European Journal of Obstetrics & Gynecology and Reproductive Biology, pages 103 - 107
To assess systolic (SBP) and diastolic (DBP) blood pressure values during labor and to analyze their predictive value for early postpartum preeclampsia.
This 6-month prospective observational study included 1435 women in labor who had no hypertensive disorders either before or during pregnancy. SBP and DBP were measured every 15 min during labor and signs of preeclampsia were checked for in the early postpartum period.
Mean maximum SBP and DBP were significantly higher during the first stage of labor without any treatment compared to the last prenatal visit: 135 vs. 119 mmHg and 81 vs. 74 mmHg, respectively (p < 0001). Epidural analgesia had no effect on maximum SBP or DBP during labor whereas oxytocin administration moderately increased SBP (137.8 vs. 135.2 mmHg;p < 0.05).
Early postpartum preeclampsia was identified in 0.9% of the women. A maximum SBP equal or higher than 150 mmHg or DBP equal or higher than 91 mmHg during labor were predictive of early postpartum preeclampsia with a sensitivity of 77% and a specificity of 71%.
SBP and DBP values during labor are higher than those observed in the antepartum period. An SBP equal or higher than 150 mmHg or DBP equal or higher than 91 mmHg are associated with an increased risk of early postpartum preeclampsia.
Keywords: Postpartum preeclampsia, Blood pressure, Labor, Prediction.
Hypertensive disorders of pregnancy represent a major cause of maternal and perinatal morbidity and mortality. Gestational hypertension complicates 6–7% of pregnancies and preeclampsia 2–7% and . Hypertension in pregnancy and in the postpartum period is currently diagnosed by a systolic blood pressure (SBP) greater than or equal to 140 mmHg and/or diastolic blood pressure (DBP) greater than or equal to 90 mmHg and . However, there are only a few relatively old studies that report normal values of blood pressure during the first stage of labor, , and .
Labor is a unique physiological situation involving major hemodynamic changes which could considerably impact blood pressure. In addition, blood pressure during labor could also be affected by the administration of certain agents such as epidural analgesia and oxytocin. Consequently, there is a need to reevaluate the usual thresholds of abnormal blood pressure values during first stage of labor. One way to do this could be to analyze blood pressure values during pregnancy and labor and define blood pressure thresholds above which postpartum preeclampsia may occur.
The primary aim of our study was therefore to address the following question: what are the normal maximal SBP and DBP values of women during the first stage of labor and what are the influences of oxytocin and epidural analgesia on such values? The secondary aim was to investigate if blood pressure values during labor could be associated with the onset of de novo early postpartum preeclampsia in women without any history of hypertensive disease before admission to the birthing suite.
Materials and methods
During 6 months (November 2010–April 2011) we conducted a prospective longitudinal study in a tertiary care hospital (Centre Hospitalier Intercommunal de Créteil, France). Inclusion criteria were women in labor with a singleton pregnancy after 22 weeks gestation (n = 1695). Exclusion criteria were women undergoing a pre-labor cesarean delivery (n = 181) and women with a hypertensive disorder during or before pregnancy (n = 79). Finally, 1435 women were prospectively analyzed ( Fig. 1 ).
Blood pressure was measured using an automated oscillometric blood pressure measurement device, DINAMAP ProCare 300, at the prenatal visits, during labor and in the postpartum period. This device is intended for clinical and hospital use and measures blood pressure within a range of 0–290 mmHg. It uses the same algorithm as a mercury sphygmomanometry reference standard such as the Dinamap ProCare 400 which has an A/A accuracy grade for pregnancy and an A/B accuracy grade for preeclampsia  . Blood pressure was measured in women in a semi-recumbent position in the left or right arm with the cuff at the level of the heart. Blood pressure was measured every 15 min, during the whole of labor and up to 2 h postpartum in the labor ward. All blood pressure values during labor were printed out.
Epidural analgesia, oxytocin use and expulsive effort times were recorded. The epidural analgesic regimen consisted of ropivacaïne 0.12% with sufentanil 0.3 μg/mL in patient-controlled epidural analgesia (PCEA) mode with a perfusion of 5 mL/h and boluses of 5 mL every 10 min if needed. The oxytocin augmentation regimen consisted of 2 mUI/min with an increasing dose of 2 mUI every 20 min.
