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Red cell distribution width (RDW) changes in pregnancy
International Journal of Gynecology & Obstetrics 62 Ž1998. 43]46
Article
Red cell distribution width Ž RDW. changes in pregnancy H.A. Shehataa,U , M.M. Ali b , J.C. Evans-Jones c , G.J.G. Uptond , I.T. Manyondae a
b
Department of Obstetrics and Gynaecology, Mayday Uni¨ ersity Hospital, London Road, Surrey, United Kingdom Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom c Department of Obstetrics and Gynaecology, Essex County Hospital, Colchester, United Kingdom d Department of Mathematics, Essex Uni¨ ersity, Colchester, United Kingdom e Department of Obstetrics and Gynaecology, St. George’s Hospital, Blackshaw Road, London, United Kingdom Received 7 January 1998; received in revised form 25 March 1998; accepted 27 March 1998
Abstract Objecti¨ e: As part of an exercise in establishing normograms of hematological parameters in pregnancy, we studied the red cell distribution width ŽRDW. in healthy pregnant women. Methods: A longitudinal study of RDW measurements in 121 pregnant women at 16 and 34 weeks gestation and during labor and at Days 3 and 7 postpartum. All the women had uncomplicated pregnancies, minimum hemoglobin ŽHb. of 11.0 grdl at recruitment and took iron supplements from 16 weeks of gestation and until 7 days after delivery. All subjects went into spontaneous labor, 110 achieving a normal vaginal delivery while the remaining 11 were delivered by cesarean section. Two-way analysis of variance was used to study the changes in RDW between any given gestations to test the variability between and within subjects. Results: RDW increased significantly Ž P- 0.0001. between 34 weeks of gestation and the onset of labor. No significant changes occurred between 16 and 34 weeks gestation, or during the 7 days postpartum. Conclusion: This is the first longitudinal study analyzing the between and within women changes in RDW with progression of pregnancy. The unexpected rise in the RDW during the last 4]6 weeks leading up to the onset of labor suggests increased bone marrow activity. The stimulus is unknown, but as RDW changes are highly significant there may well be a useful indicator of impending parturition. Q 1998 International Federation of Gynecology and Obstetrics Keywords: RDW; Pregnancy; Normogram
U
Corresponding author. Tel.: q44 181 7253663; fax: q44 181 7250078; e-mail: [email protected]
0020-7292r98r$19.00 Q 1998 International Federation of Gynecology and Obstetrics PII S0020-7292Ž98.00069-1
44
H.A. Shehata et al. r International Journal of Gynecology & Obstetrics 62 (1998) 43]46
1. Introduction RDW, which can be measured by automated instruments, is an index of the variation in red cell size Žanisocytosis.. It is expressed as the standard deviation in femtolitres Žfl. or as the coefficient of variation Ž%. of the measurements of the red cell volume. A high RDW is observed in hemolytic disorders, in which the RDW appears to reflect reticulocytosis w1x. Reticulocytosis also occurs after blood loss. In pregnancy, reticulocytosis may occur in response to the dramatic increase in blood volume which is evident by 20 weeks gestation and also in response to the blood loss associated with parturition. To date there have been one longitudinal study of RDW changes in pregnancy which showed a significant increase at the 20th week, remained at high levels until the 32nd week and thereafter declined towards delivery w2x. The establishment of normograms in pregnancy is important not only because it aids identification of deviation from normality and therefore pathology, but also such normograms may point to important biological events in normal physiology. Recent studies of maternal corticotrophin hormone ŽCRH. during pregnancy suggest the concept of the existence of a biological clock w3]8x. If such a biological clock does indeed exist for the length of human pregnancy, then it is possible that many cases of preterm labor are due to incorrect setting of the clock and this raises the prospect of being able to reliably predict such preterm labor if only a sensitive marker could be found. In establishing a normogram for the RDW in pregnancy, we have unexpectedly found a consistent rise in this parameter in the 4]6 weeks leading up to the onset of parturition. This in itself may be a useful marker, or the identification of the stimulus of reticulocytosis may prove even more fruitful. 2. Methods Informed consent for the investigations described herein were obtained from all women and the local research ethics committee gave approval for the study. We recruited 121 consecutive
