Abstract
Multisystem physiological changes in pregnancy are designed to provide for the increase in metabolic demand from the growing fetoplacental unit, the developing uterus and other maternal adaptations. Basal oxygen (O2) consumption increases by 50 ml/min or about 25% at term gestation, and basal metabolic rate increases similarly. There is further increased oxygen consumption during labour and vaginal delivery. Global O2 delivery is determined by the O2 carrying-capacity of arterial blood and cardiac output.
Multisystem physiological changes in pregnancy are designed to provide for the increase in metabolic demand from the growing fetoplacental unit, the developing uterus and other maternal adaptations. Basal oxygen (O2) consumption increases by 50 ml/min or about 25% at term gestation, and basal metabolic rate increases similarly.1 There is further increased oxygen consumption during labour and vaginal delivery. Global O2 delivery is determined by the O2 carrying-capacity of arterial blood and cardiac output. Increased O2 delivery to tissues in pregnancy is largely provided by an increase in cardiac output.
The predominant respiratory system change is hyperventilation, with mildly increased PaO2 and significant maternal hypocarbia the ultimate result.2 Maternal blood gas alterations assist both fetal oxygenation and effective offload of carbon dioxide (CO2) from the fetal to maternal circulation (and subsequent excretion by maternal ventilation). Continuous O2 supply and efficient gas exchange across the placenta is particularly important because O2 has the lowest storage-to-utilization ratio of all fetal nutrients with potentially devastating consequences from even brief interruptions of supply. Understanding the normal metabolic and respiratory adaptations of pregnancy is important. It facilitates the differentiation of disease states and safer application of supportive measures and therapies to pregnant women for optimal maternal and fetal outcomes.
Upper Airway Changes
An increase in oestrogen and placental growth factor level is the probable cause of increased oedema and vascularity of the mucosa of the upper airway in pregnancy.3,4 Nasal congestion (sometimes termed ‘rhinitis of pregnancy’) is common, and voice changes are possible.5,6 Severe epistaxis has been reported in some cases.7 The onset of these changes is from early in the first trimester. Symptomatically, they cause an increase in snoring during pregnancy, particularly in women who have additional oedema from pre-eclampsia. The airway narrowing can be demonstrated experimentally by acoustic reflection measurements and is worse in the supine position.8 In keeping with these pharyngeal mucosal changes, clinical indicators such as Mallampati score (which predicts difficult endotracheal intubation) also worsen over the course of pregnancy, and additionally during labour and delivery.9,10 With expected maternal weight gain, the combined effect is to contribute to anatomically difficult airway management in pregnant patients. Both difficult and failed oral endotracheal intubation is more frequent in the pregnant population in anaesthetic reports. A smaller than usual endotracheal tube size may be helpful, in addition to other preparations for failed airway management in both elective and emergency situations.11,12 There are functional and anatomic changes in the lower oesophageal sphincter, reduced gastric motility and increased intragastric pressure in pregnancy. Therefore these women are at increased risk of pulmonary aspiration of gastric contents during airway interventions. Nasal instrumentation (including nasendoscopy, enteral feeding tube placement and nasotracheal intubation) is expected to cause epistaxis and potential exacerbation of airway compromise because of mucosal friability.
Changes in Chest Wall Configuration
Endocrine changes also play a part in substantial changes in chest wall configuration from early in pregnancy. Relaxin alters the ligamentous attachments of the rib cage to both the sternum and thoracic spine. The ribs flare outwards (‘bucket-handle’ movement) so that the anterior–posterior and transverse dimensions of the thoracic cage are increased, with a resultant increase in thoracic circumference of approximately 8%. The subcostal angle at the xiphisternum widens to accommodate this reconfiguration – it remains wider than the pre-pregnancy value by 20% at 24 weeks post-partum although other anatomic changes regress to normal by this stage.13 As pregnancy progresses, the fetus grows and the enlarging uterus becomes an abdominal organ, which contributes to this process. It causes a rise in the resting position of the diaphragm, which sits 4–5 cm more cephalad in the thorax by term gestation.14,15 In this higher position the diaphragm tensions very well (‘pump-handle’ movement), in part because of improved contractile function due to increased pre-stretch of diaphragmatic muscle fibres in the resting position, but also because there is a greater area of apposition of the diaphragm to the edge of the rib cage.14 These anatomic changes result in altered static and dynamic lung function in pregnancy.
