The Effect of Pimpinella Anisum Herbal Tea On Human Milk Volume and Weight Gain in The Preterm Infant: A Randomized Controlled Clinical Trial

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Khalili et al.

BMC Complementary
BMC Complementary Medicine and Therapies (2023) 23:19
https://doi.org/10.1186/s12906-023-03848-6 Medicine and Therapies

RESEARCH Open Access

The effect of Pimpinella Anisum herbal


tea on human milk volume and weight gain
in the preterm infant: a randomized controlled
clinical trial
Sona Khalili1, Leila Amiri‑Farahani2*, Shima Haghani3, Arash Bordbar4, Asie Shojaii5 and Sally Pezaro6

Abstract
Background and aims Human milk supports pre-term infants to thrive. Yet human milk production can be inhibited
when infants are born prematurely. Pimpinella Anisum has been evidenced to increase milk production and infant
weight gain in previous animal studies. The present study aimed to determine the effect of Pimpinella Anisum herbal
tea on human milk volume and preterm infant weight in human populations for the first time.
Methods Human milk supports pre-term infants to thrive. Yet human milk production can be inhibited when infants
are born prematurely. Pimpinella Anisum has been evidenced to increase milk production and infant weight gain in
previous animal studies. The present study aimed to determine the effect of Pimpinella Anisum herbal tea on human
milk volume and preterm infant weight in human populations for the first time.
Results There was a statistically significant difference in terms of milk volume in the first, third, fourth, fifth, sixth and
seventh days between the three groups of intervention, placebo, and control (p < 0.05). On the first day, the mean
volume of pumped milk in the intervention group was significantly higher than the control group (p = 0.008). On
the second day, there was no statistically significant difference between groups. On the third, fourth, fifth, sixth and
seventh days, the mean volume of pumped milk in the intervention group was significantly higher than the placebo
and control groups (p < 0.05). There was no statistically significant difference in terms of preterm infant weight on days
0, 3 and 7 between the three groups.
Conclusion The use of Pimpinella Anisum or ‘Anise’ tea can increase the volume of human milk and since no specific
side effects have been reported in its use, it may be incorporated easily, cheaply, and effectively in practice where
appropriate to the benefit of preterm infant nutrition worldwide.
Keywords Pimpinella anisum, Breast milk production, Milk volume, Preterm infants, Galactagogue herbal tea,
Newborn weight, Lactation, Human milk, Breastfeeding

*Correspondence: University of Medical Sciences, Tehran, Iran


4
Leila Amiri‑Farahani Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran
l.amirifarahani@gmail.com University of Medical Sciences (IUMS), Tehran, Iran
1 5
Department of Reproductive Health and Midwifery, School of Nursing School of Persian Medicine, Research Institute for Islamic
and Midwifery, Iran University of Medical Sciences, Tehran, Iran and Complementary Medicine, Iran University of Medical Sciences,
2
Department of Reproductive Health and Midwifery, Nursing Tehran, Iran
6
and Midwifery Care Research Center, School of Nursing and Midwifery, The Centre for Healthcare research, Coventry University, Coventry,
Iran University of Medical Sciences, Tehran, Iran United Kingdom
3
Department of Biostatistics, Nursing Care Research Center, Iran

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Khalili et al. BMC Complementary Medicine and Therapies (2023) 23:19 Page 2 of 11