We identified the maximum SBP and DBP that occurred during first stage of labor for each woman. Aberrant values (i.e. a never repeated isolated increased blood pressure value greater than 20% when compared to the immediate previous and following value) were excluded. Data concerning the onset of early postpartum preeclampsia were collected for every woman on the day of hospital discharge. Supplementary data were collected a posteriori: SBP and DBP values during the last month of pregnancy at last prenatal visit. Preeclampsia was diagnosed according to the criteria of the Report of the National High Blood Pressure Education Program Working Group  : the association of hypertension (SBP greater than 140 mmHg and/or DBP greater than 90 mmHg) and proteinuria. Proteinuria was defined by a 24-h urine protein greater than or equal to 0.3 g.
Basic descriptive statistical analyses (mean, median, standard deviation, percentile distribution) were calculated with PRISM 5.0 (GraphPad Software Inc., La Jolla, USA). Categorical variables were compared with Fisher's exact test or Chi-square test as appropriate and continuous variables with unpaired two-tailed studentttest. Blood pressure thresholds were determined by ROC analysis. Sensitivity, specificity for blood pressure thresholds were calculated. Ap<05 was considered significant.
The local Ethics Committee (Groupe de Reflexion Ethique de Creteil, France) was approached for approval of the study but waived the requirement for formal approval due to the observational nature of this study.
|Maternal age (years, mean ± SD)||30.5 ± 5.5|
|Caucasian (n (%))||1001 (70)|
|African-French Antilles (n, %)||361 (25)|
|Others (n, %)||73 (5)|
|History of preeclampsia (n, % of multiparous)||8 (1)|
|History of FGR (n, % of multiparous)||13 (1.6)|
|Nulliparity (n, %)||621 (43)|
|BMI (kg/m2, mean ± SD)||24 ± 4.5|
|Delivery gestational age (weeks, mean ± SD)||38.6 ± 2.8|
|Birth weight (g, mean ± SD)||3205 ± 653|
FGR: fetal growth restriction (<3rd percentile), BMI: body mass index.
SBP and DBP values were significantly higher during labor when compared to those at the last prenatal visit: for SBP 135 mmHg ± 17 vs. 119 mmHg ± 12,p < 0.0001 ( Table 2 ) and for DBP 81 mmHg ± 13 vs. 74 mmHg ± 9,p < 0.001 ( Table 3 ). Epidural analgesia did not influence maximum blood pressure during labor (Table 2 and Table 3). SBP, but not DBP, increased significantly in women under epidural analgesia receiving oxytocin compared to those under epidural analgesia without oxytocin (138 mmHg ± 16 vs. 135 mmHg ± 16,p < 0.01) (Table 2 and Table 3).
|N||Mean ± SD||5th centile||10th centile||50th centile||90th centile||95th centile|
|Last prenatal visit a||1311||119 ± 12||100||103||120||134||140|
|During labor (with epidural)||1269||137 ± 17||113||119||135||158||164|
|During labor (with epidural, no oxytocin)b and c||505||135 ± 16||110||118||132||155||162|
|During labor (with epidural and oxytocin) c||764||138 ± 16||115||120||138||160||165|
|During labor (no epidural, with oxytocin)||10||152 ± 16|
|During labor (no epidural and no oxytocin)a and b||156||135 ± 17||110||112||135.5||152||162.5|
a Effect of labor per se, p < 0.0001.
b Effect of epidural analgesia, ns.
c Effect of oxytocin administration, p < 0.01.
|N||Mean ± SD||5th centile||10th centile||50th centile||90th centile||95th centile|
|Last prenatal visit a||1311||74 ± 9||60||61||74||85||89|
|During labor (with epidural)||1269||82 ± 12||65||70||80||100||101|
|During labor (with epidural, no oxytocin)b and c||505||82 ± 12||61||69||80||99||101|
|During labor (with epidural and oxytocin) c||764||83 ± 12||65||70||80||100||102|
|During labor (no epidural, with oxytocin)||10||92 ± 12|
|During labor (no epidural and no oxytocin)a and b||156||81 ± 13||60||67||80||99.5||101.25|
a Effect of labor per se, p < 0.0001.
b Effect of epidural analgesia, ns.
c Effect of oxytocin administration, ns.
