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ORIGINAL ARTICLE
Year : 2017  |  Volume : 7  |  Issue : 2  |  Page : 75-80

A study to determine minimum effective dose of oxytocin infusion during caesarean delivery in parturients at high risk of uterine atony


1 Department of Anaesthesiology and Critical Care, Pandit Bhagwat Dayal Sharma, Post Graduate Institute of Medical Sciences (PGIMS), Rohtak, Haryana, India
2 Department of Anaesthesia, CMC, Ludhiana, Punjab, India
3 Department of Anaesthesia, King George Medical College, Lucknow, Uttar Pradesh, India

Date of Web Publication7-Nov-2017

Correspondence Address:
Renu Bala
Department of Anaesthesiology and Critical Care, Pandit Bhagwat Dayal Sharma, Post Graduate Institute of Medical Sciences (PGIMS), Rohtak, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joacc.JOACC_42_16

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  Abstract 

Background: Oxytocin, a commonly used drug to prevent uterine atony after caesarean section, should be administered as dilute rapid infusion rather than as a bolus. This study was conducted to calculate ED90 of oxytocin infusion during caesarean delivery in parturients at high risk of postpartum haemorrhage (PPH). Materials and Methods: One hundred and twenty parturients having one or more risk factors for PPH received a blinded infusion of oxytocin following emergency caesarean delivery. The initial dose of oxytocin infusion was started as 0.4 IU min−1. The dose of oxytocin infusion for the next parturient was based on the response of preceding patient in increments or decrements of 0.1 IU min−1 as per a biased-coin design up-down sequential method (UDM). Measurements of non-invasive blood pressure and heart rate were taken at 2 min intervals from the time of oxytocin infusion. Intraoperative blood loss was noted. Side effects such as tachycardia, hypotension, nausea, vomiting, chest pain, headache and flushing were also recorded. Results: The ED90 of oxytocin infusion was found to be 0.405 IU min−1 (95% confidence interval 0.3864–0.4125) as calculated by Firth's penalised likelihood estimation using a biased-coin design UDM. Hypotension was observed for brief period of time in 25.6% of parturients and brief period of tachycardia was observed in 9.4% of parturients. No headache, flushing, chest pain and vomiting were observed in any parturients in our study. The estimated blood loss was within the normal limits. Conclusion: Our study showed that ED90 of oxytocin infusion required to achieve adequate uterine tone (UT) after an emergency caesarean delivery in parturients at high risk of uterine atony was 0.405 IU min−1. The higher doses of oxytocin did not result in further improvement of UT. Therefore, early use of alternative uterotonic therapy is preferable to achieve adequate UT.

Keywords: Caesarean section, oxytocin, postpartum haemorrhage, uterine atony


How to cite this article:
Shashikiran, Kaur H, Bala R, Gupta N. A study to determine minimum effective dose of oxytocin infusion during caesarean delivery in parturients at high risk of uterine atony. J Obstet Anaesth Crit Care 2017;7:75-80

How to cite this URL:
Shashikiran, Kaur H, Bala R, Gupta N. A study to determine minimum effective dose of oxytocin infusion during caesarean delivery in parturients at high risk of uterine atony. J Obstet Anaesth Crit Care [serial online] 2017 [cited 2017 Nov 22];7:75-80. Available from: http://www.joacc.com/text.asp?2017/7/2/75/217775


  Introduction Top


Prophylactic oxytocin is commonly administered after delivery of the infant or placenta and has been shown to reduce the incidence of postpartum haemorrhage (PPH) by up to 40%.[1] A slow intravenous (i.v.) bolus dose of 5 IU of oxytocin after delivery of the infant is recommended by the Royal College of Obstetricians and Gynaecologists (UK) during caesarean section.[2] This dose is also widely used across most of Europe and Australia.[3],[4],[5] In UK, the use of an oxytocin bolus was a standard treatment, although the dose varied between 5 and 10 IU.[6] In settings where an oxytocin bolus is used routinely, an additional infusion of oxytocin may be required if haemorrhage occurs. Therefore, some obstetricians prefer to use an additional infusion of oxytocin for high risk cases.[6],[7] In the United States, it is recommended to use an oxytocin infusion instead of a bolus dose to prevent adverse effects of bolus oxytocin.[8] Because of short half-life of oxytocin, its infusion is advantageous in maintaining uterine contractility throughout the surgical procedure and immediate postpartum period.[9]