Introduction in humans including being an antioxidant, antibacterial,


In 2018 only 42% of infants started breastfeeding in the antifungal, anticonvulsant, anti-inflammatory, analgesic,
first hour of life [1]. Due to its numerous health ben- gastro-protective, antidiabetic, and antiviral [23, 24]. In
efits, one of the global goals of infant nutrition by 2025 terms of chemical composition, approximately 90–80%
is that at least 50% of infants under the age of 6 months of Pimpinella Anisum is Anethole [24], which is known
be exclusively breastfed [2]. In Iran, the results of a 2018 to lead to increased prolactin stimulation and milk pro-
systematic review and meta-analysis reported the over- duction in animals [25, 26]. A recent review of the litera-
all prevalence of exclusive breastfeeding to be 53% [3]. ture in this field revealed only further studies including
This is encouraging, as human milk feeding is beneficial animals, and none thus far including human participants
for all infants, including those born preterm [4], which [27]. This provides a unique opportunity to conduct
are 40 times more likely to die than infants born at full founding research into the effects of Pimpinella Ani-
term [5], and yet may be saved from conditions such as sum on human milk volume, and subsequent thriving of
necrotizing enterocolitis by being exclusively breast fed the premature infant as it is reasonable to assume that
[6]. Nonetheless, when preterm infants are admitted to such effects seen in animal populations may be similar
neonatal intensive care units, the maintenance of human in humans.
milk production, and the rate of successful breastfeeding In justifying the testing of Pimpinella Anisum in
can be lower than it would be otherwise [7, 8]. Therefore, humans, we first considered safety in high regard. Indeed,
breastfeeding support, protection and promotion are of anise is one of the drugs approved by the Food and Drug
high importance in this context [9]. Administration of Iran with the registration number
The incomplete physical development which occurs 20885/56 produced by Sabz Andish Parnian Pharma-
in premature infants may lead to severe respiratory dis- ceutical Company [28]. Moreover, citing paragraph 4,
tress, hypoglycemia, and hypothermia, requiring the Article 3 of the description of the duties of the midwife,
infant to be admitted to intensive care, and thus delay the resolution dated 2009, which is related to the care of
the onset of breastfeeding alongside parental separation the infant [29] as well as Article 6; the midwife is permit-
[10]. In addition, neuralgia affects the tone of the oral ted to use medicinal plants licensed by the Ministry of
system, causing poor sucking-swallowing coordination Health, Treatment and Medical Education in the treat-
in the preterm infant [11]. This in turn means that the ment of gynecological and obstetric problems. Moreover,
breast may not be emptied of milk effectively, which in Studies conducted thus far exploring Pimpinella Anisum
turn can lead to reduced milk supply and even reduced use in animal populations have not identified any adverse
milk production [12]. With inadequate milk consumption side effects [25, 30, 31]. Considering the above, the pre-
and reduced milk supply, nutrition-related deaths, diar- sent study aimed to determine the effect of Pimpinella
rhea, stunted growth, and hyperbilirubinemia may occur, Anisum herbal tea on human milk volume and preterm
leading to neonatal rehospitalization [13]. Numerous infant weight in human populations for the first time.
studies have explored the reasons why exclusive breast-
feeding may be discontinued [14–17]. For those who Methods
choose to breastfeed premature infants, the presence of Trial design and participants
excitement, fatigue, and psychological stress and illness, Our study was conducted as a parallel randomised clini-
along with the inadequate emptying of milk may also cal trial with intervention, control, and placebo groups.
prove inhibitive [18, 19]. Thus, to maximise the benefits Reporting of this study has been done in accordance
of breastfeeding, it will be important to explore new ways with the Consolidation Standards of Reporting Tri-
in which to increase human milk volume to the benefit of als (CONSORT) statement. It was funded by Iran
newborns and families worldwide. University of Medical Sciences and conducted in July
Strategies to overcome the challenges associated with 2021. The study’s protocol was registered in the Clini-
breastfeeding include the use of nipple shields, cup cal Trial Registration Center on 14 March 2021. Code:
feeding, complementary milk, and syringe feeding [12]. IRCT20180427039436N9. Our study population included
Additionally, in the absence of breastfeeding counseling breast feeders and premature infants whose gestational
and non-pharmacological strategies, researchers’ atten- age was less than 32 weeks who were hospitalized in
tion to the use of chemical and herbal milk supplements the neonatal intensive care unit of Akbarabadi Hospital
has increased [14, 20]. In many parts of the world, herbal (referral and educational hospital) in Tehran, Iran.
medicines have been used for the augmentation of
human milk during postpartum period [21, 22]. Pimpi- Maternal inclusion criteria
nella Anisum or ‘Aniseed/Anise’ in traditional medicine Participants were included if they had a desire to exclu-
is already established to have many therapeutic benefits sively breastfeed and pump human milk using an
Khalili et al. BMC Complementary Medicine and Therapies (2023) 23:19 Page 3 of 11

