Introduction

In healthy, non-pregnant women, cyclical variations occur in a range of homeostatic mechanisms across the ovarian cycle, including thirst, fluid balance, appetite, temperature, cardiovascular, haemodynamic, metabolic and respiratory regulation. Following fertilization, luteal changes are accentuated and other physiological and behavioural adaptations unfold in response to distinct neurohormonal interactions that characterize successive phases of pregnancy and lactation. These altered regulatory mechanisms accommodate changing maternal needs and those of the conceptus, during implantation, and embryo formation, while changes occur in a variety of maternal systems to anticipate the distinct needs of the fetus and neonate.

Detailed information on the time course of specific changes and improved understanding of the coordinating factors have increased the potential number of tools to measure key adaptations and assess maternal health. For example, higher plasma concentrations of progesterone and relaxin in early pregnancy are associated with lower mean systolic blood pressure in the second and third trimester, and a positive correlation exists between the extent of plasma volume expansion and fetal growth, reduced risk of pregnancy complications, and pre-term labour (Khraibi et al 2003, Kristiansson & Wang 2001, Steer 2000). Some pre-existing and potential maternal health problems in early pregnancy may be identified through assessment of different hormone levels; and raised body mass index (BMI) (Duvekot et al 1995, Lain et al 2008, Maccarrone & Finazzi-Agro 2004).

This chapter will outline the time course and regulation of adaptive responses of maternal cardiovascular, renal and haemodynamic systems to pregnancy; adaptive responses of maternal hypothalamic–pituitary regulation of prolactin and growth hormone, and adaptive responses of maternal hypothalamic–pituitary–adrenal (HPA) axis to early and late pregnancy (Brunton et al 2008, Douglas 2010). It will conclude by examining the time course and regulation of the adaptive response of the uterus and mammary gland during pregnancy. See also website for more information.

Pulmonary and cardiovascular adaptations

During the infertile cycle, regulation of fluid balance, cardiovascular volume and blood pressure varies during different phases (Chapman et al 1997). This includes some degree of hyperventilation and changing alveolar and arterial tensions of carbon dioxide (CO₂) levels influenced by oestrogens and progesterone (see website).

When conception occurs, hyperventilation increases and the magnitude of decline in PCO₂ correlates with arterial concentrations of progesterone (Chapman et al 1998, Jensen et al 2005).

During the luteal phase, mean arterial pressure (MAP) declines significantly, leading to a reflexive rise in cardiac output, while blood volume remains constant (Chapman et al 1997, Williams et al 2001). In most studies, systolic blood pressure is slightly raised compared to the follicular phase, while diastolic pressure is 5% lower. Following conception, the largest change in blood pressure occurs before 8 weeks’ gestation. At this point, 80–90% of the total pregnancy-related fall of around 10 mmHg in MAP has already taken place (Duvekot & Peeters 1998). After 8 weeks, MAP continues to fall, reaching its lowest level by 24 weeks (Robson et al 1989). This pregnancy-related decline in MAP is largely due to the fall in diastolic pressure that begins during the luteal phase (Duvekot & Peeters 1998). Systolic blood pressure remains constant until 20 weeks, rising significantly during the second half of pregnancy, while diastolic pressure reaches its lowest point at 24 weeks and rises significantly for the remainder of pregnancy (Mabie et al 1994, Volman et al 2007) (see Figs 31.1 and 31.2).

Figure 31.1 Systemic haemodynamic changes before and during pregnancy. Mean arterial pressure (MAP) decreases and cardiac output (CO) increases significantly by 6 weeks’ gestation in association with a decline in systemic vascular resistance (SVR).

(Reproduced with permission from Chapman et al 1998: Fig. 1; 2059.)

Figure 31.2 Changes in (A) systolic and (B) diastolic blood pressure from 8 weeks’ gestation

(Reproduced from Kristiansson & Wang 2001; Figs 1 and 2: 15, with kind permission of OUP. www.oup.com)

Adaptations in fluid regulation

Osmotic thresholds for thirst and vasopressin secretion decline during the luteal phase (see website) leading to a comparable reduction in plasma osmolality, through a fall in plasma sodium and its associated anions, primarily chloride and bicarbonate (Chapman et al 1997, Vokes et al 1988). When conception occurs, plasma osmolality continues to decline to 8–10 mOsmol/kg below mid-follicular values by 10 weeks’ gestation, and this new setpoint for thirst and vasopressin secretion is maintained throughout pregnancy and labour (Chapman et al 1998, Davison et al 1981). These changes are stimulated by a primary renal and systemic vasodilation, which creates a fall in total vascular resistance (Fig. 31.3).

