertensive diseases), pregnancy
outcomes and neonatal outcomes in women with VNP, and evaluate their safety, so as
to provide high-quality evidence support for the clinical promotion and application of
needles in the treatment of VNP.
2. Study objectives
A multicenter, large-sample, randomized, controlled, double-blind clinical trial was
conducted to observe the effects of TN on nausea and vomiting, quality of life,
anxiety and depression, weight change, blood electrolyte levels, liver and kidney
function, thyroid function, intravenous fluid therapy, use of additional drugs,
hospitalization,
pregnancy
complications,
pregnancy
outcomes,
and
neonatal
outcomes in women with VNP, and to evaluate its safety.
3. Study content
3.1
The selection and exclusion of subjects
We will choose moderate or severe 320 VNP patients who take a visit during Oct.
2024 to Oct. 2028 to the departments mentioned below: Department of Integrated
Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, Hubei, China; Fujian
Provincial Maternal and Child Health Care Hospital; Jingzhou Traditional Chinese
Medicine Hospital, Jingzhou, Hubei, China; Qianjiang Maternal and Child Health
Care Hospital, Qianjiang, Hubei, China; Xiaogan Maternal and Child Health Care
Hospital, Xiaogan, Hubei, China; Qianjiang Central Hospital, Qianjiang, Hubei,
China; Shiyan People's Hospital, Shiyan, Hubei, China; Wuhan Jinxin Gynecology

and Obstetrics Hospital of Integrative Medicine, Wuhan, Hubei, China; Xiangyang
Traditional Chinese Medicine Hospital, Xiangyang, Hubei, China; Suizhou Maternal
and Child Health Care Hospital, Suizhou, Hubei, China; Nanzhang County
Traditional Chinese Medicine Hospital, Nanzhang, Hubei, China; Dongchangfu
District Maternal and Child Health Care Hospital of Liaocheng City, Liaocheng,
Shandong, China; Xiangyang Central Hospital, Xiangyang, Hubei, China; Aksu
Prefecture Maternal and Child Health Hospital, Aksu, Xinjiang, China.
The age of the patients is between 20 to 45 years. According to the Network version
of the central randomization system, patients are allocated randomly as 1:1 to TN
group, sham TN group and blank control group with 160 patients in each group. The
network version of the central randomization system designs the random parameters.
The clinical researchers log in the system and input the information of the subjects to
be enrolled, after that they can obtain the random number and grouping information
assigned by the system. The randomization protocol and the parameters set during the
generation of the protocol are collectively called blind substrates, and are all kept by
people who are not involved in the process of treatment, evaluation and statistical
analysis.
3.1.1
Inclusion criteria
Pregnant women who meet the standers below will be included in this study.
3.1.1.1 The mother's age is 20 ~ 45 years old, the gestational age is 6 ~ 12 weeks, and
the ultrasound confirms that it is an intrauterine single or multiple pregnancy,
and the weight loss is less than 10% compared with before pregnancy.;
3.1.1.2 Women diagnosed with moderate to severe NVP in the first trimester: the
severity of NVP was determined by the PUQE score (see Table 1), and the
PUQE score ranged from 3 ~ 15, < 6 was mild NVP, 6 ~ 12 was moderate
NVP, and ≥13 was severe NVP. PUQE score ≥6 may be included in this
study;
3.1.1.3 Women voluntarily sign the informed consent form.

Table 1
Quantification of NVP in the US ACOG guidelines
1. In general, how often do you feel nauseous or nauseous each day?
Never (1)
≤1 h (2)
2～3 h (3)
4～6 h (4)
＞6 h (5)
2. In general, how many times a day do you vomit?
Never (1)
1～2 (2)
3～4 (3)
5～6 (4)
≥7 (5)
3. In general, how many times a day do you retch (no contents) ?
Never (1)
1～2 (2)
3～4 (3)
5～6 (4)
≥7 (5)
Total score (add all the points together): Mild NVP: < 6, moderate NVP: 6 ～12,
severe NVP: ≥13
3.1.2
Exclusion criteria
Pregnant women who meet any of the following conditions will not be included.
3.1.2.1 Age < 20 years, or > 45 years.
3.1.2.2 Gestational age < 6 weeks, or > 12 weeks.
3.1.2.3 PUQE score < 6.
3.1.2.4 frequent nausea and vomiting, weight loss of >10% compared with before
pregnancy; or symptoms such as listlessness, paleness, dry skin, sunken eye
sockets, and a marked decrease in urine output (less than 400ml of urine in 24
hours or less than 5 times and a small amount of urine in 24 hours).
3.1.2.5 At rest, body temperature > 38 ℃, systolic blood pressure < 90 mmHg or >
140 mmHg, diastolic blood pressure < 60 mmHg or > 90 mmHg, heart rate ≥
100 beats per minute, or oxygen saturation < 95%.
3.1.2.6 Urinalysis: urine ketones: +++ and above; or (and) urine protein: ++ and
above.
3.1.2.7 Blood biochemistry: serum potassium ≤
3.0mmol/L, serum sodium ≤
130mmol/L; or abnormal liver function: elevated liver enzymes ≥2 times the
upper limit of normal; or renal dysfunction: elevated serum creatinine and urea
nitrogen.
3.1.2.8 Other
digestive
diseases
that
cause
nausea
and
vomiting,
such
as
gastrointestinal infections (with diarrhea), gastric ulcers (with epigastric pain

