Abstract
Introduction
Newborn eye examination is a painful procedure. Untreated pain experiences in infants have both short-term and long-term consequences, and pain control is essential. Unfortunately, non-pharmacological pain strategies are usually ineffective for complex and protracted procedures, whereas many pharmacologic agents have adverse effects. Magnetic auricular acupuncture (MAA) is a new method of pain relief that is potentially safe and effective. The objective of this study was to conduct a large definitive triple blinded randomized controlled trial of MAA for reducing pain in neonates undergoing ophthalmic examination. The trial was registered at the Chinese Clinical Trial Registry (ID number ChiCTR1900027474) on November 14, 2019.
Methods
This was a multi-center randomized controlled trial conducted at 16 tertiary hospitals in the People’s Republic of China. Infants were eligible for participation if they were born at 26 to 42 weeks gestational age (GA) and admitted to participating NICUs during the study enrollment period, and scheduled to receive an eye examination for the first time at <44 weeks’ corrected GA. Written informed consent was obtained from parents. Infants who were critically ill, dying or receiving sedatives were excluded. Infants randomized to the intervention (MAA) group received magnetic stickers applied prior to the ophthalmic procedure. Control group infants received placebo stickers with the magnets removed. We compared the primary outcome of Premature Infant Pain Profile (PIPP) score during the procedure between the two groups.
Results
A total of 408 patients were randomized, but 14 patients in each of the placebo and intervention groups did not receive ophthalmic examination; leaving 190 patients in control group and 190 in intervention group. Infant characteristics were similar in the two groups, mean PIPP scores during eye exam were significantly lower in the intervention group compared to the control group (median (IQR): 10.00 (5.00,13.00) v 12.00 (7.00,14.00), p = 0.038).
Conclusions
MAA may offer an alternative or adjunct to current non-pharmacologic and pharmacologic interventions to alleviate neonatal pain. Future studies should assess combinations of pain interventions and long term outcomes.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12887-025-06126-1.
Keywords: Magnetic auricular acupuncture, Neonatal pain, Ophthalmic examination, PIPP scores
Introduction
Newborn eye examination is routinely conducted to detect retinopathy of prematurity (ROP) in preterm infants, and other serious eye diseases such as congenital cataracts and congenital glaucoma in term infants [1]. However, it is a painful procedure that involves inserting a speculum or using fingers to keep the eye open, and using a bright light to examine the interior of the eye. Pain has immediate physiologic impacts on the infant, including cardiovascular changes, behavioral changes, feeding disruption, disturbed sleep, and increased energy expenditure, and may result in prolonged need for intensive care [2, 3]. Repeated exposure to painful stimuli during infancy has been associated with altered cortical development, worse neurodevelopmental outcomes, and pain sensitivity, thermal sensitivity, chronic pain and anxiety in adolescence. It is therefore morally and ethically necessary to manage pain during neonatal eye examination. Current forms of pain management include non-pharmacologic and pharmacologic methods. Many non-pharmacological pain management techniques have been tried, including breast feeding, sucrose, non-nutritive sucking and environmental modification like touch, position and music, but they have not proven efficacious [4–10]. Pharmacological methods, including paracetamol, lidocaine, opioids and other sedative agents, are more effective but they can have adverse effects, including bradycardia, hypotension, respiratory depression, constipation, poor feeding and long term neurodevelopmental consequences [11–16]. The number of safe and effective pharmacological options for managing pain during neonatal eye examinations is limited, and they have to be used with care and often require intensive monitoring.
Magnetic auriculoacupuncture (MAA) is a new method of pain relief that may be safe and effective in infants [17]. The procedure is both noninvasive and simple, involving the placement of small magnets on the ear before initiating a painful procedure. In 2017, Chen et al. [18] conducted a small pilot study in a single-blinded, randomized controlled pilot trial of 40 infants and showed that noninvasive MAA using the Battlefield Protocol [19] was safe and feasible and produced a significant, 30% reduction in pain scores compared to placebo during a heel prick procedure. In a multi-center randomized controlled trial of 100 infants at three hospitals, Gan et al. [20] reported that compared to MAA infants, those in the placebo group had significantly higher Premature Infant Pain Profile (PIPP) scores [21] during and 1 h after the ROP examination. The objective of this study was to conduct a large definitive triple blinded randomized controlled trial of MAA for reducing pain in neonates undergoing eye examination.