electronic pump from the third day following birth. method, it is necessary to ascertain the total sample
Included participants were also required to be literate size, the number of groups and the number of group
and at least 18 years of age. repetitions in each block (considered equal). In the
current study, the size of each block was twice the
Infant inclusion criteria number of groups (six groups in each block). The
Infants were required to have been born preterm (at less inclusion of a control group meant that it was not pos-
than 32 weeks of gestation), and admitted to the intensive sible to assure blindness. Therefore, a randomization
care unit, where such infants are typically fed by orogas- code was generated for each participant using a sealed
tric or nasogastric tube. envelope website. An epidemiologist, who was not part
of the study assimilated the randomization list. For
Maternal exclusion criteria allocation concealment, the assignment list remained
Participants were excluded if they were engaged in smok- with the epidemiologist.
ing, alcohol, and/or drug use, suffering from infectious Human milk volume was recorded as one of the main
diseases transmitted through human milk feeding (e.g., outcomes of the study by participants in a daily informa-
AIDS), had active pulmonary tuberculosis, had a history tion recorder form. The infant’s weight was also meas-
of infertility, were taking anticoagulants which are con- ured and recorded by the lead researcher. Statistical
traindicated with the use of Anise [32], had a history of analysis was performed by a statistician who also did not
cancer estrogen-dependent diseases (e.g., uterine cancer, know the content provided for the study groups and their
breast cancer, endometrial hyperplasia) and/or had mas- allocation.
tectomy, nipple fractures, breast abscesses and/or infec-
tious mastitis.
Description of intervention
Infant’s exclusion criteria Participants in the intervention group received Pimpi-
Infants were excluded if they had congenital anomalies nella Anisum herbal tea (2 g of dried Anise plant plus
(e.g., cleft lip and palate), and/or were born as part of a 1 g of black tea). Those in the placebo group received
multiple birth. black tea containing 3 g of dried black tea only. In both
groups, tea was ingested 3 times [32–34] a day for a week
Withdrawal criteria at breakfast, lunch, and dinnertime. The intervention
Participants were able to withdraw at any time without period was limited to 7 days, because typically after this
giving a reason. Whilst the supplementation of iron and time the preterm infant is fed human milk directly (rather
multivitamins are recommended from the 16th week than being tube fed), and thus the recording of milk pro-
of pregnancy until three months after giving birth, our duction/volume becomes impossible. Uniformity and
withdrawal criteria included cases in which there was same-color packaging for herbal compounds was consid-
use of any additional galactagogues (human milk induc- ered in both intervention and placebo groups. Both teas
ers/enhancers). Participants were similarly withdrawn if were prepared by the School of Persian Medicine in Iran
they were consuming less than 10% of Pimpinella Ani- University of Medical Sciences under the supervision of a
sum herbal tea, along with cases of allergic reaction and specialized consultant of medicinal plants (PhD of Phar-
intolerance. macognosy) (A.SH.). Participants placed a tea bag in the
cup, added 150 ml of boiling water, and sipped the tea
Data collection/recruitment after 10 min of infusion. Those in the control group did
Convenience sampling was used to recruit eligible par- not receive any herbal or chemical composition of galac-
ticipants over a period of 6 months. Those who met the tagogue. At the end of the intervention period, those in
eligibility criteria were given participant information and the control group were offered Pimpinella Anisum herbal
those who subsequently agreed to take part in the study tea also.
were invited to complete informed consent forms and Participants in the intervention and placebo groups
enrolled. had no information about the type of herbal tea they
Data collection was carried out between July 2021 were ingesting. To increase accuracy in relation to the
and November 2021. Eligible participants were intervention and placebo groups, the participants, the
assigned to three groups: (1) intervention, (2) placebo researcher, and statistical analyst did not know anything
and (3) control using the block randomization method about the type of herbal tea ingested by the either the
(https://​w ww.​seale​denve​lope.​com) and followed for intervention or placebo groups.
a period of 7 days. To determine the sequence of par- Participants in all groups used the Medela electronic
ticipants’ allocation based on the block randomization machine to pump their milk at least 6 times a day (3–4
Khalili et al. BMC Complementary Medicine and Therapies (2023) 23:19 Page 4 of 11