Early de novo postpartum preeclampsia occurred in 0.9% of the women (13/1435). All cases were mild and no women were administered magnesium sulfate to prevent eclampsia. None of the following factors were associated with a significantly increased risk of preeclampsia: body mass index (BMI), ethnicity, maternal age, nulliparity, gestational age at delivery, gestational diabetes, fetal growth restriction ( Table 4 ). SBP at the last prenatal visit was significantly higher in women who went on to develop early postpartum preeclampsia than in those who did not (130 mmHg ± 11 vs. 119 mmHg ± 12, respectively,p < 0.01) ( Table 4 ). During the first stage of labor, SBP was also significantly higher in women who went on to develop early postpartum preeclampsia as compared to those who did not: 159 mmHg ± 22 vs. 136 mmHg ± 16, respectively,p < 0.001) ( Table 4 ). The same was true for DBP (99 mmHg ± 17 vs. 82 mmHg ± 12; respectively,p < 0.001).
|Post-partum preeclampsia (n = 13)||No post-partum preeclampsia (n = 1422)||p|
|BMI (kg/m2, mean ± SD)||26.1 ± 7||23.9 ± 5||ns|
|Delivery GA (weeks, mean ± SD)||37.4||38.6||ns|
|Postpartum hospital stay (d, mean ± SD)||4.9 ± 1.4||3.7 ± 2.1||<0.05|
|Maternal age ≥30 years (n, %)||10 (77)||797 (56)||ns|
|Caucasian (n, %)||7 (54)||994 (70)||ns|
|African-French Antilles (n, %)||6 (46)||355 (25)||ns|
|Nulliparity (n, %)||5 (65)||616 (43)||ns|
|Gestational diabetes (n, %)||3 (23)||152 (11)||ns|
|FGR (<10th percentile)||1 (8)||84 (6)||ns|
|Birth weight (g, mean ± SD)||3041 ± 666||3206 ± 653||ns|
|Last prenatal visit SBP (mmHg, mean ± SD)||130 ± 11||119 ± 12||<0.01|
|Last prenatal visit DBP (mmHg, mean ± SD)||77 ± 13||74 ± 9||ns|
|SBP during labor (mmHg, mean ± SD)||159 ± 22||136 ± 16||<0.001|
|DBP during labor (mmHg, mean ± SD)||99 ± 17||82 ± 12||<0.001|
|SBP ≥150 mmHg during labor (n (%)||9 (69)||307 (22)||<0.01|
|DBP ≥91 mmHg during labor (n (%)||9 (69)||296 (21)||<0.01|
BMI: body mass index, GA: gestational age, FGR: fetal growth restriction.
We performed a ROC analysis to establish thresholds of SBP and DBP that might be associated with an increased risk of early de novo postpartum preeclampsia. The area under curve (AUC) of SBP was 0.8 (0.69–0.92;p < 0.001) and that of DBP 0.8 (0.69–0.91;p < 0.001). Best sensitivities and specificities were obtained with the following thresholds: 150 mmHg for SBP, and 91 mmHg for DBP ( Table 5 ). These thresholds corresponded to the 80th percentiles of the SBP and DBP during labor ( Table 5 ). An SBP greater than or equal to 150 mmHg and DBP greater than or equal to 91 mmHg during labor were associated with an increased risk of early postpartum preeclampsia (OR: 8.2, 95% CI: 2.5–26.7,p < 0.01; and OR: 8.6; 95% CI: 2.6–28,p < 0.01, respectively).
|(A) According to SBP thresholds|
|Percentiles||SBP (mmHg)||Sensitivity (%)||Specificity (%)|
|(B) According to DBP thresholds|
|Percentiles||DBP (mmHg)||Sensitivity (%)||Specificity (%)|
|(C) According to the selected thresholds|
|mmHg||Sensitivity (%)||Specificity (%)||OR (95% CI)|
|SBP ≥150 or DBP ≥91||77||71||8.12 (2.24–9.83)|
|SBP ≥150 and DBP ≥91||62||86||9.83 (3.14–28.73)|
SBP: systolic blood pressure, DBP: diastolic blood pressure, OR: odds ratio, CI: confidence interval.