Methods
Study design and population
We conducted a multi-center, triple-blinded, randomized, placebo-controlled trial at 16 tertiary hospitals in the People’s Republic of China from April 17, 2020 to August 30, 2021.
Participating hospitals included Children´s Hospital of Xinjiang Uygur Autonomous Region, Qinghai Red Cross Hospital, Shenzhen Maternity and Child Healthcare Hospital Affiliated to Southern Medical University, Inner Mongolia Maternal and Child Health Care Hospital, Children´s Hospital of Fudan University, First Affiliated Hospital of Anhui Medical University, The First Hospital of Jilin University, The First People’s Hospital of Yinchuan, Qingdao Maternal and Child Health Care Hospital, Affiliated Hospital of Qingdao University, Gansu Provincial Maternity and Child- Care Hospital, Dalian Municipal Women and Children´s Medical Center, Shanghai General Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Children´s Hospital of Chongqing Medical University, Children’s Hospital Affiliated to Shandong University Jinan Children’s Hospital, Children´s Hospital Affiliated to Zhengzhou University.
Infants were eligible for participation if they were born at 26 to 42 weeks gestational age (GA) and admitted to participating NICUs during the study enrollment period, and scheduled to receive an eye examination for the first time at < 44 weeks’ corrected GA, and whose parents provided informed consent. Exclusion criteria included infants who were critically ill or dying or who were receiving sedatives, opioids, or muscle relaxants.
Outcomes and data collection
The primary outcome was the PIPP, which is a validated tool commonly used for measuring pain intensity in infants, and was recorded 15 min before, during and 15 min after the eye examination procedure [19, 21]. We also recorded general behavioral state of the infant 15 min before the exam (e.g. sleeping, awake, agitated, or crying). Secondary outcomes included oxygen saturation, heart rate, episodes of desaturation, skin irritation, and other unanticipated adverse effects. Data were also collected on the baseline characteristics of the infant, the mother, and the delivery. These included infant sex, birth weight, GA, Apgar score at five minutes, and day of life at the time of eye exam; maternal age, primiparity, and mean parity; delivery mode; and whether the delivery was a multiple birth.
Sample size calculation
We used the report from Chen et al. [18] to calculate sample size. Assuming a mean (SD) PIPP score for the control group of 8 (4.5), we estimated a sample of 252 infants (126 per treatment arm) will achieve 80% power to detect a relative 20% decrease in PIPP score for the intervention group. The two-sided two sample equal-variance t-test was used for the sample size estimation at a significance level of 0.05. To account for a possible 20% missing data due to e.g. equipment failure, 380 infants were selected through non-randomized convenience sampling method and then were divided into intervention and control groups (190 infants in each group) through simple randomization.
Randomization
Written informed consent was obtained from all parents. We randomized infants to intervention and control groups using a block randomization method with block size of 4 stratified by center. We used the Randomization website (http://randomization.com/) to generate the random allocation sequence and distributed to the UN-blinded clinical fellows in each sub-center before the procedure. At each site, one UN-blinded clinical fellow was responsible for the randomization by opening a consecutive numbered, sealed, envelope containing the study group allocation, and placing the magnetic or placebo stickers on the infant. Researchers, clinicians, outcome assessors, data analysts and parents were blinded to the treatment allocation. In the event of an infant becoming ineligible after randomization, the study was postponed and recommenced when the infant became eligible, without re-randomization.