or
hematemesis),
cholecystitis,
biliary
roundworms,
pancreatitis
(with
abdominal pain, plasma amylase levels rise to 5 ~ 10 times normal), viral
hepatitis (positive hepatitis virology, liver enzyme levels ≥1 000 U/L) or acute
fatty liver during pregnancy, tumors of the digestive tract.
3.1.2.9 Suffering from immune diseases such as systemic lupus erythematosus,
scleroderma, dermatomyositis, IgG4-related diseases, immune nephropathy,
etc.
3.1.2.10 Have uncorrected diseases of the endocrine system, such as diabetes,
Addison's disease, hyperthyroidism, hypothyroidism, thyroid tumors, adrenal
tumors, etc.
3.1.2.11 Suffering from neurological diseases such as migraine, neuromyelitis optica,
epilepsy, and neurologic tumors.
3.1.2.12 In the past 1 week, have taken antiemetic drugs such as ondansetron,
metoclopramide (metoclopramide), promethazine, and anti-vomiting Chinese
medicine.
3.1.2.13 Monoamine oxidase inhibitors are used.
3.1.2.14 Had TN treatment in recent 3 months.
3.1.2.15 Unwilling to sign the informed consent of this study.
3.2
The intervention program
According to the theory of traditional Chinese medicine, the treatment plan of TN is
formulated, and the study protocol follows the CONSORT and STRICTA regulations,
and details the number of TN used, the frequency of treatment and the duration of
treatment. Both the TN group and the sham TN group were treated with a fixed
treatment regimen, which was treated once every 3 days, for a total of 5 treatments for
15 days. During the same period, the blank control group was not given TN or sham
TN treatment. All three groups of patients were given pregnancy care and dietary
guidance.
3.2.1
Protocol for TN group
The main acupoints of treatment are Zhongwan (CV12), bilateral Neiguan (SP6), and

bilateral Zusanli (ST36), with a total of 5 acupoints. Patients with Qi stagnation
should be given Danzhong (CV17) or the Ashi acupoint (Identify the most prominent
tender point between the Danzhong (CV17) and Zhongwan (CV12). If such a tender
point exists, apply a TN at the tender point, that is, the Ashi acupoint. If no tender
point is found, apply the TN at the Danzhong acupoint. Just choose one of the two.),
patients with liver and stomach disharmony should be given bilateral Geshu (BL17),
patients with phlegm-dampness obstruction should be added bilateral Fenglong
(ST40), and patients with weak spleen and stomach should be added bilateral Weishu
(BL21). The above acupoints are treated with TN.
The doctor disinfects his hands, strictly disinfects the local skin of the acupoint,
applies the disposable sterile TN to the sterilized acupoint, and after a slight pressure,
removes the isolation paper (the function of the isolation paper is to avoid direct
contact with the sterile glue surface when adhering it to the skin), and press again to
ensure that the TN stick the surface of the acupoint firmly. The TN will be kept in the
acupoints for 3 days. During the 3-day retention of TN, the patient presses the TN 3
times a day and half a minute per time per acupoint. After 3 days retention of TN, the
patient will be instructed to go to the hospital, where the doctor will remove the TN,
disinfect the local skin of acupoints and conduct the next treatment of TN. A total of 5
sessions treatment will be applied for a duration of 15 days.
3.2.2
Protocol for sham TN group
The sham TN will be used for the sham TN group. Even though the appearance and
shape of sham TN are similar to the real TN, the sham TN has no needle body.
Therefore, the sham TN does not produce a needle-like effect of TN
The acupoints of sham TN group are the same as those of TN group. The use of sham
TN was the same as that of the TN group. After 3 days retention of sham TN, the
patient was instructed to go to the hospital, where the doctor removed the sham TN,
and conducted the next treatment after local skin disinfection. A total of 5 treatments
were given for a duration of 15 days.