hourly upon waking at approximately 8am) for a period be considered statistically significant compared with the
of 7 days. Excess milk was stored in the milk bank of control group, the sample size in each group was esti-
Akbarabadi Hospital. mated to be at least 38 people using the sample size for-
mula. The total number of participants in this study was
Assessment of trial variables therefore 145 individuals.
The variables of this study were measured as follows: Based on the study by Turkyılmaz et al., (2011) the
standard deviation of milk volume was estimated to be
Demographics and baseline characteristics 53.5 and 12.9 in the intervention and control groups,
Demographics and baseline data were related to both respectively. Also, with regards to the weight of neonate,
parents and the infant. Maternal data was collected in the sample size of 15 people in each group was deter-
relation to age, body mass index, education level, employ- mined [34], allowing for a drop-out rate of 20%.
ment status, whether the pregnancy had been planned (or
(z1−α/2 + z1−β )2 × (s12 + s22 )
not), number of previous births, mode of birth, chronic n=
diseases, use of drugs during pregnancy and steroid use, d2
as well as consumption of iron and other supplements.
Paternal data collected included occupation type, level of z0.975 = 1.96
education, and socio-economic status. Data collected in
relation to the infant included birth weight, height, head z0.8 = 0.84
circumference, gestational age at birth, neonatal age upon
entry to the study, observed sex at birth, cause of hospitali- (1.96 + 0.84)2 × (53.52 + 12.92 )
zation and type of serum injected into the infant (e.g., Dex- n= ≈ 38
252
trose water) along with the infant feeding method chosen.
Maternal food consumption known to increase human
milk production such as lettuce, basil leaves, dill, fenu- Ethics
greek, carrot juice, spinach, sesame, and fennel was also The protocol of the present study was approved by the
monitored. Data relating to the infant was extracted from Ethics Committee of Iran University of Medical Sci-
medical records by the researcher. Maternal and paternal ences with the ethics code: IR.IUMS.REC.1399.1417. All
data was recorded and self-reported by the parents. participants were fully informed about the objectives
and process of the study and informed written consent
Daily information recorder form was obtained from them. The information obtained dur-
The daily information form included space for data entry ing the study process remained completely confidential.
in relation to the frequency of pump use, time spent on All participants were informed that they could with-
pump, volume of milk produced at each pumping, time draw from the study at any time. No fees were paid for
spent skin-to-skin with the baby, frequency of liquids and the study and all services were completely free. Only one
tea based on the number of glasses consumed during the code was assigned to the study, and all study data were
day, and the amount of pumped milk at the end of each entered into data systems anonymously. All participants
day. All participants pumping human milk in the study were given the researcher’s phone number at the begin-
completed this form daily for 7 days. ning of the study, as participants were asked to inform
the researcher of any side effects.
Infant weight recorder form
The infant’s weight was measured by a German Seca
Statistical analysis
scale on day 0 (before intervention), day 3 and day 7 of
One-way analysis of variance (ANOVA) was used to
the intervention period. Measurements were taken by
statistically analyse the data and to compare the groups
the researcher during the morning shift prior to the first
in terms of quantitative variables such as maternal age,
human milk feed and after the infant’s first bowel and uri-
Body Mass Index (BMI), infants’ gestational age at birth
nary outputs. Values were recorded in the infant weight
and age upon entry to the study, infant’s weight, height
recorder form.
and head circumference, and maternal consumption of
fluids and tea (glass/day). Fisher’s exact test was used to
Sample size
compare the groups in terms of variables such as eco-
To determine the required sample size at 95% confidence
nomic status, mode of birth, paternal education level,
level and 80% test power, assuming that the effect of
and type of serum injected into the infant (e.g., Dex-
Pimpinella Anisum on human milk volume in the inter-
trose water). Chi-squared test was used to compare the
vention group should be 25 unit (d = 25) for the effect to
Khalili et al. BMC Complementary Medicine and Therapies (2023) 23:19 Page 5 of 11

group in terms of maternal and paternal occupation, (IBM Corp, US). In all tests, a p-value of < 0.05 was con-
maternal education and number of previous births, sidered significant.
infant’s observed sex at birth, whether pregnancy was
planned or unplanned, chronic diseases, any drug use Result
during pregnancy, maternal use of steroids, supple- Overall, 145 participants with preterm infants partici-
ments and drugs, cause of infant hospitalization and pated in the study (50 in the intervention group, 49 in the
chosen infant feeding method. placebo group, and 46 in the control group). However,
One-way ANOVA was used to compare the fre- some (n = 5) were withdrawn due to being dissatisfied
quency of pumping, time spent on pump, time spent with the taste and thus non-compliant in ingesting the
skin-to-skin with the infant, frequency of liquids and tea. Others (n = 4) were withdrawn either due to their use
tea based on the number of glasses consumed during of other galactagogues or due to incomplete question-
the day, amount of pumped milk at the end of each naires (n = 7). Finally, 129 participants (45 in the inter-
day, and infant weight in the groups on the first to sev- vention group, 45 in the placebo group, 39 in the control
enth days after the start of the intervention. Analysis group) remained in the study and were statistically ana-
of variance with repeated measures was used for the lyzed (Fig. 1). No adverse side effects were reported by
comparison of the mean frequency of pump use, time participants.
spent on pump, time spent skin-to-skin with the infant, The three groups did not demonstrate a statistically sig-
frequency of liquids and tea based on the number of nificant difference in terms of demographics, maternal,
glasses consumed during the day, amount of pumped paternal, and infant baseline data or recorded daily infor-
milk at the end of each day, and infant weight over time mation (Table 1). Yet in comparing the variables of the
(first to seventh days after the start of the interven- mean time spent on pump and the frequency of pumping
tions). Data were analysed by SPSS software version 22 in the three groups, a statistically significant difference