Procedure
Retinal screening examinations were performed after pupillary dilation (as needed), by using binocular indirect ophthalmoscopy with a lid speculum and scleral depression (as needed) to detect ROP and congenital anomalies. Eye examinations were performed by an experienced ophthalmologist. Infants randomized to the intervention (MAA) group received noninvasive MA for at least two hours before and 30 min after eye exam. Magnets were placed by a clinical research fellow trained in traditional Chinese medicine (including acupuncture), on five auriculoacupuncture points on each ear according to the Battlefield Protocol [19] and infants were monitored for clinical stability (heart rate, oxygen saturation, and blood pressure) for the duration of magnet placement. The magnets are commercially available (Huatuo magnetic therapy stickers) and distributed to each hospital by the coordinating center. The magnetic stickers were applied by an UN-blinded clinical research fellow trained in MAA. Infants randomized to the control group were treated exactly the same as the intervention (MAA) group except that the magnets were removed from the magnet stickers to create placebo stickers. The magnetic stickers were placed on the auriculoacupuncture points in the following order: (1) Cingulate Gyrus, (2) Thalamus, (3) Omega 2, (4) Point Zero, and (5) Shenmen (HT7) (supplementary Figure S1). The magnetic stickers were checked every hour by the blinded bedside nurse until after the MAA intervention was completed and, if displaced, was replaced by the UN-blinded clinical research fellow. The magnetic stickers were removed before the end of the intervention period at a parent’s request or if there are any adverse events that put the infant’s health at risk. In this study, infants were allowed to receive parent-initiated interventions for pain relief; examples include skin-to-skin contact, kangaroo care, and breastfeeding. Such interventions were carried out per unit protocols and documented. All 16 NICUs use eye speculum during eye examinations. In accordance with clinical protocol, local anesthetic drops were administered three minutes prior to the application of the eye speculum.
Measurements
Infants in both study groups were fitted with a pulse oximeter (Philips Medicin System, Germany) across the right wrist to monitor heart rate and peripheral oxygen saturation during the eye exam procedure and PIPP scoring. The PIPP score is a composite that comprises the following indicators: (1) GA (to account for physiological differences related to prematurity); (2) baseline behavioral state in the 15 s before the potentially painful procedure; change in (3) heart rate, and (4) oxygen saturation during the procedure (from mean value in the 15 s before the procedure to maximum value in the 30 s after the procedure); presence of a (5) brow bulge, (6) nasolabial furrow, and (7) eye squeeze during the procedure (in the 30 s after start of examination of the first eye). The “during” PIPP-scoring was done within the 30 s after start of examination of the first eye as per the instructions of the PIPP scale.
The PIPP score was measured at three time points: 15 min before the eye exam; during the procedure; and 15 min after the eye exam. To obtain the PIPP score, between 0 and 3 points are allocated for each indicator and then added together. The maximum PIPP score is 21 for preterm infants < 28 weeks’ GA and 18 for term infants ≥ 36 weeks’ GA, with higher scores indicating relatively more pain during the procedure, as follows: 0–6, no pain or mild pain; >6–12, moderate pain; >12, severe pain.
The PIPP pain assessments were conducted by an experienced un-blinded nurse in each unit, who had undergone training in the Acupuncture Workshop. To ensure the accuracy of the assessments, we videorecorded the infants’ faces, heart rates, and oxygen saturation levels, as it is extremely challenging and practically unfeasible to observe both the infants’ facial expressions and physiological parameters simultaneously.
Quality control
We conducted an Acupuncture Workshop in January 2020 at the Children’s Hospital of Fudan University for participating hospitals. The workshop included an introduction to MAA, and use of a video to teach the PIPP scoring. In addition to theoretical teaching, each participant was required to affix magnetic beads on the ears of project team staff in order to ensure the accuracy of acupuncture points. Participants were also trained in the study process and data collection. The collected data was uploaded to the CHNN database, where it was subjected to rigorous quality control by the coordinating center. Feedback regarding the study process and data collection were communicated to all 16 participating NICUs to ensure standardization of information flow.
Statistical analyses
The intention-to-treat principle was applied for the data analysis. Infant characteristics were compared descriptively between the two treatment arms based on the CONSORT statement. We compared the primary outcome of PIPP score during the procedure between the two treatment arms using Wilcoxon rank sum test. The uni-variable mixed-effect linear model for repeated measures of PIPP was used to examine the difference in the change of PIPP between the two treatment arms. Time, intervention group, and interaction between time and group were included in the models.
