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Plasma Volume Expansion in Early Pregnancy

From the Departments of Obstetrics and Gynecology and Medical Biostatistics, University of Vermont College of Medicine, Burlington, Vermont.

Address reprint requests to: Ira M. Bernstein, MDDepartment of Obstetrics and Gynecology Shepardson 331, F.A.H.C.111 Colchester Avenue Burlington, VT 05401-1435 E-mail: ibernste{at}zoo.uvm.edu

	Abstract

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Objective: To determine the time course of plasma volume expansion in early pregnancy.

Methods: We prospectively measured plasma volume by Evans blue dye dilution during the menstrual (cycle day 2–3), follicular (cycle day 9–10), and luteal phases (cycle day urinary leutinizing hormone [LH] surge plus 9–10) of the menstrual cycle and at three additional time points (LH surge + 16 days, LH surge + 28 days, and LH surge + 70 days) in women achieving pregnancy. Twenty-one subjects were examined during 38 menstrual cycles to establish baseline menstrual cycle data. Ten subjects conceived within 1 year of menstrual cycle studies. All ten pregnancies were viable and reached the third trimester. Analyses used repeated-measures analysis of variance with P < .05 accepted for significance.

Results: Mean plasma volume was found to change significantly across the period of observation (P < .008) in those who conceived. Plasma volume at LH surge + 70 days (12 menstrual weeks, 2320 ± 280 mL) was greater than either menstrual cycle estimates or early pregnancy estimates of plasma volume. There was no difference in plasma volume at LH surge + 16 days (2077 ± 288 mL) or LH surge + 28 days (2010 ± 271 mL) compared with menstrual cycle measurements during the menstrual phase (2156 ± 292 mL), follicular phase (2036 ± 280 mL), and luteal phase (2120 ± 425 mL). There was no significant difference between those who conceived and those who did not in their mean menstrual cycle plasma volume.

Conclusion: Plasma volume expansion in early human pregnancy cannot be identified until after the sixth menstrual week. By 12 menstrual weeks, plasma volume has expanded by approximately 14% ± 12% (mean ± SD) over follicular phase measurements.

Inadequate plasma volume expansion in pregnancy has been linked with poor reproductive performance. Specifically, both fetal growth restriction and preeclampsia are associated with reduced plasma volume during pregnancy.^1–4 We recently demonstrated that women who carry a genetic predisposition to preeclampsia have a reduced plasma volume before becoming pregnant.⁵ Others have suggested that reduced nonpregnant plasma volume may be linked to fetal growth restriction.⁶ We sought to determine the timing of the onset of plasma volume expansion through the menstrual cycle into pregnancy in order to clarify the physiologic sequence of plasma volume expansion before conception and into the first trimester of pregnancy. We also sought to examine if reduced plasma volume before conception contributes to infertility.

	Materials and Methods

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Twenty-two nulligravidas recruited for participation had regular menses (26–35 days), were nonsmokers, were free from major medical illnesses including hypertension, and were interested in becoming pregnant. The women were between the ages of 24 and 35 years and none was taking regular medication. They were enrolled consecutively as a result of open advertisement over the course of 18 months. One subject withdrew from the study after her first cycle because of difficulty in achieving intravenous access; her data were excluded from all analyses. The remaining 21 subjects included 19 white and two Asian women. Seventeen of the women were studied in two separate complete menstrual cycles; two women conceived during their initial study cycle and had only one menstrual cycle evaluated; one study subject did not ovulate in her second studied cycle and the data from this nonovulatory cycle were excluded; and one subject donated blood during a study cycle and data from this menstrual cycle were not included in analysis. Thus 38 menstrual cycles, including 36 nonconception ovulatory cycles, in 21 subjects were available for evaluation. Menstrual cycle evaluations were performed on cycle days 2.9 ± 1.6 (mean ± SD) (menstrual), 10.3 ± 2.0 (follicular), and leutinizing hormone [LH] surge + 9.1 ± 0.8 (luteal). Menstrual cycle time points were standardized to a 28-day cycle using urinary ovulation detection kits initiated on cycle day 10 (OvuQuick One-Step; Quidel, San Diego, CA). Ovulation was confirmed in all women by a serum progesterone concentration above 4 ng/mL at the time of luteal phase evaluation. All women were followed prospectively for 1 year to identify spontaneous conception. Women achieving pregnancy had plasma volume estimates at three additional time points referenced to the timing of ovulation as determined by urinary LH detection kits. Subjects were examined on LH surge + 16.8 ± 1.1 (mean ± SD) days, LH surge + 27.3 ± 0.8 days, and LH surge + 70.3 ± 1.8 days approximately equivalent to 4, 6, and 12 menstrual weeks of gestation.

Women were provided with 12 months of urinary LH detection kits to assist in achieving pregnancy. Ten conceived without further assistance during this 12-month time. All pregnancies were viable and were maintained into the third trimester. There were nine singleton pregnancies and one twin gestation. The pattern and extent of plasma volume expansion for the twin pregnancy did not differ from the singleton pregnancies through 12 weeks of gestation and it was included in the overall analysis.

For each plasma volume estimate, all subjects were admitted to the University of Vermont General Clinical Research Center after a 12-hour overnight fast. Vital signs were measured after 15 minutes of rest in the supine position. A single saline lock was initiated and baseline values for dye dilution were obtained. A dose of Evans blue dye (15 mg) in a preweighed syringe was administered through the saline lock over 60 seconds. The Evans blue was prepared as a batched sample for this project, assuring a consistent concentration. Dosing, sample preparation, and analysis have been described previously.^5,7,8 The mean within-individual coefficient of variation for the estimation of plasma volume for a single study using this technique was less than 1.0%.