Fig. 1 Enrolment of participants into three groups of intervention, placebo and control
Khalili et al. BMC Complementary Medicine and Therapies (2023) 23:19 Page 6 of 11

Table 1 Demographics and baseline characteristics of study participants and comparisons between intervention group, placebo
group and control group
Variables Intervention group (n = 45) Placebo group (n = 45) Control group (n = 39) P—value

Maternal age (year), (Mean ± SD) 30.72 ± 6.64 29.83 ± 6.99 32.29 ± 6.69 0.594
Maternal BMI (kg/m2), (Mean ± SD) 30.1 ± 24.79 30.1 ± 01.49 29.1 ± 81.85 0.479
Maternal education, n (%)
Elementary 17 (34) 11 (16.3) 15 (32.6) 0.22
Secondary 11 (22) 21 (42.9) 17 (37)
High school 14 (28) 13 (26.5) 10 (21.7)
University 8 (16) 7 (14.3) 4 (8.7)
Maternal occupation, n (%)
Housewife 37 (74) 40 (81.6) 37 (80.4) 0.61
Employed 13 (26) 9 (18.4) 9 (19.6)
Pregnancy planned, n (%)
Yes 40 (80) 43 (87.8) 39 (84.8) 0.567
No 10 (20) 6 (12.2) 7 (15.2)
Number of previous births (Mean ± SD)
1 25 (50) 30 (61.2) 22 (7.8) 0.504
2 12 (24) 12 (24.5) 11 (23.9)
  > 3 13 (26) 7 (14.3) 13 (28.3)
Mode of birth, n (%)
Vaginal birth 42 (84) 45 (91.8) 44 (95.7) 0.151
Birth via caesarean section 8 (16) 4 (8.2) 2 (4.3)
Maternal chronic diseases, n (%)
Yes 14 (28) 7 (14.3) 13 (28.3) 0.108
No 36 (72) 42 (85.7) 40 (87)
Maternal drug use during pregnancy, n (%)
Yes 13 (26) 7 (14.3) 6 (13) 0.183
No 37 (74) 42 (85.7) 40 (87)
Maternal use of iron and complementary drugs, n (%)
Yes 35 (70) 37 (75.5) 37 (80.4) 0.496
No 15 (30) 12 (24.5) 9 (19.6)
Maternal use of steroids, n (%)
Yes 50 (100) 47 (95.9) 44 (95.7) 0.338
No 0 (0) 2 (4.1) 2 (4.3)
Paternal occupation, n (%)
Employee 7 (14) 10 (20.4) 12 (26.1) 0.418
Manual worker 9 (18) 13 (26.5) 10 (21.7)
Self- employed 34 (68) 26 (53.1) 24 (52.2)
Paternal education, n (%)
Elementary 3 (6) 5 (10.2) 5 (10.9) 0.539
Secondary 22 (44) 22 (44.9) 16 (34.8)
High school 19 (38) 17 (34.7) 14 (30.4)
University 6 (12) 5 (10.2) 11 (23.9)
Economic status of the family, n (%)
Desirable 8 (16) 3 (6.1) 6 (13) 0.287
Relatively 41 (82) 41 (83.7) 37 (80.4)
undesirable 1 (2) 5 (10.2) 3 (6.6)
Infant’s weight, (gr)(Mean ± SD) 1245.146 ± 22.84 1245.147 ± 42.08 1199.146 ± 45.8 0.22
Infant’s Height, (cm)(Mean ± SD) 39.1 ± 5.58 39.1 ± 63.69 38.1 ± 97.48 0.111
Head circumference of infant, (cm)(Mean ± SD) 29.1 ± 5.97 29.2 ± 65.06 29.1 ± 6.86 0.327
Khalili et al. BMC Complementary Medicine and Therapies (2023) 23:19 Page 7 of 11

Table 1 (continued)
Variables Intervention group (n = 45) Placebo group (n = 45) Control group (n = 39) P—value