Figure 31.3 Mean values (±SD) for plasma urea (P_urea), sodium (P_Na) and osmolality (P_osm) measured at weekly intervals during the infertile cycle and following conception to 16 weeks’ gestation

(Reproduced with permission from Baylis & Davison 1998; Fig. 10.17; 284.)

In the absence of any increase in plasma volume, the post-ovulatory fall in renal and systemic vascular resistance initiates a decline in ventricular afterload. This stimulates a reflex rise in cardiac output followed by a significant expansion in plasma volume by 6 weeks’ gestation, increasing rapidly to around 45–50% of non-pregnant values by 36 weeks (Chapman et al 1998). The fall in systemic vascular resistance from the luteal phase stimulates renal sodium and water retention, by activating fluid-retaining components of the renin–angiotensin–aldosterone system (RAAS) while blunting its vasoconstrictive effects (Chapman et al 1997, Chidambaram et al 2002, Sealey et al 1987).

When conception occurs, plasma renin activity, aldosterone and atrial natriuretic peptide (ANP) increase significantly by 6 weeks’ gestation (Chapman et al 1997, 1998, Sealey et al 1985). Despite higher basal activity of the RAAS during pregnancy, the early fall in plasma sodium sets a lower response threshold, and renal reactions to natriuretic stimuli like ANP and vascular responses to vasoconstrictor components, notably vasopressin and angiotensin II, are significantly blunted, as occurs during the luteal phase.

These responses are largely mediated by rising levels of hCG, oestrogens and progesterone (Fig. 31.4). Oestrogens stimulate hepatic synthesis of angiotensinogen (renin substrate) and promote formation of angiotensin-(1-7) [ANG-(1-7)] over angiotensin II (ANG II). ANG-(1-7) opposes the pressor effects of ANG II by releasing nitric oxide, bradykinin and prostacyclin (Valdes et al 2001, Zhang et al 2001). Rising levels of hCG in early pregnancy simultaneously attenuate the pressor effects of ANG II while progesterone counteracts its vasoconstrictive actions by decreasing mean arterial pressure. Progesterone also stimulates aldosterone synthesis, promoting water retention, while the natriuretic actions of progesterone are inactivated in the kidneys (Hermsteiner et al 2002, Quinkler et al 2001, Szmuilowicz et al 2006). Together, these modifications of the RAAS sustain volume expansion without an attendant increase in blood pressure (Duvekot & Peeters 1998, Nakamura et al 1988, Sudhir et al 1995).

Figure 31.4 Patterns of release of human chorionic gonadotrophin, progesterone and oestrogens from ovulation to birth

(Reproduced with permission from Blackburn 2007:100.)

Renal haemodynamic adaptations

Although the kidneys constitute less than 0.5% of total body weight, in resting non-pregnant adults, blood flow is equal to 25% of cardiac output, reflecting their key role in regulating fluid and electrolyte balance (Stanton & Koeppen 1993). From the mid-luteal phase of the cycle, significant changes occur in renal haemodynamics, as vascular resistance declines, while plasma flow and glomerular filtration rate increase significantly, by 6 weeks’ gestation, compared to values obtained during the mid-follicular phase of the cycle. Minimal renal vascular resistance occurs at 8 weeks’ gestation and this coincides with a peak rise in plasma flow of around 70%, which remains at slightly lower values for the remainder of pregnancy (Baylis & Davison 1998, Chapman et al 1998, Conrad & Novak 2004) (Fig. 31.5).

Figure 31.5 Renal haemodynamic changes before and during pregnancy. Changes in glomerular filtration rate, effective renal plasma flow and renal vascular resistance from mid-follicular phase until 36 weeks’ gestation.

(Reproduced with permission from Chapman et al 1998: Fig. 3; 2059.)