There is paucity of literature regarding minimum effective dose of oxytocin infusion to prevent uterine atony during caesarean delivery in parturients at high risk of PPH; therefore, this study was planned to determine the minimum effective dose of oxytocin infusion during caesarean delivery in parturients at high risk of uterine atony.


  Materials and Methods Top


After the approval of Ethics Committee of the hospital, the present prospective randomised study was conducted in our Department of Anaesthesiology and Critical Care. One hundred twenty parturients aged between 18 and 35 years, belonging to American Society of Anaesthesiologists (ASA) physical status I and II, having one or more risk factors for PPH due to uterine atony such as pre-eclampsia, placenta praevia, multiple gestation, history of uterine atony/PPH in previous pregnancy, high parity (>5 previous deliveries) and uterine fibroids, undergoing caesarean delivery under spinal anaesthesia were enrolled in the study. Patients with cardiac disease, haemodynamic instability before commencement of surgery, bleeding disorders and known drug allergy to oxytocin were excluded from the study.

All the parturients were examined before surgery and subjected to complete physical as well as systemic examination. Routine investigations such as haemoglobin, bleeding time, clotting time and urine examination were noted in all the patients. The purpose and protocol of study was explained to parturients and informed written consent was obtained. Upon arrival in operating room, usual monitoring including non-invasive blood pressure (NIBP), ECG and pulse oximetry were established. Intravenous line was secured and sample for baseline haematocrit was drawn. Parturients were preloaded with 10 ml kg −1 of Ringer's lactate infusion 15 min before spinal anaesthesia. Baseline maternal heart rate (HR) and invasive blood pressure were recorded as an average of three readings. All parturients received spinal anaesthesia in sitting position in L3-4 space with 25 G Quincke spinal needle with 1.5 ml of 0.5% hyperbaric bupivacaine along with 25 μg of fentanyl. Parturient was laid supine with wedge under the right flank to achieve leftward tilt of 15°. Surgery was commenced after a T4 sensory level to cold perception had been achieved.

Following delivery and clamping of the umbilical cord, an infusion of oxytocin was started. The initial dose of oxytocin infusion was started as 0.4 IU min −1 (24 IU of oxytocin in 250 ml normal saline over 1 h). The obstetrician was asked to palpate the uterus, which was not exteriorised and the uterine tone (UT) was assessed according to a five-point scale (1 = atonic, 2 = partial but inadequate contraction, 3 = adequate contraction, 4 = well contracted and 5 = very well contracted). If the tone was assessed as inadequate (i.e. UT scale 2 or 1) at 2, 3, 6 and 9 min, then a 'rescue' bolus of 0.5 units oxytocin was administered. A maximum of two 'rescue' doses of oxytocin were permitted during the study period. If UT was assessed as inadequate after two rescue doses of oxytocin, then 3 IU bolus of oxytocin was administered. If UT would still be inadequate, then alternative uterotonic therapy (AUT) was administered [intramuscular (IM) carboprost tromethamine 0.25 mg or rectal misoprostol 800–1000 mg). All parturients continued to receive a maintenance infusion of i.v. oxytocin at 0.04 IU min −1 (2.4 IU in 500 ml normal saline) until discharge from post-anaesthesia care unit (PACU). The dose of oxytocin infusion for the next parturient was based on the response of preceding patient in increments or decrements of 0.1 IU min −1 as per a biased-coin design up-down sequential method (UDM).

