Maternal physiology in highaltitude pregnancy

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In this section we consider that one of the possible explanations for the link between maternal hypoxia (lowered arterial oxygen pressure) and an increased risk for pre-eclampsia lies in the impact of hypoxia on multiple physiological systems (see Figures 13.1 and 13.2). In this model it is not just one effect of hypoxia that ''causes'' pre-eclampsia, rather it is the impact of hypoxic stress on several important adjustments to pregnancy that shifts the general population risk such that more women eventually develop the disease (Figure 13.1).

Incidence of pregnancy complications

Incidence of pregnancy complications

Bell Palsy Causes Risk Factors

Figure 13.1 The solid bell-shaped curve represents the distribution of any given biochemical or physiological risk factor within a normal population under normal (in this case sea-level) environmental conditions. The hatched bell-shaped curve represents the shift in the value of this factor with a change in the environment. Thus under normal sea-level conditions the risk factor may lead to a 5-10% incidence of a given pregnancy complication, while the shift in the value of risk factor "x" with a change in environment (in this case high altitude) leads to more cases of the syndrome.

Figure 13.1 The solid bell-shaped curve represents the distribution of any given biochemical or physiological risk factor within a normal population under normal (in this case sea-level) environmental conditions. The hatched bell-shaped curve represents the shift in the value of this factor with a change in the environment. Thus under normal sea-level conditions the risk factor may lead to a 5-10% incidence of a given pregnancy complication, while the shift in the value of risk factor "x" with a change in environment (in this case high altitude) leads to more cases of the syndrome.

Physiological changes in pregnancy at high relative to low altitude t Blood pressure i Plasma volume t Catecholamines t Pro-inflammatory relative to anti-inflammatory cytokines J, Uteroplacental vascular remodeling i Uterine blood flow

Figure 13.2 A model of physiological changes in pregnancy in which the normal state is represented by sea-level normal pregnancies on the left side, and intermediate state of adaptation is represented by high-altitude pregnancies in the middle, and the extremes of physiological mal-adaptation are present in pre-eclampsia, the far right side. The list below the model are the data published to date in high-altitude pregnancy showing the direction of the changes observed relative to sea-level normal pregnancies.

Maternal oxygen consumption increases by a minimum of 20% and carbon dioxide production by 25% in human pregnancy at sea level. This increase is accomplished by a 35% increase in ventilation, which in turn is due to increased tidal volume as opposed to breathing frequency. The increase in oxygen consumption is not just due to increased weight and metabolic rate; at term oxygen consumption and carbon dioxide per kilogram of body weight are still 10% higher than in the non-pregnant condition (Moore et al., 1987). At least part of the increased drive to breathe stems from a general doubling of hypoxic ventilatory response. But, as with any normally distributed variable, there must be women at the upper and lower ends of the bell-shaped curve who have greater or lesser capacity for increasing their tidal volume and hence oxygen transport. Likewise, humans are remarkably variable in their ventilatory sensitivity to hypoxia and hypercarbia, and women with low responsiveness in pregnancy do not increase their breathing as much as those with higher responses (Moore et al., 1986, 1987). In the model presented in Figure 13.1, we suggest that most physiological variables have a normal distribution, and that perturbation of the environment (e.g. by lowered oxygen pressure and hence availability) can shift a greater proportion of individuals into a higher-risk category for the development of a syndrome such as pre-eclampsia. In Figure 13.2, based on the published literature, we emphasize that for many physiological variables known to be associated with an increased risk of pre-eclampsia, high-altitude women tend be shifted towards higher risk.

Blood pressure fails to fall mid-trimester at high altitude, and is increased relative to low altitude from week 16 forward (Palmer et al., 1999). While studies testing whether isolated mean arterial pressures can predict the development of pre-eclampsia lack specificity (Moutquin et al., 1985; Sibai etal., 1995; Villar and Sibai, 1989), it has long been known that even small increments in blood pressure in an otherwise normal pregnancy are associated with increased risk of adverse outcomes, including pre-eclampsia and lower birthweight (Page and Christianson, 1976). That mean arterial pressure in pregnancy at high altitude was inversely related to maternal arterial oxygen saturation, and, in a later study, to plasma volume expansion, supports the idea that maternal oxygen transport and blood pressure during pregnancy are related (Moore et al., 1982; Zamudio et al., 1993). Disturbed oxygen extraction/metabolism has also been observed at sea level in pre-eclampsia (Belfort et al., 1993), and the extensive literature on oxidative stress as a potential contributor cannot even begin to be covered here.