Gestational age at birth, (wk) (Mean ± SD) 30.0 ± 1.83 30.0 ± 21.91 29.0 ± 92.96 0.229
Neonatal age upon entry to the study, (wk) 8.67 ± 4.94 8.50 ± 5.26 8.73 ± 4.15 0.407
(Mean ± SD)
Infant sex observed at birth, n (%)
Male 21 (42) 15 (30.6) 18 (39.1) 0.478
Female 29 (58) 34 (69.4) 28 (60.9)
Cause of infant hospitalization, n (%)
IUGR​
  yes 8 (16) 7 (14.3) 14 (30.4) 0.099
  no 42 (84) 42 (85.7) 32 (69.6)
PDA
  yes 6 (12) 7 (14.3) 10 (21.7) 0.398
  no 44 (88) 42 (85.7) 36 (78.3)
IVH < 3
  yes 15 (30) 14 (28.6) 12 (26.1) 0.912
  no 35 (70) 35 (71.4) 34 (73.9)
Type of infant feeding, n (%)
Nasogastric tube 12 (24) 12 (24.5) 15 (32.6) 0.571
Orogastric tube 38 (76) 37 (75.5) 31 (67.4)
Type of serum injected into the infant, n (%)
D.W 5% 35 (70) 35 (71.4) 30 (65.2) 0.968
D.W 7.5% 11 (22) 10 (20.4) 11 (23.9)
D.W 10% 4 (8) 4 (8.2) 5 (8.2)
SD standard deviation, BMI Body Mass Index, IUGR​ Intra Uterine Growth Restriction, PDA Patent Ductus Arteriosus, IVH Intra Ventricular Hemorrhage, D.W Dextrose
water

was observed (Table 2). This difference is largely due to results in relation to variance with repeated measures
the enhancing effect of Anise, which required that these for within-group comparisons showed that, in the inter-
individuals spent more time and frequency pumping the vention, placebo and control groups, the mean weight
larger amounts of milk produced. In terms of maternal on the seventh day of the intervention was significantly
consumption of foods with milk-enhancing properties higher than the third day (p < 0.001) and day zero (before
in the three groups, there was no statistically significant the intervention) (p < 0.001). The mean infant weight
difference observed in any of the seven days of the study on the third day was higher than day zero in all groups
(P ≥ 0.05). (p < 0.001).
In the between group comparisons, results demon-
strated that there was a statistically significant difference Discussion
in terms of human milk volume in the first, third, fourth, The purpose of this study was to determine the effect of
fifth, sixth and seventh days between the three groups Pimpinella Anisum herbal tea on human milk volume
(intervention, placebo, and control) (p < 0.05) (Table 2). and preterm infant weight in human populations for the
Results from the analysis of variance with repeated first time. We observed significant differences in milk
measures for within-group comparisons showed that in volume between the three groups. On the first, third,
the intervention, placebo, and control groups, the mean fourth, fifth, sixth and seventh days, the mean volume
volume of pumped milk at least one time was statistically of pumped milk in the intervention group was signifi-
significant (p < 0.001). Two-by-two comparisons in all cantly higher than the placebo and control groups. The
times for three groups are presented in Table 3. within-group comparison of intervention, placebo, and
There was no statistically significant difference control groups showed a statistically significant differ-
observed in the weight of preterm infants on days 0, 3 ence between the mean of milk volume before and end
and 7 of the study between the three groups of interven- of the intervention in each group. These findings in rela-
tion (1370.12 ± 168.88), placebo (1360.91 ± 144.73) and tion to human milk production are congruent with those
control (1321.3 ± 161.97) (p = 0.287) (Table 2). Yet the reported by Hosseinzadeh and colleagues in relation to
Khalili et al. BMC Complementary Medicine and Therapies (2023) 23:19 Page 8 of 11

Table 2 Recorded daily information and infant weight in three groups of study
Variables Intervention group (n = 45) Placebo group (n = 45) Control group (n = 39) P – value a, b, c, d