After spinal anaesthesia, monitoring of vitals was done continuously and recorded every 2 min till the administration of oxytocin. Hypotension was defined as a decrease in mean arterial blood pressure ≥10% of the baseline value, and each episode of hypotension was treated with an i.v. bolus of 3 mg of ephedrine. Tachycardia was defined as an increase in maternal HR ≥20% of the baseline value.

The study also included the assessment of UT at 2, 3, 6 and 9 min after starting the oxytocin infusion and the number of rescue doses of oxytocin. Intraoperative blood loss was measured by calculating the weight of blood on surgical swabs. Haematocrit values were measured before surgery and at 30 min after completion of surgery. Side effects associated with oxytocin such as tachycardia, hypotension, nausea, vomiting, chest pain, headache and flushing were noted after administration of oxytocin until discharge from PACU.

The primary outcome measure was determination of minimum effective dose of oxytocin infusion. The secondary outcome measure was to assess the side effects associated. The sample size was determined by interim analysis of data of 20 patients and it was found that 100 patients will generate power of more than 85% and alpha error <0.05. All the data was compiled and ED90 of oxytocin infusion, i.e., the dose at which 90% of women had satisfactory UT, was determined with Firth's penalised likelihood estimation method. Categorical variables were analysed using Chi-square test, and quantitative variables were analysed using analysis of variance test.


  Results Top


The demographic profile of the patients is given in [Table 1]. Out of 120 patients, 98 (81.7%) had pre-eclampsia, while 22 (18.3%) had placenta praevia. The duration of surgery was 57.73 ± 8.37 min. The ED90 of oxytocin infusion required to achieve adequate UT after an emergency caesarean delivery in parturients at high risk of uterine atony was found to be 0.405 IU min −1 [95% confidence interval (CI) 0.3864–0.4125] [Figure 1].
Figure 1: Fitted probabilities of successful responses at the specific oxytocin infusion doses tested using Firth's bias reduced penalized maximum likelihood logistic regression 95% confidence intervals

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Table 1: Demographic profile of patients

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[Table 2] shows UT at various time intervals after starting oxytocin. Adequate UT (i.e. UT score ≥3) at 2, 3, 6 and 9 min was observed in 4.2% (5 out of 120), 95% (114 out of 120), 98.3% (118 out of 120) and 100% (120) of parturients, respectively [Table 3]. The parturients who required first and second rescue boluses of oxytocin were 50% (60 out of 120) and 49.2% (59 out of 120) parturients, respectively. Three units of oxytocin were required in 26.7% (32 out of 120) parturients. AUT as IM carboprost was required in 10% (12 out of 120) of parturients, whereas no parturient required rectal misoprost [Table 4].
Table 2: UT score after starting oxytocin infusion at various time intervals

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Table 3: Number of parturients having adequate UT after starting oxytocin infusion at various time intervals

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Table 4: Number of parturients who required rescue boluses of oxytocin (RBO), 3 IU of oxytocin and AUT as IM carboprost and rectal misoprost

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The variations in HR and blood pressure are shown in [Figure 2], [Figure 3], [Figure 4], [Figure 5]. Hypotension was observed for a brief period of time in 25.6% of parturients that responded to small incremental doses of ephedrine. Brief period of tachycardia was observed in 9.4% of parturients. No side effects such as nausea, flushing, chest pain and vomiting were observed in any parturient in our study. The estimated blood loss was 865.58 ± 141.05 ml. There was significant decrease in post-operative haematocrit as compared to pre-operative haematocrit, i.e. 28.60 ± 2.22% (mean ± SD) and 25.04 ± 2.47%, respectively (P< 0.001).
Figure 2: Heart rate changes at various time intervals after administration of spinal anaesthesia

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Figure 3: Heart rate changes after delivery of baby and administration of oxytocin at various time intervals(at time of delivery of baby –ATDB)

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Figure 4: Variations in mean blood pressure after administration of spinal anaesthesia

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Figure 5: Variations in mean blood pressure at various time intervals after delivery of baby and administration of oxytocin ( at the time of birth of baby –ATDB)