Plasma volume expansion is a well-known correlate of fetal growth (Longo and Hardesty, 1984), and is impaired in a variety of pregnancy complications ranging from oligohydramnios to diabetes to IUGR in the absence of pre-eclampsia (Goodlin et al., 1981). Hypovolemia is therefore a general marker of risk for pregnancy complications, and one that has been argued, both past and present, as an indicator of abnormal vascular responsiveness (Bernstein et al., 1998a; Croall et al., 1978). In our studies at 3100m women with the lowest arterial oxygen saturations had the highest mean arterial pressures and the least increase in plasma volume late in pregnancy (Zamudio et al., 1993). Of interest here is that the only sex difference known in long-term high-altitude residents appears to be an important contributor to the risk for developing pre-eclampsia. Men residing at high altitude increase their red cell mass and have plasma volumes only slightly lower than at sea level (Hurtado et al., 1945; Sanchez et al., 1970). An increase in red cell mass leads to an increase in oxygen carrying capacity per unit of blood. In contrast, women living at high altitude have lower plasma volumes and a similar red cell mass when compared to women living at low altitude (Zamudio et al., 1993). The same net effect is accomplished — hemoconcentration increases oxygen carrying capacity, but at the cost of a lowered plasma volume, and, presumably, venoconstriction, since the veins house the majority of plasma volume at any given moment. A low non-pregnant plasma volume is associated with an increased risk for pre-eclampsia and/or intrauterine growth restriction (Bernstein et al., 1998a; Croall etal., 1978; Gibson, 1973). The chronic reduction in plasma volume noted in women residing at high altitude could be due to either arterial or venous vasoconstriction. The former is supported by the observation that plasma volume decreases as peripheral vascular resistance rises (Dustan et al., 1973) and the latter by decreased venous distensi-bility and by the increased ratio of central to total blood volume in hypertensive subjects and in acute high-altitude exposure (Ulrych et al., 1969; Weil et al., 1971; Zamudio et al., 2001). We favor venoconstriction as the cause, as blood pressure does not differ in women who are not pregnant at high versus low altitude (Palmer et al., 1999), nor is there any evidence that more women are constitutionally hypertensive or at the high end of the normal range of blood pressure when not pregnant. In our long-term residents of 3100 m altitude in Colorado, we found that while the increase in plasma volume was normal in women who remained normotensive during pregnancy at high altitude, plasma volume at 36 weeks was similar to that of non-pregnant women living at low altitude, and volume expansion was more often disrupted, with a third trimester fall in women who developed PIH, and failure to expand altogether in women who eventually developed pre-eclampsia (Table 13.1) (Zamudio et al., 1993). It should be noted that these data are entirely consistent with what has been observed in pre-eclampsia at low altitude, and that the relationship between volume expansion and infant birth weight (r = 0.58) was similar or greater than that reported in previous studies (Longo and Hardesty, 1984).

Systemic vascular resistance/response to pressor agents has not been measured in pregnant women at high altitude, although as noted above, a considerable literature on animals exists, and is thoroughly reviewed in White and Zhang with respect to the most relevant animal models, sheep and guinea pigs (White and Zhang, 2003). However, the relative lack of fall in blood pressure and impaired blood volume expansion noted in pregnant women at high altitude suggest that systemic vascular resistance may be elevated relative to normal pregnancy at low altitude. While the formation of a new uteroplacental circuit contributes to the decrease in vascular resistance observed in normal pregnancy, the residual systemic (non-uteroplacental) circulation accounts

Table 13.1. Abnormal plasma volume expansion in hypertensive pregnancies at high altitude

1600 m 3100 m 3100 m 3100 m

Normotensive Normotensive PIH (n = 5) Pre-eclampsia (n = 11) (n = 22) (n = 8)

1600 m 3100 m 3100 m 3100 m

Normotensive Normotensive PIH (n = 5) Pre-eclampsia (n = 11) (n = 22) (n = 8)

Plasma volume nonpregnant (ml)

2523 ±

: 109

2112±

42

2292 ±

180

2464 ±

157

Plasma volume nonpregnant (ml/kg)

42.4 ±

: 1.2*

33.2 ±

0.8

31.9 ±

4.9

36.2 ±

2.3

A Plasma volume nonpregnant to wk 36 (ml)

1363 ±

: 178

1111H

120

564 ±

456

216±

t203{

A Plasma volume, wk 24 to wk 36 (ml)

404 ±

67

-194 ±

t100y

-227 ±

t61{

*p<0.05 high vs. low altitude. { p<0.05 normotensive vs. pre-eclampsia at 3100 m.