The other secondary outcomes, such as heart rate, analgesia and adverse events were compared between the two treatment arms using Chi-square test or student t-test, as appropriate. The generalized linear mixed models for repeated measure of secondary outcomes were used to assess the influence of acupuncture on the secondary outcomes. In these models, the compound symmetry and the autoregressive covariance structures were used for the random effect (between-subject) and within-subject correlated errors, respectively [22, 23]. All statistical analyses were carried out in SAS version 9.4 (SAS Institute, Cary, North Carolina). A 2-sided P < 0.05 was considered significant. The study was approved by the institutional research ethics committee of each hospital. The trial was registered at ClinicalTrials.gov (ChiCTR1900027474) on 14/11/2019.
Results
A total of 408 patients were randomized from April 17, 2020 to August 30, 2021. Fourteen patients in each of the control and intervention groups did not have eye examination because they were discharged (n = 25) or became critically ill (n = 3), leaving 190 patients in the control group and 190 in intervention group (Fig. 1). Infant characteristics were similar in the two groups (Table 1) except there was a higher incidence of chorioamnionitis in the intervention group.
Fig. 1.
The flow chart of the study
Table 1.
Comparison of baseline characteristics between acupuncture and placebo group
| Characteristics | Placebo | Acupuncture | Total | Statistics | Pvalue |
|---|---|---|---|---|---|
| Number | 204 | 204 | 408 | ||
| Infant Characteristics | . | . | |||
| Gestational Age, wk, median (IQR) | 32.86 (30.21, 37.00) | 33.00 (30.71, 37.93) | 33.00 (30.50, 37.57) | 0.82 | 0.412 |
| Birth weight, g, mean (std) | 2,085.49 (893.13) | 2,175.75 (920.59) | 2,130.62 (906.97) | −1.005 | 0.315 |
| Male, n/N (%) | 118/204 (57.8) | 115/204 (56.4) | 233/408 (57.1) | 0.09 | 0.764 |
| SGA, n/N (%) | 23/204 (11.3) | 16/204 (7.8) | 39/408 (9.6) | 1.389 | 0.239 |
| Inborn, n/N (%) | 136/204 (66.7) | 138/204 (67.6) | 274/408 (67.2) | 0.044 | 0.833 |
| Day of Life at enrollment, days, median (IQR) | 25.00 (7.00, 31.50) | 22.00 (5.50, 32.50) | 23.00 (7.00, 32.00) | −0.141 | 0.888 |
| Twin, n/N (%) | 48/204 (23.5) | 45/204 (22.1) | 93/408 (22.8) | 0.125 | 0.723 |
| 1 min Apgar less than 7,n/N (%) | 33/195 (16.9) | 29/193 (15.0) | 62/388 (16.0) | 0.26 | 0.61 |
| 5 min Apgar less than 7,n/N (%) | 13/195 (6.7) | 8/189 (4.2) | 21/384 (5.5) | 1.1 | 0.294 |
| Maternal Characteristics | . | . | |||
| Marriage Status, n/N (%) | 203/204 (99.5) | 201/204 (98.5) | 404/408 (99.0) | 1.01 | 0.315 |
| University, n/N (%) | 81/204 (39.7) | 85/204 (41.7) | 166/408 (40.7) | 0.163 | 0.687 |
| Assitant pregnancy, n/N (%) | 37/203 (18.2) | 38/204 (18.6) | 75/407 (18.4) | 0.011 | 0.917 |
| C-section, n/N (%) | 126/204 (61.8) | 138/204 (67.6) | 264/408 (64.7) | 1.545 | 0.214 |
| Uterine contraction, n/N (%) | 84/133 (63.2) | 72/135 (53.3) | 156/268 (58.2) | 2.658 | 0.103 |
| Primigravida, n/N (%) | 104/204 (51.0) | 112/204 (54.9) | 216/408 (52.9) | 0.63 | 0.427 |
| ROM over 24 h, n/N (%) | 28/164 (17.1) | 36/169 (21.3) | 64/333 (19.2) | 0.959 | 0.328 |
| Maternal Fever, n/N (%) | 6/204 (2.9) | 3/204 (1.5) | 9/408 (2.2) | 1.023 | 0.312 |
