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The effect of the homeopathic remedies Arnica montana and Bellis perennis on mild postpartum bleeding - A randomized, double-blind, placebo-controlled study - Preliminary results

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To evaluate the effect of Arnica Montana and Bellis perennis on postpartum blood loss. Double blind, placebo-controlled, randomized, clinical trial. Department of Gynecology, Shaare Zedek Medical Center, Jerusalem. Forty parturients were randomized to one of three groups: Arnica montana C6 and Bellis perennis C6 (n=14), Arnica montana C30 and Bellis perennis C30 (n=14), or double placebo (n=12). After 48 h the Arnica/placebo was halted, and patients continued the Bellis/placebo until cessation of lochia. Hemoglobin levels (Hb) at 48 and 72 h postpartum. At 72 h postpartum, mean Hb levels remained similar after treatment with homeopathic remedies (12.7 versus 12.4) as compared to a significant decrease in Hb levels in the placebo group (12.7 versus 11.6; p<0.05), in spite of less favorable initial characteristics of the treatment group. The mean difference in Hb levels at 72 h postpartum was -0.29 (95% CI -1.09; 0.52) in the treatment group and -1.18 (95% CI -1.82; -0.54) in the placebo group (p<0.05). Treatment with homeopathic Arnica montana and Bellis perennis may reduce postpartum blood loss, as compared with placebo.
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UNCORRECTED PROOF
YCTIM 765 1—4
Complementary Therapies in Medicine (2005) xxx, xxx—xxx
3
The effect of the homeopathic remedies Arnica
montana and Bellis perennis on mild postpartum
bleeding—A randomized, double-blind,
placebo-controlled study—Preliminary results
4
5
6
7
Menachem Oberbauma,, Narine Galoyanb, Liat Lerner-Gevac, Shepherd
Roee Singera, Sorina Grisarub, David Shashar d, Arnon Samueloffb
8
9
aThe Center for Integrative Complementary Medicine, Shaare Zedek Medical Center, Jerusalem 91031,
Israel
10
11 bDepartment of Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel12 cWomen and Children’s Health Research Unit, Gertner Institute for Epidemiology and Health Policy
Research, Chaim Sheba Medical Center, Tel Hashomer, Israel
13
14 dDepartment of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, Israel
15
Summary
Objective: To evaluate the effect of Arnica Montana and Bellis perennis on postpar-
tum blood loss.
Design: Double blind, placebo-controlled, randomized, clinical trial.
Setting: Department of Gynecology, Shaare Zedek Medical Center, Jerusalem.
Interventions: Forty parturients were randomized to one of three groups: Arnica
montana C6 and Bellis perennis C6 (n= 14), Arnica montana C30 and Bellis perennis
C30 (n= 14), or double placebo (n= 12). After 48 h the Arnica/placebo was halted,
and patients continued the Bellis/placebo until cessation of lochia.
Main outcome measures: Hemoglobin levels (Hb) at 48 and 72 h postpartum.
Results: At 72 h postpartum, mean Hb levels remained similar after treatment with
homeopathic remedies (12.7 versus 12.4) as compared to a significant decrease in
Hb levels in the placebo group (12.7 versus 11.6; p< 0.05), in spite of less favorable
initial characteristics of the treatment group. The mean difference in Hb levels at
72 h postpartum was 0.29 (95% CI 1.09; 0.52) in the treatment group and 1.18
(95% CI 1.82; 0.54) in the placebo group (p< 0.05).
Conclusion: Treatment with homeopathic Arnica montana and Bellis perennis may
reduce postpartum blood loss, as compared with placebo.
© 2005 Published by Elsevier Ltd.
The funding source was not involved in any way in the collection, analysis, and interpretation of data; in the writing of the
report; and in the decision to submit the paper for publication.
*Corresponding author. Tel.: +972 2 6666 395; fax: +972 2 6666 975.
E-mail addresses: oberbaum@szmc.org.il, oberbaum@netvision.net.il (M. Oberbaum).
10965-2299/$ — see front matter © 2005 Published by Elsevier Ltd.
