Physiological mechanisms of hyperventilation during human pregnancy

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Abstract

This study examined the role of pregnancy-induced changes in wakefulness (or non-chemoreflex) and central chemoreflex drives to breathe, acid–base balance and female sex hormones in the hyperventilation of human pregnancy. Thirty-five healthy women were studied in the third trimester (TM3; 36.3 ± 1.0 weeks gestation; mean ± S.D.) and again 20.2 ± 7.8 weeks post-partum (PP). An iso-oxic hyperoxic rebreathing procedure was used to evaluate wakefulness and central chemoreflex drives to breathe. At rest, arterialized venous blood was obtained for the estimation of arterial PCO2 (PaCO2) and [H+]. Blood for the determination of plasma strong ion difference ([SID]), albumin ([Alb]), as well as serum progesterone ([P4]) and 17β-estradiol ([E2]) concentrations was also obtained at rest. Wakefulness and central chemoreflex drives to breathe, [P4] and [E2], ventilation and V˙CO2 increased, whereas PaCO2 and the central chemoreflex ventilatory recruitment threshold for PCO2 (VRTCO2) decreased from PP to TM3 (all p < 0.01). The reductions in PaCO2 were not related to the increases in [P4] and [E2]. The alkalinizing effects of reductions in PaCO2 and [Alb] were partly offset by the acidifying effects of a reduced [SID], such that arterial [H+] was still reduced in TM3 vs. PP (all p < 0.001). A mathematical model of ventilatory control demonstrated that pregnancy-induced changes in wakefulness and central chemoreflex drives to breathe, acid–base balance, V˙CO2 and cerebral blood flow account for the reductions in PaCO2, [H+] and VRTCO2. This is the first study to demonstrate that the hyperventilation and attendant hypocapnia/alkalosis of human pregnancy results from a complex interaction of pregnancy-induced changes in wakefulness and central chemoreflex drives to breathe, acid–base balance, metabolic rate and cerebral blood flow.

Introduction

Human pregnancy is characterized by significant increases in minute ventilation (V˙E) with attendant reductions in arterial (PaCO2) and cerebrospinal fluid (CSF) PCO2 at rest (Machida, 1981, Hirabayashi et al., 1996, Jensen et al., 2005b). The underlying mechanisms of these changes remain highly conjectural, but several investigators have suggested that they may be due to the combined facilitatory effects of progesterone and estrogen on central and peripheral chemoreflex drives to breath (Moore et al., 1986, Moore et al., 1987, Hannhart et al., 1989, Jensen et al., 2005b). Nevertheless, experimental confirmation that maternal hyperventilation can be attributed solely to hormone-mediated increases in chemoreflex responsiveness has not yet been obtained.

As reviewed in detail elsewhere (Dempsey et al., 1986, Bayliss and Millhorn, 1992, Jensen et al., 2007), female sex hormones may also contribute to the increased V˙E of human pregnancy via an estrogen-dependent progesterone-receptor mediated facilitation of central neural mechanisms, independent of [H+] and therefore the respiratory chemoreflexes. Skatrud et al. (1978) found that medroxyprogesterone acetate (a synthetic progestin) significantly increased V˙E and reduced arterial and CSF [H+] in healthy men at rest, despite having no effect on the central or peripheral chemoreflex response to CO2 ([H+]) and O2, respectively. Similarly, we recently found that, in healthy eumennorheic women, menstrual cycle phase had no demonstrable effect on the central or peripheral chemoreflex response to CO2, despite cyclic changes in V˙E, PaCO2 and female sex hormone concentrations (Slatkovska et al., 2006). The most convincing evidence comes from a series of studies by Bayliss et al., 1987, Bayliss et al., 1990 and Bayliss and Millhorn (1992) who observed dose-dependent increases in phrenic nerve activity – the neural equivalent of V˙E – following the administration of progesterone to anaesthetized, paralyzed, carotid and vagus denervated, and ovariectomized cats pre-treated with estradiol under controlled isocapnic conditions, i.e., in the absence of central and peripheral chemoreceptor feedback influences. In keeping with these observations, a recent cross-sectional study from our laboratory found that estimates of wakefulness (or non-chemoreflex) drives to breath were significantly greater in healthy pregnant compared with non-pregnant women (Jensen et al., 2005b). Nevertheless, the contribution of wakefulness drives to breath to the hyperventilation of human pregnancy has not been previously examined.