*p<0.05 high vs. low altitude. { p<0.05 normotensive vs. pre-eclampsia at 3100 m.

for the majority (>70%) of the fall in resistance observed in pregnant animals (Curran-Everett et al., 1991). Hence, change in vascular responsiveness of the non-uteroplacental circulation and/or changes in the levels of circulating pressors must be present in human pregnancy. A substantial literature supports the former, i.e. that attenuated systemic vascular response to a number of pressor agents, including catecholamines, contributes to the fall in systemic vascular resistance, which, in turn, facilitates the normal increase in cardiac output and redistribution of blood flow to favor the uteroplacental circuit (Chapman et al., 1998; Chesley, 1978; Gant et al., 1973; Nisell et al., 1985a; Palmer et al., 1992). These changes in vasoreactiv-ity are, in part, mediated by increases in estrogen and progesterone as reviewed (White et al., 1995). Pregnancy attenuates the vascular response to norepinephrine in pelvic and hindlimb vascular beds, as well as contractile responses in isolated aortic, mesenteric, femoral, caudal and uterine arteries (Crandall et al., 1990; Dogterom and DeJong, 1973; McLaughlin et al., 1989; Magness and Rosenfeld, 1986; Parent etal., 1990). Pregnancy also diminishes venous sensitivity to norepineph-rine, although sensitivity can be increased several fold by increasing intraluminal pressure (Hohmann et al., 1990). This latter finding supports that pregnancy-induced changes in venous volume may be important contributors to venous reactivity. Since it is the venous system that houses 80% of plasma volume at any given moment, aberration of venous vascular reactivity may be an underlying cause of the widely observed relationship between impaired plasma volume expansion and preeclampsia (Bernstein et al., 1998a), and consistent with genetic data indicating polymorphisms of relevance to angiotensin are associated with the syndrome (Bernstein etal., 1998b).

Several lines of evidence support that women who develop pre-eclampsia have greater activation of the sympathetic nervous system, in particular the alpha limb. Arterial norepinephrine levels are increased by >40% in pre-eclamptic women over their own nonpregnant values (Nisell etal., 1985a). Arterial norepinephrine levels are several-fold higher in pre-eclamptic than normal women, and while venous levels do not differ, this is most likely due to increased arterial to venous extraction in pre-eclamptic women (Nisell et al., 1985a; Oian et al., 1986; Pedersen et al., 1982). Increased urinary excretion of catecholamines in pre-eclampsia is consistent with greater circulating concentrations (Coussons-Read et al., 2002; Zuspan, 1976). Enhanced pressor and systemic vascular resistance response to catecholamines are noted in hypertensive pregnancy (Nisell et al., 1985b,c; Raab et al., 1956; Talledo et al., 1968). Moreover, circulating norepinephrine and epinephrine levels correlate with elevated blood pressure, reduced plasma volume and elevated heart rate in pre-eclamptic, but not normotensive pregnant women (Nisell et al., 1985a). More recently, directly measured sympathetic neural outflow (muscle

60000

15000

MMhiiMA

1st 2nd 3rd 3 mos.

1st 2nd 3rd 3 mos.

postpartum postpartum

Trimester

Trimester

Figure 13.3 Norepinephrine (left side) and epinephrine concentrations were measured using HPLC (Mazzeo et al., 1991) at 1600 m (white bars) and 3100m (solid black bars) during each trimester of pregnancy and 3 months postpartum in nine women at 1600 m and women at 3100 m. Values are elevated for both catecholamines in women at high altitude throughout pregnancy, although high variability and small sample sizes precludes significance within any given trimester of pregnancy or postpartum. (Data adapted from Coussons-Read et al., 2002.)

sympathetic nerve activity — MSNA) is markedly greater in women who develop pre-eclampsia or PIH when compared with normal pregnant women (Greenwood et al., 1998, 2001; Schobel et al., 1996). Moreover, a pre-eclampsia-like syndrome can be induced in animals by inducing sympathetic over-reactivity (Kanayama et al., 1997), and eclamptic seizures can occur in pre-eclamptic women given anticholinergics (Kobayashi etal., 2002), suggesting that diminution of para-sympathetic activity potentiates an already hyperreactive sympathetic vascular stimulation. While this particular theory concerning the etiology of pre-eclampsia waxes and wanes in popularity, and is sometimes spoken of somewhat derisively as a hypothesis about ''a case of nerves,'' there is far too much evidence of SNS disruption and dysregulation to simply ignore the possibility (Greenwood et al., 2003; Khatun et al., 2000; Lewinsky and Riskin-Mashiah, 1998; Nisell andLunell, 1984; Schobel etal., 1996;Zuspan, 1977, 1979). Taken together, the data support that alpha-sympathetic activity in pre-eclamptic women is enhanced compared with normal pregnant women.