2doi:10.1016/j.ctim.2005.03.006
UNCORRECTED PROOF
YCTIM 765 1—4
2 M. Oberbaum et al.
Introduction
1
Postpartum hemorrhage (PPH) is a major cause of2
perinatal morbidity and mortality worldwide. It oc-
3
curs in 4% of all vaginal deliveries and is the third4
leading cause of maternal mortality in the USA.1
5
Worldwide, PPH is responsible for up to 125,000 ma-6
ternal deaths, and morbidity in 20 million women
7
annually. Prophylactic administration of oxytocic8
agents is the standard of care for this condition,9
reducing the incidence of PPH by 40%.2However,10
these intravenous agents have significant side ef-11
fects and contraindications. Therefore, an alterna-12
tive hemostatic therapy, administered orally, de-13
void of side effects and safe to use while breast-
14
feeding would be a welcome advent.15
For more than 200 years, homeopathy has been16
used during pregnancy and labor (e.g. Ref. 3), but17
only few, poorly performed studies have been per-18
formed to investigate its effect.4The need for indi-19
vidualization presents a major obstacle to the sci-
20
entific evaluation of homeopathic remedies. Home-
21
opathic medications are generally prescribed based22
upon the characteristics of the individual patient,23
and only secondarily upon diagnosis. A few ex-24
ceptions exist, in which a particular homeopathic25
medicine may be employed based upon a spe-26
cific indication. Two of these are Arnica montana
27
(Leopard’s bane), and Bellis perennis (the common
28
daisy).3,5 Arnica is used to treat trauma in any sys-29
tem, particularly with extravasation of blood, while30
Bellis is widely employed in trauma to the uterus,
31
including the trauma of labor and cesarean sec-32
tion. Both drugs are considered anti-hemorrhagic33
and analgesic. Therefore, both are commonly used
34
in homeopathy to treat complaints developing in
35
conjunction with labor.3,5 We examined the efficacy36
of these two medicines in preventing PPH in a dou-
37
ble -blinded, randomized placebo controlled trial.38
Methods39
Between February and August 2003, parturients at40
Shaare Zedek Medical Center who fulfilled inclusion41
criteria were invited to participate in the study. In-42
cluded were women aged 20—35, at week 37—4343
of pregnancy, after one to four previous deliveries,
44
and scheduled for spontaneous vaginal delivery of
45
a single fetus. Exclusion criteria were previous ce-
46
sarean section, antepartum or postpartum hemor-47
rhage in previous pregnancies, and coagulopathies.48
All women received standard obstetric care. The49
study was approved by the hospital’s institutional
50
review board.
51
After obtaining informed consent, patients were 52
randomized in a double-blinded manner using block 53
randomization lists6into three groups: (1) Arnica 54
and Bellis, both in a dilution of 106of the stem 55
solution; (2) Arnica and Bellis, both in dilution of 56
1060; and (3) identical placebos. Two different 57
potencies were chosen in order to be able to 58
compare the effect of remedies below (1012)to 59
remedies above Avogadro’s number (1060). Based 60
on the experience, low potencies have a weaker 61
effect than high potencies, but their specificity is 62
not as pronounced as high potencies. We added this 63
explanation in Patients where withdrawn from the 64
study if cesarean section or instrumental delivery 65
was later required. 66
Experimental and placebo drugs were prepared 67
by Ainsworth Pharmacy, London, in accordance 68
with the British Homoeopathic Pharmacopoeia. The 69
stem tinctures of Arnica, Bellis, and 40% alcohol as 70
placebo were diluted by a factor of ten with 40% al- 71
cohol, and vigorously shaken. This was repeated 6 72
and 30 times, yielding final concentrations of 1012 73
and 1060, respectively. One drop of each of the fi- 74
nal dilutions was impregnated separately on seven 75
grams of 3—4 mm spherical sucrose pills (Werners, 76
Germany). One dose of all medications consisted of 77
three tablets. 78
The study medications were distributed in two 79
vials containing pills impregnated with either 80
Arnica and Bellis 1012, Arnica and Bellis 1060 ,81
or two placebos. Patients were treated immedi- 82
ately after delivery by sucking three pills of the 83
medicated or placebo Arnica pills, followed a few 84
minutes later by medicated or placebo Bellis. This 85
was repeated every 5 h for the first 24 h, then three 86
times daily. After 48 h the Arnica/placebo was 87
halted and patients continued the Bellis/placebo 88
until cessation of lochia. 89
Venous hemoglobin levels were measured before 90
delivery (baseline) and 48 and 72 h later. 91
Non-compliance was defined as failure to take 92
medications during the first 48 h (during hospital- 93
ization). Non-compliant patients were included in 94
their intention to treat group for the purpose of 95
analyses. 96
This report presents preliminary results of an 97
on going clinical trial. The sample size for the 98
entire trial was calculated to be 210 eligible pa- 99
tients, under the assumptions of ˛= 0.05, power 100
80%, expected differences in Hb level 1 gram% in 101
the placebo and 0.4 gram% in the treatment groups. 102
We present herein the preliminary results of the 103
first 45 patients that were enrolled. For purposes 104
of analysis of this pilot sample, patients receiv- 105
ing Arnica and Bellis in either dilution were ag- 106
gregated (treatment group) and compared with 107
UNCORRECTED PROOF
YCTIM 765 1—4
Effect of homeopathic remedies on mild postpartum bleeding 3
Table 1 Baseline characteristics of the homeopathy and placebo groups.