Duffin (2005) recently demonstrated that the acidifying effects of a reduced plasma and CSF strong ion difference concentration ([SID]), such as occurs during human pregnancy (Machida, 1981, Hirabayashi et al., 1996, Heenan and Wolfe, 2000, Charlesworth et al., 2006), alters the obvious but often neglected relationship between PCO2 (the measured stimulus to the chemoreceptors) and [H+] (the actual stimulus to the chemoreceptors) such that arterial and central [H+] are increased at any given PaCO2 and CSF PCO2, respectively (refer to Figs. 7 and 14 in Stewart, 1983). Consequently, the chemoreflex ventilatory recruitment threshold for PCO2 (VRTCO2) is reduced, which in turn increases V˙E and decreases PaCO2 (Duffin, 2005). To date, no published study has examined how pregnancy-induced changes in acid–base balance affects the chemoreflex control of breathing, and in this manner resting steady-state V˙E and PaCO2.

Therefore, our primary objective was to test the hypothesis that pregnancy-induced increases in central chemoreflex and wakefulness (or non-chemoreflex) drives to breath are important factors contributing to the increased V˙E and reduced PaCO2 of human pregnancy, and that these changes are associated with increased circulating female sex hormone concentrations. Our second objective was to test the hypothesis that pregnancy-induced reductions in [SID] contribute significantly to the hyperventilation of human pregnancy by altering the relationship between PCO2 and [H+], and thereby the central chemoreflex VRTCO2. A mathematical model of ventilatory control (Duffin, 2005) was employed for this purpose.

Section snippets

Subjects

Subjects included 35 healthy women, 20–40 years, parity ≤2, who were experiencing uncomplicated singleton pregnancies; had no history of smoking or cardiorespiratory disease; and were not taking medications (other than prenatal vitamins) that could affect ventilatory control or acid–base balance. Subjects were recruited via posted announcements, newspaper advertisements and contact with local obstetricians, midwives and health care providers. Prior to participation, subjects completed the

Results

Thirty-five young, healthy, non-smoking, regularly active women with no history of cardiorespiratory disease completed the study. Twenty-five women were nulliparous, seven were para 1, and three were para 2. Mean gestational age at the time of TM3 testing was 36.3 ± 1.0 weeks, and PP testing was conducted 20.2 ± 7.8 weeks after delivery. Pregnancy-induced changes in baseline measurements are shown in Table 1: body mass and body mass index increased; forced expiratory volume in 1 s and forced vital

Discussion

This is the first study to demonstrate that the hyperventilation and attendant hypocapnia/alkalosis of human pregnancy results from a complex interaction between alterations in acid–base balance and other factors that directly affect ventilation, including increased wakefulness drives to breathe, increased central chemoreflex sensitivity, increased metabolism and decreased cerebral blood flow. We also found that the alkalinizing effects of pregnancy-induced reductions in PaCO2 and plasma [Alb]

Conclusion

This is the first longitudinal study, in humans, to employ a novel, integrative approach to elucidate the physiological mechanisms underlying the ventilatory adaptations of healthy human pregnancy. We concluded that the hyperventilation and attendant hypocapnia/alkalosis of human pregnancy results from a complex interaction between alterations in acid–base balance and other factors that directly affect ventilation, including increased wakefulness drives to breathe, increased central chemoreflex

Acknowledgements

This study was supported by the Ontario Thoracic Society Grant-in Aid, Ontario Thoracic Society Block Term Grant and William M. Spear Endowment Fund for Pulmonary Research at Queen's University. D. Jensen was supported by an Ontario Graduate Scholarship.

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