healthy pregnant women who fulfilled the following criteria: singleton pregnancy; minimum Hb at recruitment of 11.0 grdl; healthy, with no co-existing maternal disease; all women took iron supplements commencing at the booking visit and until 7 days after delivery. Monitoring the women’s requests for monthly repeat iron tablets prescriptions checked compliance. Gestational age was determined from the maternal menstrual history and by an ultrasound dating scan in early pregnancy. All women had spontaneous onset of labor, 110 achieving a vaginal delivery, and 11 delivered by cesarean section of which seven were for suspected fetal distress, three for failure to progress in first stage of labor and one for fetal malpresentation. Full blood count measurements were performed at 16 and 34 weeks of gestation, intrapartum, and Days 3 and 7 postpartum. A 2.7-ml venous blood sample was obtained and put into an EDTA bottle. A Sysmex NE8000 Analyzer Žwith a coefficient of variation of 0.41% at 15.4 grdl. was used in the analysis of the specimens. The Generalized Linear Models ŽGLM. procedure in SAS was used to estimate the between and within women variances w9x. 3. Results The study group included 59 primiparous and 62 multiparous women aged between 16 and 40 years with a mean age of 29 years. They weighed between 44.5 kg and 108.2 kg with a mean weight of 68.5 kg. The mean gestational age at delivery was 38 completed weeks for both groups. The mean birthweight and placental weight were 3340 g and 690 g, respectively. The RDW increased significantly between 34 weeks of gestation and labor Ž P- 0.0001.. No significant changes in RDW occurred between 16 and 34 weeks of gestation, or during the 7 days postpartum ŽFig. 1.. In addition to the figure an analysis of variance was conducted to control for the variability between women. The result showed that the difference between occasions remained highly significant Ž Ps 0.0001..
H.A. Shehata et al. r International Journal of Gynecology & Obstetrics 62 (1998) 43]46
45
Fig. 1. Mean RDW Ž%. And Its 95% Confidence Interval In Relation To Pregnancy Stage.
4. Discussion To the best of our knowledge, this is the first longitudinal study analyzing the between and within women changes in RDW with progression of pregnancy. One previous study showed a decline in RDW levels in the last few weeks of pregnancy w2x. In comparison to our study, Lurie’s group included only five patients, which makes statistical analysis almost impractical. We had predicted a rise in RDW between 16 and 34 weeks gestation to reflect the dramatic increase in blood volume that occurs in normal pregnancy by 20 weeks gestation; which was reflected in a previous study w2x. No such rise occurred. We might also have expected a rise in RDW in the puerperium in response to the blood loss sustained at delivery. However, there are at least two explanations for the apparent lack of change in RDW in the puerperium. Firstly, the blood loss may not have been sufficient to stimulate reticulocytosis, especially as parturition is also associ-
ated with a contraction in blood volume. Secondly, we estimated RDW on Days 3 and 7 and this may have been too early to detect a bone marrow response. However, the rise between 34 weeks and parturition was significant Ž P- 0.0001., consistent and unexpected. This suggests that there is a stimulus Žor stimuli., as yet unidentified, which acts to induce reticulocytosis in the last 4]6 weeks leading to normal parturition. All the women in our study group had uncomplicated antenatal periods and went into spontaneous labor at term. Whatever the biological significance of the RDW changes, they appear to occur consistently in the 4]6 weeks leading up to the spontaneous onset of labor. Thus this rise in RDW might be viewed as a reliable marker of impending parturition, although its clinical usefulness would require that it be further refined. For example, the measurements should be performed at more frequent intervals in the first instance in pregnancies at risk of preterm delivery in comparison to normal term delivery and a
46
H.A. Shehata et al. r International Journal of Gynecology & Obstetrics 62 (1998) 43]46
search for the relevant stimulus of reticulocytosis might in fact yield the more useful marker. Evidence for the existence of a biological clock determining the length of gestation is accumulating. For example, maternal plasma CRH levels have been shown to rise during pregnancy w3]5x and to be elevated at the time of preterm labor w6,7x. An even more recent report suggests that measurement of CRH levels as early as 16]20 weeks gestation identifies women who are destined to experience normal term, pre-term or post-term delivery w8x. This suggests that the length of gestation is pre-determined and this concept of a biological clock is consistent with similar phenomena in other important biological systems such as the timing of puberty or senescence. There may be other markers of the maturation process that ultimately leads to the onset of labor. References w1x Roberts GT, El-Badawi SB. Red blood cell distribution width in some hematological diseases. Am J Clin Invest 1985;83:222.