Characteristic Treatment group (n= 28) Control group (n= 12)
Maternal age (years) 26.4 ±0.6 27.4 ±1.8
Parity (n) 1.82 ±1.59 1.83 ±1.40
First delivery 8 (28.57%) 2 (16.67%)
Episiotomy (yes) 9 (32.14%) 3 (25.00%)
Birth weight (g) 3327 ±461.39 3447.27 ±366.71
Birth weight 4000 g (n) 4 (14.28%) 1 (8.33%)
Oxytocin use (yes) 5 (19.2%) 2 (18.2%)
Hct at baseline (%) 33.79 ±3.73 32.81 ±4.33
Hemoglobin level at baseline (gram%) 12.7 ±0.2 12.7 ±0.4
placebo, in order to achieve the most conservative108
results.
109
Primary endpoint was change in average Hb
110
levels at 48 and 72 h postpartum as compared
111
with baseline. Statistical methods included two-112
sample T-test and non-parametric test for evaluat-113
ing differences between the study groups for quan-114
titative parameters. The paired T-test and non-
115
parametric Sign rank test were applied for test-
116
ing differences between baseline assessment and
117
post-baseline assessment. Due to the small sample118
size, all analyses were performed using both meth-119
ods. Since similar results were evident, T-test and
120
paired T-test calculations are presented. All statis-121
tical analysis was performed using SAS statistical122
package.6
123
Results
124
Forty-five patients enrolled in the study, 31 in the
125
treatment group and 14 in the control group. Five126
patients, three in the treatment group and two in127
the control group, were excluded because of need128
for cesarean section or instrumental delivery; thus129
40 women, 28 in the treatment group and 12 in the130
control group concluded the study. One patient in131
each group was defined as non-compliant.132
Table 1 summarizes the baseline characteristics133
of women in two groups. There was no difference in134
the baseline mean Hb level (Hb = 12.7) in the treat-135
ment and placebo groups (95% CI 12.3; 13.3 and 95%
136
CI 11.8; 13.6, respectively). At 48 h following deliv-
137
ery, the mean Hb levels were 12.5 (95% CI 12.3;
138
13.2) and 11.4 (95% CI 11.7; 13.6) in the treatment
139
and placebo groups, respectively (n.s.).
140
At 72 h the mean Hb levels were 12.4 (95% CI141
11.5; 13.3) and 11.6 (95% CI 10.4; 12.8) in the treat-
142
ment and placebo groups, respectively (p< 0.05)143
(Fig. 1).144
The mean difference in Hb levels at 72 h postpar-145
tum was 0.29 (95% CI 1.09; 0.52) in the treat-
146
Figure 1 Mean Hb levels at baseline, after 48 and 72 h
in the treatment and placebo groups.