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  Discussion Top


Our study shows that the ED90 of oxytocin infusion required to achieve adequate UT after an emergency caesarean delivery in parturients at high risk of uterine atony was 0.405 IU min −1 (95% CI 0.3864–0.4125). The UDM is a method used most commonly to determine the ED50 of intrathecal local anaesthetics and opioids; i.v. and inhalational anaesthetics.[10] The UDM is used to choose the drug dose levels, to select the sample size of subjects from a target population and to specify the definition of positive response. Earlier UDM studies sought the ED50 of various drugs, e.g., the dose of inhaled anaesthetics that by definition is effective in 50% of subjects. Anaesthesiologists were left to extrapolate the results to doses that were more clinically useful, i.e., ED90 or ED95 that would be effective in 90–95% of patients. The biased-coin design allows the researchers to set the quantile effect dose of interest, i.e., 90%, 95%, or even 50%. Although calculation of ED95 may lead to results that are slightly more clinically relevant, but it has been suggested that calculation of ED95 may sacrifice the precision of estimate.[11]

Zarzur et al. conducted a study in 20 patients undergoing elective caesarean delivery and suggested that 0.024 IU min −1 of oxytocin provides a satisfactory outcome with no incidence of hypotension, nausea or vomiting. The results are different from our study as we calculated ED90 of oxytocin, which is more precise and the number of patients was very less in his study which limited the power of his conclusions.[12]

Our results are different from a study conducted by Balki et al., who estimated the minimum effective dose of oxytocin required for adequate uterine contraction after caesarean delivery for labour arrest in 30 parturients. Oxytocin was given as a slow i.v. bolus (0.5 IU ml −1 at the rate of 1 ml over 5 s) according to biased-coin up-down sequential allocation scheme and they calculated ED90 of oxytocin bolus as 2.99 IU, which was nine times higher than in parturients after elective caesarean delivery in non-labouring women at term. This suggested that prolonged labour and use of oxytocin to augment labour may desensitise the uterus, making it less responsive to oxytocin during caesarean delivery.[13] However, in our study, the oxytocin was given as 0.4 IU min −1 according to biased-coin up-down sequential allocation and ED90 of oxytocin infusion was 0.405 IU min −1. It is a usual practice to increase the dose of oxytocin, assuming higher doses will result in more effective uterine contraction. It is advocated that higher doses of oxytocin are unlikely to improve uterine contraction further and thus, prevent PPH, because the population of oxytocin receptors will not only be reduced but also be sensitised. Sarna et al. found no advantage in increasing oxytocin dose above 5 IU during elective caesarean delivery.[14] Munn et al. compared two high doses of oxytocin infusions (at the rate of 2667 and 333 mU min −1) after caesarean delivery in labouring women.[15] Additional uterotonic agents were required in 19 and 39% of their cases, respectively. Further, if a larger dose of oxytocin is rapidly infused, its side effects may outweigh its uterotonic action. Hence, it is suggested that, especially in labouring patients, consideration should be given to the alternate pathway uterotonic medications, such as ergot derivatives, carboprost or misoprostol.[13] A significant reduction in the oxytocin binding sites in induced labour group was shown by some workers as continuous exposure of myometrial cells to oxytocin leads to significant loss in their capacity to respond to oxytocin due to oxytocin receptor desensitization.[16] Attenuation of oxytocin receptor signalling was indicated in labouring women at the time of caesarean delivery by Robinson et al.[17] In our study, AUT as IM carboprost was required in 10% of the parturients, whereas no parturient required rectal misoprost.

