Nausea and vomiting in pregnancy (NVP) is one of the most common symptoms of pregnancy affecting 50-85% of women during the first half of pregnancy. Maternal morbidity is common and includes psychological effects, financial burden, clinical complications from nutritional deficiencies, gastrointestinal trauma, and in rare cases, neurological damage. As the main means of alternative treatment, economical and easy to obtain; the clinical efficacy of acupuncture treatment of this disease has low level of evidence and needs to be reconfirmed. Doxylamine vitamin B6 sustained release tablets (Diclectin, combination of doxylamine succinate (10mg) and pyridoxine hydrochloride (10mg) are The American College of Obstetricians and Gynecologists recommends with Level A evidence the use of vitamin B6 in combination with doxylamine as first-line pharmacotherapy for treatment of NVP. The efficacy and safety of Diclectin has been confirmed in many years of research, but there is no evidence of high-level evidence-based medicine for the Chinese population. The purpose of this multicenter, randomized, double-blind, placebo-controlled trial was to investigate the efficacy and safety of acupuncture versus Diclectin in the treatment of NVP. We hypothesis that: (1)Sham acupuncture and Diclectin (Arm B) is more effective than sham acupuncture and placebo (Arm D); (2)Active acupuncture and placebo (Arm C) is more effective than sham acupuncture and placebo (Arm D); (3) There is no interaction (either synergistic or antagonistic effects) between the two interventions of active acupuncture and Diclectin in patients with NVP.
Subjects will be randomized into one of the four treatment arms: A) active acupuncture (30 min /every day) + Diclectin (combination of doxylamine succinate (10 mg) and pyridoxine hydrochloride (10 mg) , 2-4 tablets/day); B) sham acupuncture (30 min /every day) + Diclectin (2-4 tablets/day); C) active acupuncture (30 min / every day) + Diclectin placebo (2-4 tablets/day); D) sham acupuncture (30 min /every day) + Diclectin placebo (2-4 tablets/day). Participants will receive active acupuncture or sham acupuncture treatment daily, 14 times in total, and receive Diclectin or placebo treatment every day (2 tablets at bedtime for the first two days, if the symptoms are unrelieved, add one tablet in the morning, if the symptoms are still unrelieved, add another one tablet at three o 'clock in the afternoon) for 2 consecutive weeks, 28-56 tablets in total. Daily measurement PUQE score, Visual analog scale (VAS), Adverse events and concomitant medications. Weekly visits will include global assessment of well being, adverse events and concomitant medications. The visit after treatment will assess NVP quality of life (NVPQoL), SAS, SDS and so on. Participants will be followed up 30 days after treatment. Primary outcomes is difference of the mean change in PUQE score from baseline to the last visit. Secondary outcomes were some core outcome set for hyperemesis gravidarum, including weight difference, quality of life (change in Global assessment of well-being, NVPQOL, VAS, SDS and SAS), pregnancy complication, treatment compliance, neonatal outcomes; area under the curve of PUQE score, effect of intervention on PUQE score reduction over treatment period and adverse events.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
352
Diclectin (combination of 10 mg doxylamine and 10 mg pyridoxine hydrochloride in a delayed release tablet) During the first two days, patients will start with an initial oral dose of 2 tablets at bedtime. If the symptoms assessed on the second day are not relieved, 3 tablets will be administered on the third day (1 tablet in the morning and 2 tablets at bedtime). On the third day if the symptoms are still not relieved, another tablet will be added in the afternoon on the fourth day (1 tablet in the morning, 1 tablet in the afternoon and 2 tablets at bedtime). Therefore, the maximum assigned dosage of Diclectin or placebo tablets do not exceed 4 tablets per day. The treatment duration will lasts for 14 days.
Diclectin placebo will be packed and tested by a commercial pharmacy supply company specifically for this study. It have the same appearance, size, batch, odor, and taste compared with Diclectin. During the first two days, patients will start with an initial oral dose of 2 tablets at bedtime. If the symptoms assessed on the second day are not relieved, 3 tablets will be administered on the third day (1 tablet in the morning and 2 tablets at bedtime). On the third day if the symptoms are still not relieved, another tablet will be added in the afternoon on the fourth day (1 tablet in the morning, 1 tablet in the afternoon and 2 tablets at bedtime). Therefore, the maximum assigned dosage of placebo tablets do not exceed 4 tablets per day. The treatment duration will lasts for 14 days.