| Chorioamnionitis, n/N (%) | 20/186 (10.8) | 34/188 (18.1) | 54/374 (14.4) | 4.069 | 0.044 |
| Maternal Smoking, n/N (%) | 0/198 (0) | 1/201 (0.5) | 1/399 (0.3) | 0.988 | 0.32 |
| MgSO4 usage, n/N (%) | 58/187 (31.0) | 61/188 (32.4) | 119/375 (31.7) | 0.089 | 0.766 |
| Depression during pregnancy, n/N (%) | 2/184 (1.1) | 1/186 (0.5) | 3/370 (0.8) | 0.347 | 0.556 |
| Neonatal Outcome | . | . | |||
| RDS, n/N (%) | 92/201 (45.8) | 86/204 (42.2) | 178/405 (44.0) | 0.537 | 0.464 |
| IVH Grade ≥ 3,n/N (%) | 2/204 (1.0) | 2/204 (1.0) | 4/408 (1.0) | 0 | 1 |
| ROP Stage ≥ 3,n/N (%) | 5/204 (2.5) | 6/204 (2.9) | 11/408 (2.7) | 0.093 | 0.76 |
| Moderate & severe BPD, n/N (%) | 12/204 (5.9) | 15/204 (7.4) | 27/408 (6.6) | 0.357 | 0.55 |
| Moderate & severe HIE, n/N (%) | 2/204 (1.0) | 1/204 (0.5) | 3/408 (0.7) | 0.336 | 0.562 |
There was no difference in mean PIPP scores between the intervention and control groups, before and after eye exam (Fig. 2). However, mean PIPP scores during eye exam were significantly lower in the intervention group compared to the control group (median (IQR): 10.00 (5.00,13.00) v 12.00 (7.00,14.00), p = 0.038) (Table 2).
Fig. 2.
Mean PIPP scores before, during and after procedure. The Y-axis represents the PIPP core, The X-axis represents different time of procedure, The blue block indicated placebo group and red block indicated acupuncture group
Table 2.
PIPP scores before, during and after ophthalmic examination procedure
| Outcome | Placebo | Acupuncture | P-value |
|---|---|---|---|
| PIPP, median (IQR) | . | ||
| Before procedure | 3.00 (2.00, 4.00) | 3.00 (1.00, 4.00) | 0.755 |
| During procedure | 12.00 (7.00, 14.00) | 10.00 (5.00, 13.00) | 0.038 |
| After procedure | 3.00 (2.00, 4.00) | 3.00 (2.00, 4.00) | 0.152 |
There was no significant difference in heart rate, oxygen saturation, or episodes of desaturation between the intervention and control groups before, during and after eye exam (Table 3). Eleven infants in the control group and 9 infants in intervention group (p = 0.15) experienced skin irritation on the ear, and there were no other anticipated adverse effects. There were no differences in other pain management use between the groups.
Table 3.
Secondary outcomes of magnetic auricular acupuncture on pain during ophthalmic examination
| Placebo | Acupuncture | Total | P-value | |
|---|---|---|---|---|
| SaO2 < 90%,n/N (%) | ||||
| Before procedure | 6/190 (3.2) | 12/190 (6.3) | 18/380 (4.7) | 0.147 |
| During procedure | 67/190 (35.3) | 54/190 (28.4) | 121/380 (31.8) | 0.152 |
| After procedure | 5/190 (2.6) | 4/190 (2.1) | 9/380 (2.4) | 0.736 |
| Heart Rate, beats per min, mean (std) | . | |||
| Before procedure | 144.47 (14.76) | 142.98 (13.94) | 143.72 (14.36) | 0.312 |
| During procedure | 171.14 (22.64) | 169.11 (21.40) | 170.13 (22.03) | 0.369 |
| After procedure | 144.39 (12.44) | 142.47 (13.56) | 143.43 (13.03) | 0.151 |
| Adverse Effect, n/N (%) | . | |||
| Before procedure | 1/190 (0.5) | 2/190 (1.1) | 3/380 (0.8) | 0.562 |
| During procedure | 26/190 (13.7) | 17/190 (8.9) | 43/380 (11.3) | 0.145 |
| After procedure | 1/190 (0.5) | 1/190 (0.5) | 2/380 (0.5) | 1 |
| Skin irritation, n/N (%) | . | |||
| Before procedure | 2/190 (1.1) | 0/190 (0) | 2/380 (0.5) | 0.156 |