ment group and 1.18 (95% CI 1.82; 0.54) in the 147
placebo group (p< 0.05). 148
No side effects were recorded in either group. 149
Discussion and conclusion 150
To the best of our knowledge, this is the first study 151
that examines homeopathic treatment in a double 152
blinded, randomized, placebo controlled trial in a 153
delivery ward setting. While the hemoglobin level 154
following delivery dropped in the control group as 155
expected, the hemoglobin level in the treatment 156
group remained stable. 157
The therapeutic effect was marked and statisti- 158
cally significant at 72 h. No side effects were ob- 159
served in either group. Our results may be limited 160
by the small sample size and possible imbalance in 161
initial parameters. However, in comparing groups 162
we note more nulipara (28.57% versus 16.67%), epi- 163
siotomies (32.14% versus 25.00%) and macrosomia’s 164
(14.28% versus 8.33%) in the treatment group than 165
in the placebo group (Table 1), suggesting that the 166
treatment group was at higher risk for bleeding than 167
the control group, enhancing rather than mitigat- 168
ing our findings. We are aware on no similar stud- 169
ies with which to compare our results. We have 170
no plausible biological explanation for our findings 171
UNCORRECTED PROOF
YCTIM 765 1—4
4 M. Oberbaum et al.
in light of the miniscule concentrations of homeo-172
pathic medicines involved.173
A larger study is currently in progress to cor-
174
roborate these findings, as well as evaluate the
175
analgesic effect of this combination.
176
Conflict of interest statement
177
178
None declared.
179
Acknowledgment180
This study was supported by the Mirski Foundation,181
Shaare Zedek Medical Center, Jerusalem.
References 182
1. ACOG educational bulletin. Postpartum hemorrhage. Num- 183
ber 243, January 1998. American College of Obstetricians 184
and Gynecologists. Int J Gynaecol Obstet 1998;61:79—86. 185
2. Prendiville WJ, Harding JE, Elbourne DR, Stirrat GM. The Bris- 186
tol third stage trial: active versus physiological management 187
of third stage of labour. BMJ 1988;297:1295—300. 188
3. Moskowitz R. Homoeopathic medicines for pregnancy &189
childbirth. Berkley, CA: North Atlantic Books; 1992. 190
4. Smith C. Homoeopathy for induction of labour. Cochrane 191
Database Syst Rev 2003;4:CD003399. 192
5. Jouanny J. The essentials of homeopathic materia medica.193
Bordeaux, France: Laboratoires Boiron; 1980. p. 44—7, 68—9. 194
6. SAS Institute Inc.. SAS/STAT®software: changes and en- 195
hancements through release 6.11. Cary SAS Institute Inc.; 196
1996, 1104 pp. 197
198
... A number of clinical and basic science studies published in the peer-reviewed literature have demonstrated the antiinflammatory and reparatory effects of homeopathy. Given their low cost and lack of known side effects, homeopathic therapies are becoming increasingly integrated into conventional treatment [27][28][29][30][31][32][33][34]. ...
... Bellis perennis is a common European species of daisy belonging to the Asteraceae family, which impacts on female internal organs and deep tissues. It is effective in reducing postpartum bleeding [29,30] and, in an animal model, was successfully utilized to treat circular lesions without scar formation [32]. Arnica montana is commonly used for traumatic cuts and bruises, and is already employed in plastic surgery. ...
... In the present study, we treated patients with two remedies known to have anti-traumatic effects; Arnica montana, commonly used for traumatic cuts and bruises, already employed in plastic surgery to reduce edema and ecchymosis following rhinoplasty, occulofacial surgery, and facelift [36][37][38]; and Bellis perennis, effective in reducing postpartum bleeding [29,30]. Homeopathic treatment reduced mean drainage time by 2.4 days, from 13.5 days in the placebo group to 11.1 days in the study group (P < 0.05). ...
... It is, therefore, common practice to insert surgical drains, which often remain in place for long periods and delay recovery [26,27]. In light of the many advantages of homeopathic treatment, there has been a global trend of integrating this with conventional medicine [29]. In this study, we examined the effect of Arnica montana and Bellis perennis on seroma prevention after mastectomy and breast reconstruction. ...
... A number of clinical and basic science studies published in the peer-reviewed literature have demonstrated the antiinflammatory and reparatory effects of homeopathy. Given their low cost and lack of known side effects, homeopathic therapies are becoming increasingly integrated into conventional treatment [27][28][29][30][31][32][33][34]. ...
... Bellis perennis is a common European species of daisy belonging to the Asteraceae family, which impacts on female internal organs and deep tissues. It is effective in reducing postpartum bleeding [29,30] and, in an animal model, was successfully utilized to treat circular lesions without scar formation [32]. Arnica montana is commonly used for traumatic cuts and bruises, and is already employed in plastic surgery. ...