Participants will receive active acupuncture every day for 2 consecutive weeks, a total of 14 sessions. The needle will be left for 30 minutes. After de qi induced by acupuncture, the paired electrodes of the electroacupuncture device will be connected to the needle handle horizontally (except for PC6).
Blunt-tipped placebo needles will be used. Participants will receive sham acupuncture every day for 2 consecutive weeks, a total of 14 sessions. The needle will be left for 30 minutes. After de qi induced by acupuncture, the paired electrodes of the electroacupuncture device will be connected to the needle handle horizontally (except for PC6). Then, the paired electrodes of the electroacupuncture device will be connected to the needle handle horizontally (except for PC6).
First Affiliated Hospital of Heilongjiang Chinese Medicine University
Harbin, Heilongjiang, China
Heilongjiang provincial hospital
Harbin, Heilongjiang, China
Hegang Maternal and Child Health Hospital
Hegang, Heilongjiang, China
Affiliated Hospital of Jiamusi Medical University
Jiamusi, Heilongjiang, China
Jiamusi Maternal and Child Health Hospital
Jiamusi, Heilongjiang, China
Jixi Maternal and Child Health Hospital
Jixi, Heilongjiang, China
Mudanjaing Maternal and Child Health Hospital
Mudanjiang, Heilongjiang, China
Shuangyashan Maternal and Child Health Hospital
Shuangyashan, Heilongjiang, China
Suihua Maternal and Child Health Hospital
Suihua, Heilongjing, China
Luoyang Hospital of TCM
Luoyang, Henan, China
...and 3 more locations
Score change of pregnancy unique quantification of emesis (PUQE) scale from baseline to day 15
Score change of pregnancy unique quantification of emesis (PUQE) scale from baseline to day 15
Time frame: Baseline to day 15; Scores ranged 3 to 15, with higher scores indicating more
Score change of maternal weight from baseline to the last visit
Score change of maternal weight from baseline to the last visit
Time frame: Baseline to day 15; no range of variation
Change of electrolyte index (sodium)
Value changes from baseline to last Visit. Unit: mmol/L
Time frame: Baseline to day 15
Change of electrolyte index (potassium)
Value changes from baseline to last Visit. Unit: mmol/L
Time frame: Baseline to day 15
Change of electrolyte index (calcium)
Value changes from baseline to last Visit. Unit: mmol/L
Time frame: Baseline to day 15
Change of electrolyte index (chlorine)
Value changes from baseline to last Visit. Unit: mmol/L
Time frame: Baseline to day 15
Change of electrolyte index (phosphorus)
Value changes from baseline to last Visit. Unit: mmol/L
Time frame: Baseline to day 15
Change of electrolyte index (magnesium)
Value changes from baseline to last Visit. Unit: mmol/L
Time frame: Baseline to day 15
Change of electrolyte index (iron)
Value changes from baseline to last Visit. Unit: μmol/L
Time frame: Baseline to day 15
Change of electrolyte index (zinc)
Value changes from baseline to last Visit. Unit: μmol/L
Time frame: Baseline to day 15
Change of AST
Value changes from baseline to last Visit. Unit: U/L
Time frame: Baseline to day 15
Change of ALT
Value changes from baseline to last Visit. Unit: U/L
Time frame: Baseline to day 15
Change of ALP
Value changes from baseline to last Visit. Unit: U/L
Time frame: Baseline to day 15
Change of creatinine
Value changes from baseline to last Visit. Unit: μmol/L
Time frame: Baseline to day 15
Change of urea
Value changes from baseline to last Visit. Unit: mmol/L
Time frame: Baseline to day 15
Change of TSH
Value changes from baseline to last Visit. Unit: mIU/L
Time frame: Baseline to day 15
Change of free triiodothyronine
Value changes from baseline to last Visit. Unit: pmol/L
Time frame: Baseline to day 15
Change of free thyroxine
Value changes from baseline to last Visit. Unit: pmol/L
Time frame: Baseline to day 15
Change of vitamin b1
Value changes from baseline to last Visit. Unit: ng/ml
Time frame: Baseline to day 15
Change of vitamin b6