We reported previously the follicular phase plasma volumes for 15 of these women in an examination of the relationship between nonpregnant plasma volume and angiotensinogen M235T genotype.⁵ Subjects signed informed written consent and this study was approved by the University of Vermont Committee on Human Research in the Medical Sciences.

Statistical analysis was performed using repeated-measures analyses of variance. Fisher’s least significant difference test was used to perform pair-wise comparisons. Multiple cycles within an individual were not considered independent observations and were treated as being nested within subject. Demographic characteristics compared between women who conceived and nonconceiving women were compared using t tests. Statistical significance was determined based on P < .05.

	Results

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The 21 subjects had an average age of 29.7 ± 2.3 (mean ± SD) years and a mean follicular phase body weight of 64.5 ± 11.2 kg. The average height was 164.5 ± 5.7 cm and the mean body mass index was 23.8 ± 3.0. Women who conceived were significantly younger than those who did not and had a tendency to be shorter and weigh less (Table 1).

We also examined the pattern of plasma volume change over the course of the menstrual cycle in the 21 subjects examining nonconception cycles. We combined nonconception cycle data from women who conceived with those who did not. We found a significant increase in the mean plasma volume during menses (2258 ± 346 mL, mean ± SD) compared with either the midfollicular (2134 ± 328 mL) or midluteal (2146 ± 369 mL) measurements (P < .05). There was no difference between the midfollicular and midluteal estimate of plasma volume. There were no overall differences across subjects who eventually conceived compared with those who did not, nor was the pattern across the menstrual cycle different for the two groups (Table 2). Additionally, there was no evidence for an interaction between the pattern of plasma volume through the menstrual cycle and conception. We further compared estimates of plasma volume, corrected for body size by dividing by body mass index, during the menstrual cycle between subjects who conceived and those who did not. Again, we found no significant difference between these groups at all phases of the menstrual cycle, or in the trend over time during the menstrual cycle.

	Discussion

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These findings are consistent with a placental signal playing a primary role in the first trimester plasma volume expansion as the time course of plasma volume expansion overlaps with the luteoplacental shift.¹¹ Although the placental signal sequence responsible for plasma volume expansion remains uncertain, Longo¹² summarized evidence suggesting that placental estrogen may well be the primary signal.

We found a significant increase in the estimation of plasma volume during menses in women experiencing regular ovulatory menstrual cycles when nonconception cycles from all 21 subjects were combined. This finding is consistent with publications regarding plasma volume measured by indirect techniques.^13,14 Using changes in hemoglobin and hematocrit levels as indirect measures of changes in plasma volume, these two studies demonstrated that menstrual estimates of plasma volume exceed those of the midfollicular phase.^13,14 Luteal phase plasma volume estimates have varied more widely. We did not detect a difference between luteal and follicular phase estimates consistent with the findings of Cullinane et al,¹³ who estimated plasma volume on days 20 and 25 of the cycle. Pahwa et al¹⁴ suggested that plasma volume increased slightly when estimates were made at a similar time (days 22–24 of the menstrual cycle) in a group of slightly younger women, aged 17–22 years. The course of plasma volume during the luteal phase of the menstrual cycle is therefore less clear and may be more variable. Our data do not exclude the possibility that a late luteal expansion of the plasma volume is detected with our midmenses assessments.

While it is clear that reduced plasma volume is associated with abnormal pregnancy outcome,^1–4,6 we were unable to identify any information in the literature (MEDLINE search terms: infertility, blood volume, plasma volume, 1966–2000) regarding the association of plasma volume and fertility. In this study, we compared the plasma volume estimates across the menstrual cycle between women achieving spontaneous conception within 1 year of initiating attempts and those who did not conceive. We found no differences between these groups in comparing any phase of the menstrual cycle or in the pattern of plasma volume adaptation over the course of the menstrual cycle. There was a tendency for women who did not conceive to have higher estimates of plasma volume, even when corrected for their size. Although this study did not have sufficient power to conclusively identify the lack of a relationship between plasma volume constriction and infertility, the results suggest that it is unlikely to be a major factor.

	Footnotes

 
Supported in part by the University of Vermont General Clinical Research Center NIH GCRC MO1-RR109.

PII S0029-7844(00)01222-9

Received August 16, 2000. Received in revised form November 18, 2000. Accepted December 7, 2000.

	References

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1. Gallery ED, Hunyor SN, Gyory AZ. Plasma volume contraction: A significant factor in both pregnancy associated hypertension (preeclampsia) and chronic hypertension in pregnancy. Q J Med 1979;48:593–602.

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8. El-Sayed H, Goodal SR, Hainsworth R. Re-evaluation of Evans blue dye dilution method of plasma volume measurement. Clin Lab Haematol 1995;17:189–94.[Medline]

9. Whitaker PG. The intravascular mass of albumin during human pregnancy: A serial study in normal and diabetic women. Br J Obstet Gynaecol 1993;100:587–92.[Medline]

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13. Cullinane EM, Yurgalevitch SM, Saritelli AL, Herbert PN, Thompson PD. Variations in plasma volume affect total and low-density lipoprotein cholesterol concentrations during the menstrual cycle. Metabolism 1995;44:965–71.[Medline]

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