| During procedure | 8/190 (4.2) | 8/190 (4.2) | 16/380 (4.2) | 1 |
| After procedure | 1/190 (0.5) | 1/190 (0.5) | 2/380 (0.5) | 1 |
| Desaturation, n/N (%) | . | |||
| Before procedure | 0/190 (0) | 0/190 (0) | 0/380 (0) | N/A |
| During procedure | 18/190 (9.5) | 9/190 (4.7) | 27/380 (7.1) | 0.072 |
| After procedure | 0/190 (0) | 0/190 (0) | 0/380 (0) | N/A |
| Analgesia, n/N (%) | . | |||
| Before procedure | 12/190 (6.3) | 11/190 (5.8) | 23/380 (6.1) | 0.83 |
| During procedure | 9/190 (4.7) | 12/190 (6.3) | 21/380 (5.5) | 0.501 |
| After procedure | 22/190 (11.6) | 20/190 (10.5) | 42/380 (11.1) | 0.744 |
| Breastfeeding, n/N (%) | . | |||
| Before procedure | 4/190 (2.1) | 6/190 (3.2) | 10/380 (2.6) | 0.522 |
| During procedure | 2/190 (1.1) | 4/190 (2.1) | 6/380 (1.6) | 0.41 |
| After procedure | 16/190 (8.4) | 16/190 (8.4) | 32/380 (8.4) | 1 |
| Pacificer, n/N (%) | . | |||
| Before procedure | 5/190 (2.6) | 1/190 (0.5) | 6/380 (1.6) | 0.1 |
| During procedure | 6/190 (3.2) | 6/190 (3.2) | 12/380 (3.2) | 1 |
| After procedure | 4/190 (2.1) | 2/190 (1.1) | 6/380 (1.6) | 0.41 |
| Kangaroo care, n/N (%) | . | |||
| Before procedure | 3/190 (1.6) | 4/190 (2.1) | 7/380 (1.8) | 0.703 |
| During procedure | 1/190 (0.5) | 2/190 (1.1) | 3/380 (0.8) | 0.562 |
| After procedure | 2/190 (1.1) | 2/190 (1.1) | 4/380 (1.1) | 1 |
Discussion
To our best knowledge, this is the largest definitive trial of MAA pain management during eye examination in infants. Our study confirms the results of previous smaller trials by Chen et al. [18] and Gan et al. [20]. Our results show that MAA results in a 20% reduction in PIPP scores, which is consistent with the 30% reduction reported by Chen et al. [18]. There were no ill effects except for mild transient skin irritation in 4.2% (n = 16/380) of infants, equally distributed between the intervention and control groups. The MAA magnet stickers were cheap, easily placed by trained personnel and did not interfere with routine newborn care.
An important observation is the low frequency use of analgesia use (11.6%) for pain control in eye examinations in China (Table 3).
Non-pharmacologic methods like sucrose, breast-feeding and non-nutritive sucking are commonly used but are only marginally effective. In a randomized controlled trial conducted in four groups to evaluate the use of oral sucrose and or pacifier for reducing pain responses during neonatal eye examinations using the premature infant pain profile (PIPP) scoring system, Boyle et al. [5] reported that the mean (SD) PIPP scores were 15.3 (1.9), 14.3 (1.6), 12.3 (2.9), and 12.1 (3.4) for sterile water, sucrose, pacifier, and sucrose combined pacifier groups respectively, indicating that these methods reduced pain only marginally. It is also unclear whether sucrose really produces analgesia or only modifies pain-associated expressions and behavior [24, 25] and its long-term effects are poorly understood. Similarly, Nayak et al.’s study [7] of expressed breast milk, 10% dextrose or sterile water administered orally before ROP screening in preterm neonates did not significantly alleviate pain during the procedure. The frequent use of pharmacologic agents like sedatives (e.g. diazepam) and Opioids (e.g. morphine, fentanyl) may have negative consequences for neurodevelopment [26].