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Background Seroma is a common surgical complication created by the inflammatory process that follows mastectomy and reconstruction [9, 10, 11, 12, 13, 14, 15]. It is, therefore, common practice to insert surgical drains, which often remain in place for long periods and delay recovery [26, 27]. In light of the many advantages of homeopathic treatment, there has been a global trend of integrating this with conventional medicine [29]. In this study, we examined the effect of Arnica montana and Bellis perennis on seroma prevention after mastectomy and breast reconstruction. Methods This was a prospective double-blinded randomized analysis of 55 consecutive patients (78 breasts), who underwent mastectomy and immediate breast reconstruction between January 2016 and August 2017. Patients were randomly assigned and treated with Arnica montana and Bellis perennis or placebo from surgery and up to the time of drain removal. Results The mean patient age was 47.9 years. Comorbidities included obesity, diabetes mellitus, essential hypertension, fibromyalgia, and hypothyroidism (1, 4, 6, 2, and 4 patients respectively). Age, body mass index, mastectomy type, and lymph node dissection were similar among groups. Forty-two breasts underwent one-stage procedure, and the remaining were two-stage. Arnica montana and Bellis perennis significantly reduced drain removal time (discharge < 30 ml) by 18% (2.4 days, p < 0.05), 11.1 (6.1) days in the study groups compared with 13.5 (6.4) days in the placebo group. Patient opioid intake was lower (p < 0.057) in the study group. Quality of life, postoperative pain, hemoglobin and cortisol levels, and complications were not associated with any treatment. Conclusions Arnica montana and Bellis perennis have been shown to reduce seroma formation and opioid intake following mastectomy and reconstruction. As this treatment lacks side effects and is inexpensive, it should serve as a valuable treatment adjunct in patients undergoing mastectomy and reconstruction. Level of evidence: Level I, therapeutic study.
... ▪ Another study depicted that Arnica and Bellis per helped in reducing postpartum haemorrhage. After major blood loss after delivery as compared to placebo group, Hb levels remained same while the placebo group showed marked decrease in Hb levels [28] . ...
... 13 Homeopathy is the second largest medical system in the world today, recognized by the World Health Organization. 14 The effects of this method on pain relief, [15][16][17] cancer recovery, 18 treatment of middle ear infection, 19 chronic periodontitis, 20 and treatment of AUB [21][22][23] have been reviewed. However, researchersare still looking for more evidence in the field about the effectiveness of this method in the treatment of AUB. ...
... 15 Arnica in combination with Ruta graveolens, Aconitum napellus, Bellis perennis, Hamamelis virginiana, Hypericum perforatum, Calendula officinalis, Ledum palustre, Bryonia alba is effective for treating inflammation 16 . Various analytical methods such as gas chromatography with mass selective detection (GC-MSD), spectrophotometric, reverse-phase liquid chromatography (RPLC) and proton nuclear magnetic resonance spectroscopy (HNMR) have been used for analysing the quantity of lactones presents in the plant 17 . Arnica montana has significant anti-inflammatory potential. ...
... The family consists of over 1600 genera and 23,000 species which have been recorded in grassland, wooded grassland, montane vegetation, and tropical forests [1]. Research by Jeschke et al. [4] showed that the family Asteraceae has at least 420 known medicinal species and these include Arnica montana L. [5][6][7][8][9][10][11], Artemisia annua L. [12][13][14][15][16][17][18][19], Calendula officinalis L. [20][21][22][23][24][25], Chamaemelum nobile (L.) All. [26][27][28][29][30], Inula helenium L. [31][32][33][34][35][36], and Matricaria recutita L. [37][38][39][40][41][42][43]. ...