Frequency of tea based on the 1 day 2.26 ± 0.85 1.97 ± 0.8 1.93 ± 0.99 0.148
number of glasses consumed 2 day 2.34 ± 0.98 2.2 ± 0.99 2.13 ± 1.18 0.614
during the day (Mean ± SD)
3 day 2.34 ± 1.13 2.22 ± 1.02 2.13 ± 1.1 0.642
4 day 2.18 ± 1.06 2.02 ± 0.94 2.04 ± 1.22 0.731
5 day 2.32 ± 0.99 2.24 ± 1.03 2.19 ± 1.22 0.852
6 day 2.32 ± 1.03 2.31 ± 1.1 2.1 ± 1.23 0.592
7 day 2.34 ± 1.06 2.26 ± 1.07 2.11 ± 1.23 0.593
Frequency of liquids based 1 day 1.4 ± 0.81 1.48 ± 0.76 1.28 ± 0.86 0.462
on the number of glasses 2 day 1.2 ± 0.85 1.48 ± 0.98 1.17 ± 0.85 0.162
consumed during the day
(Mean ± SD) 3 day 1.06 ± 0.86 1.22 ± 0.87 1.3 ± 1.01 0.41
4 day 0.98 ± 0.71 1.22 ± 0.89 1 ± 0.78 0.251
5 day 1.06 ± 0.73 1.24 ± 0.77 1.08 ± 0.81 0.446
6 day 1.04 ± 0.87 1.1 ± 0.98 1.13 ± 0.83 0.881
7 day 1.29 ± 0.79 1.08 ± 0.91 1.02 ± 0.85 0.921
Frequency of using pump 1 day 6.1 ± 1.37 6.12 ± 1.39 5.61 ± 2.04 0.226
(Mean ± SD) 2 day 6.24 ± 1.43 6.46 ± 1.47 5.8 ± 2.13 0.159
3 day 6.06 ± 1.92 6.42 ± 1.76 5.95 ± 2.22 0.469
4 day 6.28 ± 2.02 6.46 ± 1.86 5.76 ± 2.35 0.236
5 day 6.38 ± 2.04 6.53 ± 1.9 5.8 ± 2.4 0.219
6 day 6.6 ± 2.14 6.46 ± 1.89 5.8 ± 2.37 0.157
7 day 6.78 ± 2.2 6.41 ± 1.86 5.69 ± 2.33 0.046
Time spent on pump (min) 1 day 39.9 ± 12.18 39.8 ± 10.28 34.45 ± 14.46 0.056
(Mean ± SD) 2 day 40 ± 12.33 40.71 ± 9.94 36.1 ± 14.66 0.068
3 day 42. 7 ± 15.39 41.32 ± 12.49 37.17 ± 15.86 0.164
4 day 45.3 ± 16.42 43.77 ± 12.85 36.52 ± 16.99 0.015
5 day 47.2 ± 16.78 43.06 ± 12.11 38.15 ± 17.74 0.021
6 day 48.5 ± 17.5 44.59 ± 13.06 37.39 ± 17.69 0.004
7 day 48.6 ± 18.01 43.77 ± 13.52 36.95 ± 17.43 0.003
Time spent skin-to-skin with 1 day 18.2 ± 9.4 19.28 ± 10.45 15 ± 9.24 0.088
the infant (min) (Mean ± SD) 2 day 20.1 ± 10.71 19.38 ± 9.16 16.19 ± 10.91 0.149
3 day 19.1 ± 11.14 19.79 ± 11.41 16.3 ± 11.71 0.294
4 day 18.2 ± 12.76 19.28 ± 10.75 15.97 ± 11.95 0.388
5 day 16.80 ± 13. 23 19.08 ± 12.69 16.19 ± 12.91 0.516
6 day 17 ± 11.82 17.55 ± 12.46 16.52 ± 11.19 0.914
7 day 17.4 ± 13.21 19.69 ± 12.26 15.11 ± 10.97 0.192
Amount of pumped milk 1 day 137.9 ± 39.53 131.42 ± 32.38 112.82 ± 47.24 0.008, 0.007, 0.06, 0.64
at the end of each day (cc) 2 day 151.8 ± 45.15 136.83 ± 38.21 126.3 ± 70.6 0.061
(Mean ± SD
3 day 169.2 ± 66.17 138.26 ± 51.9 125.54 ± 55.18 0.001, 0.001,0.025, 0.054
4 day 193.7 ± 78.78 148.77 ± 53.87 130.21 ± 60.67 < 0.001, < 0.001, 0.002, 0.35
5 day 220.5 ± 89.65 155 ± 56.77 141.19 ± 69.13 < 0.001, < 0.001, < 0.001, 0.63
6 day 244.3 ± 102.21 164.69 ± 63.9 151.41 ± 80. 37 < 0.001, < 0.001, < 0.001, 0.72
7 day 268.1 ± 98.53 170.1 ± 66. 69 154.78 ± 82.07 < 0.001, < 0.001, < 0.001, 0.69
Infant weight (gr) 0 day 1262.16 ± 151.48 1263.34 ± 139.1 1219.43 ± 151.39 0.261
(Mean ± SD) 3 day 1307.82 ± 162.17 1305.89 ± 140.87 1263.15 ± 155.48 0.287
7 day 1370.12 ± 168.88 1360.91 ± 144.73 1321.3 ± 161.97 0.287
a,b,c,d
Repeated measurement test was used for comparison of the three groups and Tukey post hoc test was used for two- by-two comparison of groups
a
comparison of the three groups
b
comparison of intervention vs control
c
comparison of intervention vs placebo
d
comparison of placebo vs control
Khalili et al. BMC Complementary Medicine and Therapies (2023) 23:19 Page 9 of 11