w2x Lurie S. Changes in age distribution of erythrocytes during pregnancy: a longitudinal study. Gynecol Obstet Invest 1993;36:141]144. w3x Campbell EA et al. Plasma corticotrophin-releasing hormone concentration during pregnancy and parturition. J Clin Endocrinol Metab 1987;64:1054]1059. w4x Chan E-C et al. Plasma corticotropin releasing hormone, beta-endorphin and cortisol inter-relationships during human pregnancy. Acta Endocrinol 1993;128:339]344. w5x Sasaki A et al. Immunoreactive corticotropin releasing hormone in human plasma during pregnancy, labor and delivery. J Clin Endocrinol Metab 1987;64:224]229. w6x Wolfe CDA et al. Plasma corticotrophin releasing factor ŽCRH. in abnormal pregnancy. Br J Obstet Gynaecol 1988;95:1003]1006. w7x Kurki T, Laatikainen T, Salminen-Lappalainen K, Ylikorkala O. Maternal plasma corticotrophin releasing hormone is elevated in preterm labor but unaffected by indomethacin or nylidrin. Br J Obstet Gynaecol 1991;98:685]691. w8x McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R. A placental clock controlling the length of human pregnancy. Nature Med 1995;1:460]463. w9x SAS Institute Inc. SASrSTAT User Guide, Release 6.11. Cary, NC: SAS Institute Inc., 1994.
Article
Red cell distribution width Ž RDW. changes in pregnancy H.A. Shehataa,U , M.M. Ali b , J.C. Evans-Jones c , G.J.G. Uptond , I.T. Manyondae a
b
Department of Obstetrics and Gynaecology, Mayday Uni¨ ersity Hospital, London Road, Surrey, United Kingdom Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom c Department of Obstetrics and Gynaecology, Essex County Hospital, Colchester, United Kingdom d Department of Mathematics, Essex Uni¨ ersity, Colchester, United Kingdom e Department of Obstetrics and Gynaecology, St. George’s Hospital, Blackshaw Road, London, United Kingdom Received 7 January 1998; received in revised form 25 March 1998; accepted 27 March 1998
Abstract Objecti¨ e: As part of an exercise in establishing normograms of hematological parameters in pregnancy, we studied the red cell distribution width ŽRDW. in healthy pregnant women. Methods: A longitudinal study of RDW measurements in 121 pregnant women at 16 and 34 weeks gestation and during labor and at Days 3 and 7 postpartum. All the women had uncomplicated pregnancies, minimum hemoglobin ŽHb. of 11.0 grdl at recruitment and took iron supplements from 16 weeks of gestation and until 7 days after delivery. All subjects went into spontaneous labor, 110 achieving a normal vaginal delivery while the remaining 11 were delivered by cesarean section. Two-way analysis of variance was used to study the changes in RDW between any given gestations to test the variability between and within subjects. Results: RDW increased significantly Ž P- 0.0001. between 34 weeks of gestation and the onset of labor. No significant changes occurred between 16 and 34 weeks gestation, or during the 7 days postpartum. Conclusion: This is the first longitudinal study analyzing the between and within women changes in RDW with progression of pregnancy. The unexpected rise in the RDW during the last 4]6 weeks leading up to the onset of labor suggests increased bone marrow activity. The stimulus is unknown, but as RDW changes are highly significant there may well be a useful indicator of impending parturition. Q 1998 International Federation of Gynecology and Obstetrics Keywords: RDW; Pregnancy; Normogram
U
Corresponding author. Tel.: q44 181 7253663; fax: q44 181 7250078; e-mail: [email protected]
0020-7292r98r$19.00 Q 1998 International Federation of Gynecology and Obstetrics PII S0020-7292Ž98.00069-1
44
H.A. Shehata et al. r International Journal of Gynecology & Obstetrics 62 (1998) 43]46