The results of our study are different from a study conducted by George et al. in which they found ED90 of oxytocin for elective caesarean delivery to prevent uterine atony in 40 term parturients.[11] In our study, we included 120 parturients in our study and calculated ED90 of oxytocin for emergency caesarean delivery to prevent uterine atony in high-risk parturients of uterine atony unlike George et al. who included only the low-risk parturients and also, the number of parturients was less. The ED90 in their study was 0.29 IU min −1, whereas in our study it was higher, i.e. 0.405 IU min −1. This may be attributed to our patient population who were at high risk of uterine atony and also, due to emergency caesarean delivery in which the uterine responsiveness to oxytocin may be greatly decreased, so higher doses of oxytocin are often required and the early use of alternative uterotonics may be preferable. Also, desensitisation of uterine oxytocin receptors has been described after continuous oxytocin infusions. Oxytocin induced desensitisation is concentration-dependant and is characterised by a reduction in the number of oxytocin binding sites on intact myometrial cells.[13]

In our study, we noted a brief period of tachycardia in 9.4% of parturients, and brief period of hypotension was noted in 25.6% of parturients which was treated by slow incremental doses of ephedrine. The results are different from a study where ED90 of oxytocin was 0.29 IU min −1 and two subjects out of 40 developed hypotension requiring vasopressor administration.[11] This difference could be attributed to inclusion of parturients in our study who were having one or more risk factors of uterine atony/PPH. Our results are similar to a study conducted by Carvalho et al. where ED90 of oxytocin was 0.35 IU, in which hypotension was observed in 30% of the parturients.[18] None of the studies calculating ED90 of oxytocin have commented upon HR changes after oxytocin administration.

In our study, no headache, flushing, chest pain, nausea and vomiting were noted, whereas in a study where ED90 of oxytocin was 0.35 IU, nausea was noted in 37.5%, vomiting in 12.5% and flushing in 62.5% of the patients.[18] This difference could be explained by the fact that the authors used oxytocin as a bolus, whereas we used oxytocin as a dilute infusion.

The average blood loss associated with a caesarean delivery is approximately 1000 ml.[19] In our study, the estimated blood loss was 865.5833 ± 141.05125 ml, which is well within the normal limits, indicating that the low dose of oxytocin used in our study was not associated with increased blood loss. In our study, there was significant decrease in post-operative haematocrit as compared to pre-operative haematocrit; however, haematocrit is not a reliable marker of blood loss as the calculation of haematocrit can be inaccurate based on the hydration status of the parturient, especially with the i.v. loading conducted with regional anaesthesia or with pregnancy-induced hypertension. Also, the maternal physiologic blood volume changes may alter the haematocrit values.[20]

Our study had few limitations. First, our results may have been influenced by subjective estimation of UT by the obstetrician, which is an invalidated measure. However, in our study, we did limit this factor to some extent by assessment of UT by the obstetrician having a minimum of 5 years of experience.

Another limitation was that the method of estimating blood loss was not accurate in our study. The methods to accurately determine blood loss that are not labour intensive or expensive are desperately needed so that various interventions to decrease blood loss at birth could be more easily trialled and effectively studied.[20]

Another pitfall in our study was that the patient population broadly consisted of two subgroups of parturients at high risk of uterine atony, i.e. pre-eclampsia and placenta praevia. As the rate of caesarean delivery is ever-increasing, further research should aim at estimating ED90 of oxytocin in each subgroup of parturients at high risk of uterine atony (pre-eclampsia, placenta praevia, multiple gestation, history of uterine atony/PPH in previous pregnancy, high parity, and uterine fibroids) so that protocols can be made regarding dosing of oxytocin for achieving adequate UT for each subgroup of parturients at high risk of PPH.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Devikarani D, Harsoor SS. Are we using right dose of oxytocin. Ind J Anaesth 2010;54:371-3.  Back to cited text no. 1
    
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National Collaborating Centre for Women's and Children's Health. Caesarean section. Clinical guideline. RCOG Press, 2004.  Back to cited text no. 2
    
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Cotter A, Ness A, Tolosa J. Prophylactic oxytocin for the third stage of labour. Cochrane Database Syst Rev 2003;10:CD001808.  Back to cited text no. 3
    
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Begley CM, Gyte GM, Murphy DJ, Devane D, McDonald SJ, McGuire W. Active versus expectant management for women in the third stage of labour. Cochrane Database Syst Rev 2010;7:CD007412.  Back to cited text no. 4
    