3.2.3
Record for the treatment
The treatment date, time and the name of the acupuncturist are recorded when the
patient receives TN or sham TN treatment. No treatment is given to the blank control
group, but the date and times of the inquiry of blank control group are also recorded.
During the treatment, the local hematoma or turquoise, pain or skin allergies that may
occur during the treatment, as well as other discomforts after the treatment (nausea,
vomiting, palpitations, dizziness, headache, anorexia and insomnia), should be
recorded in detail and disposed in time.
3.3
Outcome measures
3.3.1
Primary outcome measure
PUQE scores were evaluated before treatment and on days 3, 6, 9, 12, and 15 of
treatment. The primary outcome measure was the change of PUQE score on day 15 at
the end of the treatment when compared with the baseline.
3.3.2
secondary efficacy endpoints
3.3.2.1 Questionnaires
Evaluation is performed before and after treatment.
3.3.2.1.1
Quality of life survey: The NVP Quality of Life questionnaire (NVPQOL)
is used to evaluate the quality of life of pregnant women.
3.3.2.1.2
Anxiety and depression status survey: Zung anxiety self-rating scale
(Zung-SAS) and Zung depression self-rating scale (Zung-SDS) are used to evaluate
the anxiety and depression status.
3.3.2.1.3
Sleep status survey: The Pittsburgh sleep quality index (PSQI) was used to
survey the sleep status of patients.
3.3.2.2
changes in the patient's weight; changes in electrolytes (sodium, potassium,
chloride, magnesium, calcium, iron, and zinc) in the blood; arterial blood gas analysis;
changes in liver and kidney function; Changes in thyroid function.
3.3.2.3
Situation of intravenous fluid therapy, use of additional medications,
hospitalization, and termination of pregnancy.

3.3.2.4
Pregnancy complications, including miscarriage (first and second trimester),
hypertensive disorders during pregnancy, and gestational diabetes.
3.3.2.5
Pregnancy outcomes, including termination of pregnancy and delivery
outcomes (including live birth, vaginal birth, caesarean section, gestational age, etc.)
3.3.2.6
Neonatal outcomes, including preterm birth, birth weight, and small for
gestational age (SGA). "Small gestational age" refers to babies with birth weight
below the 10th percentile according to the sex and gestational age of the Chinese
population.
3.3.2.7
Patient’s satisfaction with treatment.
3.3.2.8
Patient's adherence to treatment.
3.4
Follow-up
After 15 days of the treatment, participants will be followed up once a week for a total
of 4 weeks, and then once a month until live birth.
3.5
Safety assessment
Adverse events will be classified, and the percentage of adverse events and severe
adverse events occurred during treatment will be recorded in detail. Chi-square test is
used to analyze the total proportion of adverse events in each treatment regimen and
the differences between the classifications. Unless otherwise formally requested, each
data safety oversight board report will report details and summaries of adverse events
in a double-blind manner.
3.6
Statistics
3.6.1
Calculation of sample size
The calculation of the sample size is based on the measurement of the primary
outcome. The primary outcome is the change of PUQE score on day 15 at the end of
the treatment when compared with the baseline.
The change of PUQE score from baseline is used to compare the efficacies between
the TN group and the sham TN group. Since there are no randomized controlled trials

of TN for the treatment of VNP, this project hypothesizes that TN can achieve the
same efficacy as acupuncture, and the sample size is calculated according to the effect
of acupuncture in the references [7], assuming that the PUQE score decreased by 4.9
points from baseline with a standard deviation of 2.4 after TN treatment, and the
PUQE score also decreased by 4 points from baseline with a standard deviation of 2.7
after sham TN, the combined variance was 2.0, and the α = 0.05 (bilateral), β = 0.20,
and power = 0.80 were taken to allocate each group according to 1:1, and the
statistical sample size was 128 cases in each group. Considering factors such as
dropout/rejection, the number of enrolled cases was increased by 20%, and 160
subjects in each group were planned to be enrolled, with a total of 320 cases.
3.6.2
Statistical test
The method of intention analysis set is used to detect the difference of the change of
PUQE scores among three groups. Persenka square test is used to compare the live
yield of the main index. The secondary indicators are analyzed by the corresponding
statistical methods (Chi-Square test is used for counting data, and t test is used for
measuring data with equal variance). The primary outcome was analyzed according to
the intention-to-treat (ITT) principle. Chained multiple imputation under the
missing-at-random assumption was used to generate 20 imputed data sets for missing
PUQE scores over the intervention period in participants who withdrew (MI
procedure in SAS), and the estimates were combined using the Rubin rules
(MIANALYZE procedure in SAS) across the imputed sets. The modified ITT
population was defined as the participants who completed the primary outcome
measurement. The per protocol set (PPS) referred to participants who adhered to the
treatment protocol they were originally allocated to.
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