1. Introduction RDW, which can be measured by automated instruments, is an index of the variation in red cell size Žanisocytosis.. It is expressed as the standard deviation in femtolitres Žfl. or as the coefficient of variation Ž%. of the measurements of the red cell volume. A high RDW is observed in hemolytic disorders, in which the RDW appears to reflect reticulocytosis w1x. Reticulocytosis also occurs after blood loss. In pregnancy, reticulocytosis may occur in response to the dramatic increase in blood volume which is evident by 20 weeks gestation and also in response to the blood loss associated with parturition. To date there have been one longitudinal study of RDW changes in pregnancy which showed a significant increase at the 20th week, remained at high levels until the 32nd week and thereafter declined towards delivery w2x. The establishment of normograms in pregnancy is important not only because it aids identification of deviation from normality and therefore pathology, but also such normograms may point to important biological events in normal physiology. Recent studies of maternal corticotrophin hormone ŽCRH. during pregnancy suggest the concept of the existence of a biological clock w3]8x. If such a biological clock does indeed exist for the length of human pregnancy, then it is possible that many cases of preterm labor are due to incorrect setting of the clock and this raises the prospect of being able to reliably predict such preterm labor if only a sensitive marker could be found. In establishing a normogram for the RDW in pregnancy, we have unexpectedly found a consistent rise in this parameter in the 4]6 weeks leading up to the onset of parturition. This in itself may be a useful marker, or the identification of the stimulus of reticulocytosis may prove even more fruitful. 2. Methods Informed consent for the investigations described herein were obtained from all women and the local research ethics committee gave approval for the study. We recruited 121 consecutive
healthy pregnant women who fulfilled the following criteria: singleton pregnancy; minimum Hb at recruitment of 11.0 grdl; healthy, with no co-existing maternal disease; all women took iron supplements commencing at the booking visit and until 7 days after delivery. Monitoring the women’s requests for monthly repeat iron tablets prescriptions checked compliance. Gestational age was determined from the maternal menstrual history and by an ultrasound dating scan in early pregnancy. All women had spontaneous onset of labor, 110 achieving a vaginal delivery, and 11 delivered by cesarean section of which seven were for suspected fetal distress, three for failure to progress in first stage of labor and one for fetal malpresentation. Full blood count measurements were performed at 16 and 34 weeks of gestation, intrapartum, and Days 3 and 7 postpartum. A 2.7-ml venous blood sample was obtained and put into an EDTA bottle. A Sysmex NE8000 Analyzer Žwith a coefficient of variation of 0.41% at 15.4 grdl. was used in the analysis of the specimens. The Generalized Linear Models ŽGLM. procedure in SAS was used to estimate the between and within women variances w9x. 3. Results The study group included 59 primiparous and 62 multiparous women aged between 16 and 40 years with a mean age of 29 years. They weighed between 44.5 kg and 108.2 kg with a mean weight of 68.5 kg. The mean gestational age at delivery was 38 completed weeks for both groups. The mean birthweight and placental weight were 3340 g and 690 g, respectively. The RDW increased significantly between 34 weeks of gestation and labor Ž P- 0.0001.. No significant changes in RDW occurred between 16 and 34 weeks of gestation, or during the 7 days postpartum ŽFig. 1.. In addition to the figure an analysis of variance was conducted to control for the variability between women. The result showed that the difference between occasions remained highly significant Ž Ps 0.0001..
H.A. Shehata et al. r International Journal of Gynecology & Obstetrics 62 (1998) 43]46
45
Fig. 1. Mean RDW Ž%. And Its 95% Confidence Interval In Relation To Pregnancy Stage.