Table 3 Comparison of within-group of volume of pumped milk in three groups of study


Variables comparison Comparison Comparison Comparison Comparison Comparison Comparison
of the times between between between between between between seventh
a
seventh and seventh and seventh and seventh and seventh and and sixth day
first day second day third day fourth day fifth day

Intervention < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
group
Placebo group < 0.001 < 0.001 < 0.001 0.003 0.04 1 1
Control group < 0.001 < 0.001 0.001 0.001 0.033 0.109 1
All of numbers are P-value
a
Repeated measurement test was used for comparison of the times and Bonferroni correction test was used for two-by-two comparison of times in each group
separately

mice [25], Sallam and colleagues in relation to Egyptian Anise supplementation has been evidenced elsewhere to
buffaloes [30] and Ying Wang and colleagues in relation improve calf weight gain in line with increased milk vol-
to sows [31]. In terms of implications, our findings sug- ume and feed intake in cows [31]. These differences in
gest that Pimpinella Anisum augments human lactation findings may be due to our comparatively short interven-
as it does in animal populations. Such augmentation may tion period (one week) [40].
act as a crucial beneficial factor in preterm infant nutri- All infants participating in the present study were born
tion worldwide. preterm and were fed through a tube, and only 8.7% of
Anise causes milk production in animals by stimulating birthing parents participating had a university educa-
the hormone lactogen (prolactin) [35]. The compounds tion. This is important to note as premature infants
of Pimpinella Anisum include: anisaldehyde, methylchav- gain weight more slowly than term infants, and preterm
icol, eugenol, estragole. It’s most essential oil is anethole, infants along with tube-fed infants, cup-fed infants, and
which makes up 93.9% of its content and is considered infants with birthing parents having low levels of literacy
the main factor of milk production, and the main source can weigh even less overall [41]. These factors are impor-
of its aroma. This plant is rich in phytoestrogenic com- tant to consider as additional predictors of poor weight
pounds and is warm in nature. Structurally, anethole is gain in preterm infants and may also partially account for
similar to dopamine and acts as a competitive antago- some of the findings presented here.
nism in the dopamine receptor. This key mechanism
stimulates the release of prolactin and thereby increases Strengths and limitations
milk production [23, 36]. A key strength of this study is that it is the first to deter-
No side effects were reported by participants in our mine the effect of Pimpinella Anisum herbal tea on
study. Other studies confirming the quasi-estrogenic human milk volume and preterm infant weight in human
(phytoestrogenic) effects of Anise have similarly noted populations. Limitations include the individual differ-
an absence of side effects in humans. For example, in ences in milk production. By allocating the participants
reducing the frequency and severity of hot flashes post in the study groups in a random manner, variable effects
menopause [37], pain during labor [38] and in improving may be somewhat mitigated. Due to the prevalence of
oligomenorrhea in cases of polycystic ovary syndrome covid-19 pandemic and the use of home-prepared foods
[39]. Our results bring new insights in relation to the use by those hospitalized, it was virtually impossible to
of Anise in human milk production, and further demon- standardize the intake of foods that may have a lactat-
strate safety in its use in human populations. ing effect. Thus, our findings should be interpreted with
There was no statistically significant difference caution. However, those who used any additional galacta-
observed in terms of preterm infant weight on days 0, gogues (human milk inducers/enhancers) were excluded
3 and 7 between the intervention, placebo and control from the study, though the supplementation of iron and
groups. The within-group comparison showed a statisti- multivitamins are recommended from the 16th week of
cally significant difference between the mean of preterm pregnancy until three months after giving birth. The pre-
infant weight before and end of the intervention in each sent study could not be performed with an intervention
group. This contrasts with the findings of Hosseinzadeh duration longer than 7 days, after which time the preterm
et al. (2014), which demonstrated a significant increase infant is typically fed human milk directly (rather than
in the weight of mice (pups) when compared to con- being tube fed), and thus the recording of milk produc-
trol groups [25]. Similarly in contrast with our findings, tion/volume becomes impossible. Future studies of this
Khalili et al. BMC Complementary Medicine and Therapies (2023) 23:19 Page 10 of 11

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