These findings suggest that hormonal changes in the corpus luteum, before and after conception, stimulate a primary fall in renal and systemic vascular resistance that initiates a chain of events leading to an early rise in cardiac output, renal sodium and water retention, despite the increase in glomerular filtration rate, leading to an expansion in plasma volume, before any increase in basal metabolic rate (Spaanderman et al 2000). A primary reduction in vascular resistance of non-reproductive organs may be initiated in preparation for the dramatic increase in uteroplacental blood flow during the second and third trimesters.

Considerable evidence suggests that the luteal decline in vascular resistance and plasma osmolality and the subsequent rise in plasma volume and total body water are positive indicators of maternal adaptations to pregnancy and long-term health, because of their strong association with increased fetal growth, reduced perinatal mortality and risk of cardiovascular disease in later life (Churchill et al 1997, Conrad et al 2001, Duvekot et al 1995, Steer et al 1995) (see website).

Hormonal regulation

Current findings suggest that the renal and systemic fall in vascular resistance and the rise in cardiac output are stimulated by the post-ovulatory increase in relaxin, oestrogens and progesterone from the corpus luteum followed by a significant rise in adrenomedullin, a long-lasting vasorelaxant, from a variety of tissues by 8 weeks’ gestation (Conrad et al 2001, Di Iorio et al 1999, Hermsteiner et al 2002, Nakamura et al 1988, Novak et al 2001, Sudhir et al 1995).

In pregnancy, relaxin is detectable in the peripheral circulation 6 days after the midcycle LH/FSH surge. By 11 days, concentrations are significantly higher in fertile than in non-fertile cycles and concentrations increase rapidly up to 20 weeks’ gestation (Johnson et al 1991, Stewart et al 1993). Limited human studies have demonstrated that higher plasma concentrations of relaxin and progesterone in early pregnancy are associated with lower mean systolic blood pressure in late pregnancy (Kristiansson & Wang 2001). Recent evidence suggests that while oestrogens have a stimulatory effect on cardiac output and oestrogens and progesterone stimulate systemic and uterine vasodilation, neither hormone seems to influence renal blood vessels, which show a marked degree of dilation following ovulation (Chapman et al 1997, Nakamura et al 1988, Sudhir et al 1995) (Fig. 31.6).

Figure 31.6 Serum relaxin concentrations from ovulation in a non-conceptive and a conceptive cycle.

(Reproduced with permission from Jaffe 1999: Fig. 27-16; 775.)

Cardiovascular adaptations

The maternal cardiovascular system undergoes an extensive expansion in response to pregnancy. The first event is decreased vascular resistance of non-reproductive organs, leading to a profound fall in systemic vascular resistance, which reaches its lowest point at the end of the first trimester (Poppas et al 1997). By reducing cardiac afterload, this primary adaptation stimulates an overall rise of approximately 40–50% in cardiac output (Duvekot et al 1995, Volman et al 2007). Longitudinal studies suggest that cardiac output rises significantly during the first trimester, and peaks at 20 to 32 weeks, with no significant changes thereafter, or continues to show further small rises until term (Chapman et al 1997, Desai et al 2004, Duvekot & Peeters 1998, Mabie et al 1994, Volman et al 2007). Measures of the pattern and relative contribution of heart rate (HR) and stroke volume (SV) to increased cardiac output suggest that HR rises progressively until 38 weeks while SV increases significantly by 8 weeks and rises further to reach maximum values between 20 and 37 weeks and declines slightly over the remainder of pregnancy (Desai et al 2004, Robson et al 1989, Volman et al 2007).

Stroke volume increases significantly by 8 weeks, peaks at 16–22 weeks and plateaus or shows further small increases during the third trimester (Volman et al 2007). This represents a rise of 21–22% over pre-pregnancy values. In different studies, HR has been found to increase significantly above pre-pregnancy values by 5 and 16 weeks’ gestation. Data on the remainder of pregnancy suggest that the increase peaks at 31–36 weeks and shows no significant change or a slight decline thereafter. Current evidence indicates that HR may increase by between 11% and 17% over pre-pregnancy values (Capeless & Clapp 1989, Duvekot et al 1993, Robson et al 1989, Volman et al 2007) (see website).