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To compare the effects on fetal and maternal morbidity of routine active management of third stage of labour and expectant (physiological) management, in particular to determine whether active management reduced incidence of postpartum haemorrhage. Randomised trial of active versus physiological management. Women entered trial on admission to labour ward with allocation revealed just before vaginal delivery. Five months into trial high rate of postpartum haemorrhage in physiological group (16.5% v 3.8%) prompted modification of protocol to exclude more women and allow those allocated to physiological group who needed some active management to be switched to fully active management. Sample size of 3900 was planned, but even after protocol modification a planned interim analysis after first 1500 deliveries showed continuing high postpartum haemorrhage rate in physiological group and study was stopped. Maternity hospital. Of 4709 women delivered from 1 January 1986 to 31 January 1987, 1695 were admitted to trial and allocated randomly to physiological (849) or active (846) management. Reasons for exclusion were: refusal, antepartum haemorrhage, cardiac disease, breech presentation, multiple pregnancy, intrauterine death, and, after May 1986, ritodrine given two hours before delivery, anticoagulant treatment, and any condition needing a particular management of third stage. All but six women allocated to active management actually received it, having prophylactic oxytocic, cord clamping before placental delivery, and cord traction; whereas just under half those allocated to physiological management achieved it. A fifth of physiological group received prophylactic oxytocic, two fifths underwent cord traction and just over half clamping of the cord before placental delivery. ENDPOINT: Reduction in incidence of postpartum haemorrhage from 7.5% under physiological management to 5.0% under active management. Incidence of postpartum haemorrhage was 5.9% in active management group and 17.9% in physiological group (odds ratio 3.13; 95% confidence interval 2.3 to 4.2), a contrast reflected in other indices of blood loss. In physiological group third stage was longer (median 15 min v 5 min) and more women needed therapeutic oxytocics (29.7% v 6.4%). Apgar scores at one and five minutes and incidence of neonatal respiratory problems were not significantly different between groups. Babies in physiological group weighed mean of 85 g more than those in active group. When women allocated to and receiving active management (840) were compared with those who actually received physiological management (403) active management still produced lower rate of postpartum haemorrhage (odds ratio 2.4;95% CI1.6 to 3.7). Policy of active management practised in this trial reduces incidence of postpartum haemorrhage, shortens third stage, and results in reduced neonatal packed cell volume.
Article
This is one of series of reviews of cervical ripening and labour induction using standardised methodology. Homoeopathy involves the use, in dilution, of substances which cause symptoms in their undiluted form. A type of herb, 'caulophyllum' is one type of homoeopathic therapy that has been used to induce labour. To determine the effects of homoeopathy for third trimester cervical ripening or induction of labour. The Cochrane Pregnancy and Childbirth Group Trials Register (13 May 2003), and bibliographies of relevant papers. Randomised controlled trials comparing homeopathy used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods. A generic strategy was developed to deal with the large volume and complexity of trial data relating to labour induction. This involved a two-stage method of data extraction. The initial data extraction was done centrally. Two trials involving 133 women were included in the review. The trials were placebo controlled and double blind, but the quality was not high. Insufficient information was available on the method of randomisation and the study lacked clinically meaningful outcomes. This trials demonstrated no differences in any primary or secondary outcome between the treatment and control group. There is insufficient evidence to recommend the use of homoeopathy as a method of induction. It is likely that the demand for complementary medicine will continue and women will continue to consult a homoeopath during their pregnancy. Although caulophyllum is a commonly used homoeopathic therapy to induce labour, the treatment strategy used in the one trial in which it was evaluated may not reflect routine homoeopathy practice. Rigorous evaluations of individualised homeopathic therapies for induction of labour are needed.
Homoeopathic medicines for pregnancy & 189 childbirth
  • R Moskowitz
Moskowitz R. Homoeopathic medicines for pregnancy & 189 childbirth. Berkley, CA: North Atlantic Books; 1992. 190
changes and enhance-ments through release 6.11. Cary SAS Institute Inc.; 1996
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SAS Institute Inc. SAS/STAT ® software: changes and enhance-ments through release 6.11. Cary SAS Institute Inc.; 1996. 1104 p.
The essentials of homeopathic materia medica
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Jouanny J. The essentials of homeopathic materia medica. 193
American College of Obstetricians and Gynecologists
ACOG educational bulletin. Postpartum hemorrhage. Num-183 ber 243, January 1998. American College of Obstetricians 184 and Gynecologists. Int J Gynaecol Obstet 1998;61:79-86. 185
SAS/STAT ® software: changes and en-195 hancements through release 6.11. Cary SAS Institute Inc
  • Sas Institute Inc
SAS Institute Inc.. SAS/STAT ® software: changes and en-195 hancements through release 6.11. Cary SAS Institute Inc.; 196 1996, 1104 pp.