The main objective of this study was to analyze normal blood pressure changes that occur during the first stage of labor. We found that the first stage of labor was associated with a significant increase in SBP and DBP. In the group of patients without either epidural or oxytocin (n = 156), SBP and DBP 95th percentiles were 162 and 101 mmHg, respectively. The usual upper blood pressure limits, 140 mmHg for SBP and 90 mmHg for DBP, corresponded respectively to the 56th and 74th percentile during the first stage of labor. As expected, 140 and 90 mmHg corresponded to the SPB and DPB 95th percentiles in the same population at the last prenatal visit thereby confirming the physiological specificity of labor. We were meticulous in excluding aberrant blood pressure values during labor (i.e. a never repeated isolated increased blood pressure value greater than 20% when compared to the immediate previous and following value) to avoid attributing clinical relevance to an incorrect measurement. To the best of our knowledge we provide here new data regarding blood pressure during labor. In an extremely small sample of patients (n = 15), Robson et al. have previously described a 9 mmHg increase in mean arterial blood pressure (from 82 to 91 mmHg) when cervical dilatation reached 8 cm  . The authors attributed blood pressure increase to the effect of uterine contractions which cause an increase in both stroke volume and heart rate  . However, several confounding factors were not controlled in their study: half of the women received oxytocin and all received nitric oxide, the anti-hypertensive effect of which is now established  .
In agreement with previous studies and , we found that epidural analgesia had no effect on SBP or DBP during labor. Our results, however, challenge a former study which suggests that pain was responsible for increased cardiac output leading to increased blood pressure during labor  . In our population, blood pressure was not reduced after pain suppression when comparing women with and without epidural analgesia.
Oxytocin, on the other hand, did cause a slight significant increase in SBP but not in DBP. Although clinically insignificant, this result strengthens the hypothesis of the role played by uterine contractions in blood pressure increase during labor through cardiac output elevation  . Interestingly, a few teams have described a decrease in blood pressure after oxytocin administration but in different clinical situations (high dose administration during cesarean section in prevention of postpartum hemorrhage) and .
The second aim of the study was to assess whether high blood pressure values during first stage of labor could predict the onset of early de novo postpartum preeclampsia in women without any hypertensive disease during or before pregnancy. To our knowledge, our study is the first to find this incidence of 0.9% of de novo early postpartum preeclampsia in a population of women without any hypertensive disorder during or before pregnancy analyzed prospectively. In his review, Sibai et al. reported a range of prevalence of postpartum hypertensive disorders of between 0.3 and 27%  . However, none of the studies quoted in this review specifically focused on de novo postpartum preeclampsia. In a retrospective study, Clark et al. found a 3% prevalence but this value included postpartum preeclampsia and hypertension as well as women presenting pregnancy hypertensive disorders  . Matthys et al. found a 5.7% prevalence of postpartum preeclampsia in a retrospective analysis  although it is not clear whether some of these women had hypertension or proteinuria just before delivery. Finally, Atterbury et al. found a rate of 0.1% of severe preeclampsia and eclampsia in the postpartum period  .
During first stage of labor, we found that an SBP greater than or equal to 150 mmHg or a DBP greater than or equal to 91 mmHg was associated with the occurrence of de novo postpartum preeclampsia with a sensitivity of 77% and a specificity of 71% ( Table 5 ). Several studies have defined blood pressure thresholds for the prediction of the onset of preeclampsia during pregnancy, , , , and , but only one specifically focused on postpartum preeclampsia  . In this study, the authors found that a 10 mmHg increase of mean arterial blood pressure between delivery and the early postpartum period in women who were normotensive during labor was associated with an increased risk of severe postpartum preeclampsia (RR = 3.6)  . In Sibai et al.’s study, six women who had postpartum eclampsia had normal blood pressure both during labor and in the early postpartum period  . In all of these studies, however, the definition of high blood pressure was based on usual thresholds.
In our 13 patients with early postpartum preeclampsia, one had a history of preeclampsia during her previous pregnancy and none had a history of fetal growth restriction. Excluding the patients with previous preeclampsia (n = 8) or fetal growth restriction (n = 13) does not significantly change results (data not shown). In addition, all these women had normal blood pressure without any treatment either after the index pregnancy or during the current pregnancy.