Value changes from baseline to last Visit. Unit: ng/ml
Time frame: Baseline to day 15
Change of vitamin b12
Value changes from baseline to last Visit. Unit: ng/ml
Time frame: Baseline to day 15
Change of cortisol
Value changes from baseline to last Visit. Unit: ug/dL
Time frame: Baseline to day 15
Change of ghrelin
Value changes from baseline to last Visit. Unit: ng/ml
Time frame: Baseline to day 15
Change of leptin
Value changes from baseline to last Visit. Unit: ng/ml
Time frame: Baseline to day 15
Change of 5-hydroxytryptamine
Value changes from baseline to last Visit. Unit: ng/ml
Time frame: Baseline to day 15
Change of substance P
Value changes from baseline to last Visit. Unit: pg/ml
Time frame: Baseline to day 15
Change of arginine vasopressin plasma
Value changes from baseline to last Visit. Unit: pg/ml
Time frame: Baseline to day 15
Change of GDF 15
Value changes from baseline to last Visit. Unit: pg/ml
Time frame: Baseline to day 15
Change of IGFBP 7
Value changes from baseline to last Visit. Unit: ng/ml
Time frame: Baseline to day 15
Intravenous fluid treatment during treatment
Intravenous fluid treatment during treatment
Time frame: Baseline to day 15
Concomitant treatment
Concomitant treatment
Time frame: Baseline to day 15
Hospital admission during treatment
Hospital admission during treatment
Time frame: Baseline to day 15
Termination of pregnancy
Termination of pregnancy. If the patient is suffering further aggravation of hyperemesis gravidarum, the termination of a wanted pregnancy will be done due to life in danger. Or congenital anomalies are found by ultrasound, the termination of a wanted pregnancy will be done.
Time frame: Data collected from baseline to the end of follow-up period (four weeks after the end of treatment).
Maternal outcomes
Including pregnancy complications, termination of pregnancy and birth outcomes. Pregnancy complications including miscarriage (in the first trimester and in the second trimester), hypertensive disorders, and gestational diabetes; birth outcomes including live birth, vaginal delivery, cesarean section, gestational age, preterm, birth weight and small for gestational age.
Time frame: Data collected from baseline to 42 days after postpartum.
Patient satisfaction with treatment
Such as loss of confidence or intolerance to daily acupuncture and so on
Time frame: Baseline to day 15
Treatment compliance
Such as the percentage of drug or needle used; or drug tablets or acupuncture sessions.
Time frame: Baseline to day 15
Offspring outcomes
Including fetal and neonatal congenital anomalies, fetal and neonatal mortality, neonatal hypoglycemia and NICU admission.
Time frame: Data collected from baseline to to 42 days after postpartum.
Area under the curve (AUC) of PUQE score over treatment
Scores ranged 3 to 15, with higher scores indicating more severe NVP
Time frame: Baseline to day 15
PUQE score reduction based on different TCM patterns
PUQE score reduction based on different TCM patterns
Time frame: Scores ranged 3 to 15, with higher reduction indicating the better
Adverse events and serious adverse events
The percentage of adverse events and serious adverse events
Time frame: Baseline to the end of follow-up (four weeks after the end of treatment)
Quality of life: NVPQoL
Range 30-210, high being poor QoL
Time frame: Baseline to day 15
Quality of life: VAS
Ranged 0-10, high being more severe symptoms
Time frame: Baseline to day 15
Quality of life: SDS
Range 25-10, high being more severe
Time frame: Baseline to day 15
Quality of life: SAS
Range 25-100, high being more severe
Time frame: Baseline to day 15
Quality of life: global assessment of well-being
Range 0-10, low being more severe
Time frame: Baseline to day 15
PUQE score reduction at different levels of NVP
PUQE score reduction at different levels of NVP
Time frame: Scores ranged 3 to 15, with higher reduction indicating the better
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