4. Discussion To the best of our knowledge, this is the first longitudinal study analyzing the between and within women changes in RDW with progression of pregnancy. One previous study showed a decline in RDW levels in the last few weeks of pregnancy w2x. In comparison to our study, Lurie’s group included only five patients, which makes statistical analysis almost impractical. We had predicted a rise in RDW between 16 and 34 weeks gestation to reflect the dramatic increase in blood volume that occurs in normal pregnancy by 20 weeks gestation; which was reflected in a previous study w2x. No such rise occurred. We might also have expected a rise in RDW in the puerperium in response to the blood loss sustained at delivery. However, there are at least two explanations for the apparent lack of change in RDW in the puerperium. Firstly, the blood loss may not have been sufficient to stimulate reticulocytosis, especially as parturition is also associ-
ated with a contraction in blood volume. Secondly, we estimated RDW on Days 3 and 7 and this may have been too early to detect a bone marrow response. However, the rise between 34 weeks and parturition was significant Ž P- 0.0001., consistent and unexpected. This suggests that there is a stimulus Žor stimuli., as yet unidentified, which acts to induce reticulocytosis in the last 4]6 weeks leading to normal parturition. All the women in our study group had uncomplicated antenatal periods and went into spontaneous labor at term. Whatever the biological significance of the RDW changes, they appear to occur consistently in the 4]6 weeks leading up to the spontaneous onset of labor. Thus this rise in RDW might be viewed as a reliable marker of impending parturition, although its clinical usefulness would require that it be further refined. For example, the measurements should be performed at more frequent intervals in the first instance in pregnancies at risk of preterm delivery in comparison to normal term delivery and a
46
H.A. Shehata et al. r International Journal of Gynecology & Obstetrics 62 (1998) 43]46
search for the relevant stimulus of reticulocytosis might in fact yield the more useful marker. Evidence for the existence of a biological clock determining the length of gestation is accumulating. For example, maternal plasma CRH levels have been shown to rise during pregnancy w3]5x and to be elevated at the time of preterm labor w6,7x. An even more recent report suggests that measurement of CRH levels as early as 16]20 weeks gestation identifies women who are destined to experience normal term, pre-term or post-term delivery w8x. This suggests that the length of gestation is pre-determined and this concept of a biological clock is consistent with similar phenomena in other important biological systems such as the timing of puberty or senescence. There may be other markers of the maturation process that ultimately leads to the onset of labor. References w1x Roberts GT, El-Badawi SB. Red blood cell distribution width in some hematological diseases. Am J Clin Invest 1985;83:222.
w2x Lurie S. Changes in age distribution of erythrocytes during pregnancy: a longitudinal study. Gynecol Obstet Invest 1993;36:141]144. w3x Campbell EA et al. Plasma corticotrophin-releasing hormone concentration during pregnancy and parturition. J Clin Endocrinol Metab 1987;64:1054]1059. w4x Chan E-C et al. Plasma corticotropin releasing hormone, beta-endorphin and cortisol inter-relationships during human pregnancy. Acta Endocrinol 1993;128:339]344. w5x Sasaki A et al. Immunoreactive corticotropin releasing hormone in human plasma during pregnancy, labor and delivery. J Clin Endocrinol Metab 1987;64:224]229. w6x Wolfe CDA et al. Plasma corticotrophin releasing factor ŽCRH. in abnormal pregnancy. Br J Obstet Gynaecol 1988;95:1003]1006. w7x Kurki T, Laatikainen T, Salminen-Lappalainen K, Ylikorkala O. Maternal plasma corticotrophin releasing hormone is elevated in preterm labor but unaffected by indomethacin or nylidrin. Br J Obstet Gynaecol 1991;98:685]691. w8x McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R. A placental clock controlling the length of human pregnancy. Nature Med 1995;1:460]463. w9x SAS Institute Inc. SASrSTAT User Guide, Release 6.11. Cary, NC: SAS Institute Inc., 1994.