Other papers have underlined the usual risk factors associated with hypertensive disorders of pregnancy – ethnicity, , , , and , high BMI, , , , and , pre-existing diabetes and , age greater than 35 years and , and nulliparity and – in very large samples of patients, , , , , , , , and and two of these focus on de novo late postpartum preeclampsia and . Although, we did not find these traditional factors to be associated with an increased risk of postpartum preeclampsia in our population, a type II error cannot be excluded because of our small sample size of postpartum preeclampsia. Another limitation of our study is related to the absence of any analysis of late postpartum preeclampsia as our women were not systematically transferred to our center in case of late postpartum complications.
Finally, narcotics were used in 39/166 patients in whom epidural analgesia was not used during labor. They had intravenous patient controlled analgesia of remifentanil, at 3 mg/kg/h, with bolus of 0.25 mg/kg if needed and a 3 min lockout. We did not specifically analyze this sub-group of patients it has been demonstrated that this drug was not responsible for blood pressure changes  .
In summary, our findings suggest new thresholds of normal blood pressure during the first stage of labor and the respective influences of epidural analgesia and oxytocin on such values. In addition, we have identified blood pressure thresholds above which close monitoring of the mother is advisable as they could be at higher risk of developing early de novo postpartum preeclampsia.
Conflict of interest
The authors report no conflict of interest.
-  Report of the National High Blood Pressure Education Program Working Group on high blood pressure in pregnancy. Am J Obstet Gynecol. 2000;183:S1-S22
-  B. Sibai, G. Dekker, M. Kupferminc. Pre-eclampsia. Lancet. 2005;365:785-799
-  K.A. Douglas, C.W. Redman. Eclampsia in the United Kingdom. BMJ. 1994;309:1395-1400
-  J.J. Duvekot, E.C. Cheriex, F.A. Pieters, P.P. Menheere, L.H. Peeters. Early pregnancy changes in hemodynamics and volume homeostasis are consecutive adjustments triggered by a primary fall in systemic vascular tone. Am J Obstet Gynecol. 1993;169:1382-1392
-  C.H. Hendricks, E.J. Quilligan. Cardiac output during labor. Am J Obstet Gynecol. 1956;71:953-972
-  S.C. Robson, W. Dunlop, R.J. Boys, S. Hunter. Cardiac output during labour. Br Med J (Clin Res Ed). 1987;295:1169-1172
-  A. De Greeff, D. Ghosh, J. Anthony, A. Shennan. Accuracy assessment of the Dinamap ProCare 400 in pregnancy and preeclampsia. Hypertens Pregnancy. 2010;29:198-205
-  S. Moncada. Nitric oxide. J Hypertens Suppl. 1994;12:S35-S39
-  A. Deschamps, I. Kaufman, S.B. Backman, G. Plourde. Autonomic nervous system response to epidural analgesia in laboring patients by wavelet transform of heart rate and blood pressure variability. Anesthesiology. 2004;101:21-27
-  G.J. Scheffer, B.J. TenVoorde, J.M. Karemaker, H.H. Ros. Effects of epidural analgesia and atropine on heart rate and blood pressure variability: implications for the interpretation of beat-to-beat fluctuations. Eur J Anaesthesiol. 1994;11:75-80
-  M.G. Moertl, S. Friedrich, J. Kraschl, C. Wadsack, U. Lang, D. Schlembach. Haemodynamic effects of carbetocin and oxytocin given as intravenous bolus on women undergoing caesarean delivery: a randomised trial. BJOG. 2011;118:1349-1356
-  A.J. Pinder, M. Dresner, C. Calow, G.D. Shorten, J. O’Riordan, R. Johnson. Haemodynamic changes caused by oxytocin during caesarean section under spinal anaesthesia. Int J Obstet Anesth. 2002;11:156-159
-  B.M. Sibai. Etiology and management of postpartum hypertension-preeclampsia. Am J Obstet Gynecol. 2012;206:470-475