Acupuncture is a form of non-pharmacological pain management that has been practiced for over 2000 years by Traditional Chinese Medicine (TCM) practitioners and has recently been applied to neonates [17]. It involves the insertion of very thin needles through the skin at strategic points on the body, and is based on the idea of energy (“Chi”) circulating through the body through meridian pathways. Although the mechanism of action is unknown, some speculate that it works by stimulation of the endorphin system [17]. In addition to needle acupuncture, there are also noninvasive methods such as MAA that involve applying small magnets to strategic points on the meridians. MAA is an attractive method for pain management in neonates who have thin sensitive skin, as it is non-invasive, affordable, portable, can easily be administered in a busy NICU setting [18, 20]. MAA may offer an alternative pain control modality that can potentially be used in combination with other non-pharmacologic methods or may reduce the dose of pharmacologic agents needed, and future research could explore these possibilities.
Limitations
The study was disrupted by the CONVID pandemic, which led to intermittent suspension of patient recruitment, prevention of hospital visits by parents, hospital and bed closures, staff displacement and other inconveniences. This led to repeated study starts and stops at different hospitals. Consequently, we had to prolong the study period and abandon sequential patient recruitment in favor of convenient subject sampling. The mean GA in our study was 32.8 weeks in the control group and 33 weeks in the MAA group, with no involvement of extremely preterm infants. We did not measure the impact of acupuncture on long term outcomes, including neurodevelopment and future studies should take these knowledge gaps into account.
Supplementary Information
Supplementary Material 1. Supplementary Figure S1. Battlefield acupuncture protocol. Magnets were placed on five auriculoacupuncture points on each ear according to the Battlefield Protocol. The five auricular points were stimulated sequentially in the following order on each ear: 1- Cingulate Gyrus, 2- Thalamus, 3- Omega 2, 4- Point Zero, 5- Shenmen (HT7). Cotton plugs were used to prevent magnets falling into external auditory canal
Acknowledgements
We thank the infants, parents, nurses, neonatologists, and other clinical staff who participated in this trial. We also thank all the recruiting hospitals involved in the study. Their help and support were invaluable since they contributed significantly to the trial’s success. We also thank Chinese Neonatal Network for technical and material support.
Consort-statement
The study adheres to CONSORT guidelines and includes a completed CONSORT checklist.
Authors’ contributions
Drs Li, Tuerxun, and Shoo K. Lee conceptualized and designed the trial, and contributed to interpreting the results; Drs Tuerxun and Yajie Su contributed to acquisition of data, coordinated and supervised data collection, Drs Li, Shoo K. Lee and Yancheng Wang contributed to the data analysis and interpreted the results; Drs Li, Shoo K. Lee, Laishuan Wang and Tuerxun contributed to drafting of the manuscript. All authors contributed to acquisition of data and critically reviewed the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Funding
Dr Lee is supported by a grant from the Canadian Institutes of Health Research.
Data availability
All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.
Declarations
Ethics approval and consent to participate
The study received ethical approval from the ethics committee of People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China (KY2019082101) and the 16 recruiting hospitals obtained approval from their respective hospitals. Informed consent was obtained from all parents, with the same informed consent form being used at all participating centers. The trial was registered at Chinese Clinical Trial Registry (ID number ChiCTR1900027474) on 14/11/2019. The trial was performed in accordance with the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from all parents.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Long Li and Roukeyan Tuerxun contributed equally to the manuscript and are co-first authors.
Contributor Information
Long Li, Email: lilong65@126.com.
Laishuan Wang, Email: laishuanwang@fudan.edu.cn.
Shoo K. Lee, Email: shoo.lee@sinaihealth.ca
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material 1. Supplementary Figure S1. Battlefield acupuncture protocol. Magnets were placed on five auriculoacupuncture points on each ear according to the Battlefield Protocol. The five auricular points were stimulated sequentially in the following order on each ear: 1- Cingulate Gyrus, 2- Thalamus, 3- Omega 2, 4- Point Zero, 5- Shenmen (HT7). Cotton plugs were used to prevent magnets falling into external auditory canal
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.