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Mockler JC, Murphy DJ, Wallace EM. An Australian and New Zealand survey of practice of the use of oxytocin at elective caesarean section. Aust N Z J Obstet Gynaecol 2010;50:30-5.  Back to cited text no. 5
    
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Wedisinghe L, Macleod M, Murphy DJ. Use of oxytocin to prevent haemorrhage at caesarean section: A survey of practice in the United Kingdom. Eur J Obstet Gynecol Reprod Biol 2008;137:27-30.  Back to cited text no. 6
    
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Sheehan SR, Wedisinghe L, Macleod M, Murphy DJ. Implementation of guidelines on oxytocin use at caesarean section: A survey of practice in Great Britain and Ireland. Eur J Obstet Gynecol Reprod Biol 2010;148:121-4.  Back to cited text no. 7
    
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ACOG. Practice bulletin: Clinical management guidelines for obstetrician-gynaecologists. Number 76. Postpartum hemorrhage. Obstet Gynecol 2006;108:1039-47.  Back to cited text no. 8
    
9.
Sheehan SR, Montgomery AA, Carey M, McAuliffe FM, Eogan M, Gleeson R, et al. Oxytocin bolus versus oxytocin bolus and infusion for control of blood loss at elective caesarean section: Double blind, placebo controlled, randomised trial. BMJ 2001;343:d4661.  Back to cited text no. 9
    
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Pace NL, Stylianou MP. Advances in and limitations of up-and-down methodology: A précis of clinical use, study design, and dose estimation in anesthesia research. Anaesthesiology 2007;107:144-52.  Back to cited text no. 10
    
11.
George RB, McKeen D, Chaplin AC, McLeod L. Up-down determination of the ED90 of oxytocin infusions for the prevention of postpartum uterine atony in parturients undergoing cesarean delivery. Can J Anesth 2010;57:578-82.  Back to cited text no. 11
    
12.
Zarzur E. Intravenous oxytocin in patients undergoing elective caesarean section. Anesth Analg 1998;86:1334.  Back to cited text no. 12
    
13.
Balki M, Ronayne M, Davies S, Fallah S, Kingdom J, Windrin R, et al. Minimum oxytocin dose requirement after cesarean delivery for labor arrest. Obstet Gynecol 2006;107:45-50.  Back to cited text no. 13
    
14.
Sarna MC, Soni AK, Gomez M, Oriol NE. Intravenous oxytocin in patients undergoing elective cesarean section. Anesth Analg 1997;84:753-6.  Back to cited text no. 14
    
15.
Munn MB, Owen J, Vincent R, Wakefield M, Chestnut DH, Hauth JC. Comparison of two oxytocin regimen to prevent uterine atony at cesarean delivery: A randomized controlled trial. Obstet Gynecol 2001;98:386-90.  Back to cited text no. 15
    
16.
Phaneuf S, Rodriguez Linares B, Tamby Raja RL, MacKenzie IZ, Lopez Bernal A. Loss of myometrial oxytocin receptors during oxytocin-induced and oxytocin-augmented labour. J Reprod Fertil 2000;120:91-7.  Back to cited text no. 16
    
17.
Robinson C, Schumann R, Zhang P, Young RC. Oxytocin induced desensitization of the oxytocin receptors. Am J Obstet Gynecol 2003;188:497-502.  Back to cited text no. 17
    
18.
Carvalho JCA, Balki M, Kingdom J, Windrim R. Oxytocin requirements at elective cesarean delivery: A dose finding study. Obstet Gynecol 2004;104:1005-10  Back to cited text no. 18
    
19.
Joy S. Cesarean delivery. Medscape [online]; 2011: Available from URL http://emedicine.medscape.com/article/263424-overview#a15. [last accessed on 2016 Mar 15].  Back to cited text no. 19
    
20.
Schorn MN. Measurement of blood loss: Review of the literature. J Midwifery Women's Health 2010;55:20-7.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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