-  S.L. Clark, M.A. Belfort, G.A. Dildy, et al. Emergency department use during the postpartum period: implications for current management of the puerperium. Am J Obstet Gynecol. 2010;203(38):e1-e6
-  L.A. Matthys, K.H. Coppage, D.S. Lambers, J.R. Barton, B.M. Sibai. Delayed postpartum preeclampsia: an experience of 151 cases. Am J Obstet Gynecol. 2004;190:1464-1466
-  J.L. Atterbury, L.J. Groome, C. Hoff. Blood pressure changes in normotensive women readmitted in the postpartum period with severe preeclampsia/eclampsia. J Matern Fetal Med. 1996;5:201-205
-  K.L. Ales, M.E. Norton, M.L. Druzin. Early prediction of antepartum hypertension. Obstet Gynecol. 1989;73:928-933
-  A. Conde-Agudelo, J.M. Belizan, R. Lede, E.F. Bergel. What does an elevated mean arterial pressure in the second half of pregnancy predict – gestational hypertension or preeclampsia. Am J Obstet Gynecol. 1993;169:509-514
-  J. Masse, J.C. Forest, J.M. Moutquin, S. Marcoux, N.A. Brideau, M. Belanger. A prospective study of several potential biologic markers for early prediction of the development of preeclampsia. Am J Obstet Gynecol. 1993;169:501-508
-  B.M. Sibai, M. Ewell, R.J. Levine, et al. Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol. 1997;177:1003-1010
-  B.M. Sibai, T. Gordon, E. Thom, et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. The National Institute of Child Health and Human Development Network of Maternal–Fetal Medicine Units. Am J Obstet Gynecol. 1995;172:642-648
-  S.H. Bouthoorn, R. Gaillard, E.A. Steegers, et al. Ethnic differences in blood pressure and hypertensive complications during pregnancy: the Generation R study. Hypertension. 2012;60:198-205
-  A. Khalil, J. Rezende, R. Akolekar, A. Syngelaki, K.H. Nicolaides. Maternal racial origin and adverse pregnancy outcomes: a cohort study. Ultrasound Obstet Gynecol. 2013;41:278-285
-  B.T. Nguyen, Y.W. Cheng, J.M. Snowden, T.F. Esakoff, A.E. Frias, A.B. Caughey. The effect of race/ethnicity on adverse perinatal outcomes among patients with gestational diabetes mellitus. Am J Obstet Gynecol. 2012;207(322):e1-e6
-  C.A. Bigelow, G.A. Pereira, A. Warmsley, et al. Risk factors for new-onset late postpartum preeclampsia in women without a history of preeclampsia. Am J Obstet Gynecol. 2014;210(338):e1-e8
-  W.I. Larsen, J.E. Strong, J.H. Farley. Risk factors for late postpartum preeclampsia. J Reprod Med. 2012;57:35-38
-  T.E. O’Brien, J.G. Ray, W.S. Chan. Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiology. 2003;14:368-374
-  S. Caritis, B. Sibai, J. Hauth, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 1998;338:701-705
-  A. Shiozaki, Y. Matsuda, S. Satoh, S. Saito. Comparison of risk factors for gestational hypertension and preeclampsia in Japanese singleton pregnancies. J Obstet Gynaecol Res. 2013;39:492-499
-  J.I. Einarsson, H. Sangi-Haghpeykar, M.O. Gardner. Sperm exposure and development of preeclampsia. Am J Obstet Gynecol. 2003;188:1241-1243
-  J.M. Blair, G.T. Dobson, D.A. Hill, G.R. McCracken, J.P. Fee. Patient controlled analgesia for labour: a comparison of remifentanil with pethidine. Anaesthesia. 2005;60:22-27
a CHI Creteil, CRC CHI Creteil, University Paris Est Creteil, Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, 40 avenue de Verdun, 94000 Créteil, France
b INSERM U1016, COCHIN, UMR8104 CNRS, 24 rue du faubourg St Jacques, 75014 Paris, France
c The University of Texas Medical School at Houston, 6431 Fannin Street, MSB 3.286, Houston, TX 77030, USA
Corresponding author at: University Paris Est Creteil, Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Créteil, 40 avenue de Verdun, 94000 Créteil, France. Tel.: +33 6 59 47 04 28.
© 2014 Elsevier Ireland Ltd, All rights reserved.