It is well known that acute altitude-induced hypoxia stimulates the sympathoadrenal system (Mazzeo et al., 1991; Reeves et al., 1992). While epinephrine rises early during acclimatization, and is associated with increases in metabolic rate, heart rate and cardiac output, levels decline rapidly after a few days in conjunction with rises in arterial oxygen tension and content (Grover et al., 1986; Mazzeo et al., 1991, 1998). In contrast, norepi-nephrine, an indicator of alpha-adrenergic stimulation, rises later in acclimatization, plateaus in about a week, but remains higher even with 12—21 days of altitude exposure. Such rises parallel increases in blood pressure (Mazzeo et al., 1991), venoconstriction, increased peripheral vascular resistance and a decrease in plasma volume (Mazzeo et al., 2001a; Stokke et al., 1986; Weil et al., 1971; Wolfel et al., 1991). Reasoning by analogy, we suspected that catecholamine levels might be elevated in high altitude pregnancy. Twenty-four hour urinary excretion of catechol-amines were measured in a limited number of women pregnant at high vs. low altitude (Coussons-Read et al., 2002). As predicted, urinary excretion of catecholamines was elevated at high altitude when all trimesters were considered together (Figure 13.3). Altitude-associated differences in both norepinephrine and epinephrine were most pronounced early in pregnancy (46% and 109% greater, respectively), although even non-pregnant values were 37% (norepinephrine) and 47% (epinephrine) greater among the high-altitude women. However, the high variability in the measurements and the small sample size precluded significant differences within specific trimesters or 3 months postpartum (Coussons-Read et a/., 2002).

Previous work suggests that switching from Th1-type (pro-inflammatory) to Th2-type immunity (suppression of the inflammatory response) during pregnancy is one way the maternal immune system prevents rejection of the fetoplacental unit as an allograft (Piccinni and Romagnani, 1996; Piccinni et a/., 2000). Moreover, increased Th1 type activity in pregnancy is associated with complications, including pre-eclampsia and premature labor and delivery (Greer et a/., 1994; Kupferminc eta/., 1994; Omu eta/., 1999; Redman, 1991; Saito and Sakai, 2003; Veith and Rice, 1999; Vives et a/., 1999). More proinflammatory cytokines are produced by lymphocytes from pre-eclamptic women than from women with normal pregnancies (Darmochwal-Kolarz et a/., 2002; Saito et a/., 1999a, 1999b). While infection during pregnancy stimulates production of these cytokines, there is no evidence whatsoever that women pregnant at high altitude have a greater incidence of infections, despite substantial evidence that they have an increased incidence of pregnancy complications (Jensen and Moore, 1997; Moore et a/., 1998; Palmer et a/., 1999).

Catecholamines modulate immune function in humans and animals and thus catecholamines may contribute to the altered cytokine profiles observed in complicated pregnancies (Elenkov and Chrousos, 1999, 2002; Minagawa et a/., 1999). For example, catecholamines can induce an increase in the pro-inflammatory cytokines IL-6 and IL-8, while they tend to decrease TNF-alpha, but such responses vary by the tissue sites of production and whether or not other external stressors are present or absent (Elenkov and Chrousos, 2002). Acute high-altitude exposure leads to an increase in IL-6 and other indicators of an immune system inflammatory response (Bailey et a/., 2003; Kubo et a/., 1998; Mazzeo et a/., 2001b). Therefore in the same women in whom catecholamines were monitored, the hypothesis that pro-inflammatory cytokines would be elevated during high-altitude pregnancy was tested.

We found that maternal circulating concentrations of the pro-inflammatory cytokines IL-6, TNF-alpha, and IL-8 were all elevated late in pregnancy in women residing at high altitude, but did not differ even marginally in the non-pregnant state. The same subjects failed to increase their levels of anti-inflammatory (Th-2) IL-10 during pregnancy, causing a marked reduction in circulating concentrations relative to low altitude control subjects that was, again, most pronounced in the third trimester when pregnancy complications develop (Coussons-Read et al., 2002). The complexity of the systems involved can support a number of different explanations. It may be that pregnant women at high altitude do not make as complete a switch from Th1 to Th2-type immune responsiveness as women residing at lower altitude (Coussons-Read et al., 2002). It may be that the overall profile of cytokine production during pregnancy at high altitude is altered by sympatho-adrenal activation secondary to the interaction of hypoxia and pregnancy (a general stress) and therefore favors the development of complications at the extremes of the normal range of variation. Alternatively, altered cytokine production or degradation may be a reflection of underlying mechanisms that contribute both to the observed alterations in circulating concentrations and the development of complications without one necessarily causing the other.

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