Static Lung Function
The flared ribs and higher diaphragmatic position cause a change in static lung volumes Table 4.1. Published studies are not entirely consistent because of methodological differences: plethysmographic and inert gas dilution methods give differing results; nor are they consistent for stage of pregnancy or position of measurement.16 Although total lung capacity doesn’t change very much, there is an important reduction of functional residual capacity and its component volumes (expiratory reserve volume and residual volume) from the end of the second trimester that progressively declines to the end of pregnancy.17,18 Functional residual capacity (FRC) describes the volume left in the lungs at the end of passive expiration: the balance between (inward) elastic recoil of the lungs and (outward) recoil of the chest wall plus (downward) pull of abdominal contents against it. Pregnancy-related alterations in chest wall configuration and dynamic influence of abdominal forces with fetal growth and maternal positional change influence this balance. FRC is about 80% of pre-pregnancy value by term pregnancy in an upright position and decreases further to 70% of pre-pregnancy values in a supine position. FRC is hugely clinically significant because it determines the oxygen reserve available to the pregnant woman. In the absence of respiratory disease, but with anticipated hypopnoea/apnoea during endotracheal intubation attempts, meticulous pre-oxygenation is necessary to maximize oxygen reserve in the decreased FRC. Combined with the increased oxygen consumption of pregnancy to sustain fetoplacental metabolic demand, the pregnant woman can be considered to have a physiologically difficult airway and is susceptible to rapid, profound desaturation during apnoeic airway manoeuvres. Notably, a 30° head-up position can reverse some of the decrease in FRC at term gestation and might be a suitable position to optimize oxygenation in later pregnancy for at-risk patients.19 High-flow humidified nasal oxygen and other apnoeic oxygenation strategies may also be useful adjuncts in this setting.20,21
| Static lung volumes | Change from pre-gravid state |
|---|---|
| Total lung capacity (TLC) | ↓ 200–400 ml (−4%) |
| Functional residual capacity (FRC) | ↓300–500 mL (−17% to −20%) |
| Expiratory reserve volume (ERV) | ↓100–300 mL (−5% to −15%) |
| Residual volume (RV) | ↓200–300 mL (−20% to −25%) |
| Inspiratory capacity (IC) | ↑100–300 ml (+5% to +10%) |
| Vital capacity (VC) | unchanged |
From reference 17.
Dynamic Lung Function
Spirometry assessments do not differ substantially between pregnant and non-pregnant subjects. There are small increases in forced vital capacity and peak expiratory flow as pregnancy progresses in some longitudinal studies,22 but this is not consistently reported.23 The reduction in FRC, upper airway congestion and the hypocarbia of pregnancy tend to increase airway resistance in pregnancy, but this effect is offset by a decrease in airway resistance brought about by the bronchodilator effects of increased relaxin, progesterone and other steroid hormones.24 The clinical relevance of unchanged dynamic lung function in pregnancy is that abnormal spirometry results are a useful discriminator of pulmonary or bronchial disease and not simply attributable to pregnancy per se.
Changes in Ventilation
The increased metabolic demands of fetoplacental development and maternal adaptations to pregnancy (increased cardiorespiratory workload itself increases metabolic demand) drive increased oxygen consumption and therefore carbon dioxide production. Increased CO2 production results in increased minute ventilation to excrete CO2. However, the proportionate increase in minute ventilation greatly exceeds the increase in O2 consumption and CO2 production. That this is a primary hormonal effect was first hypothesized by Hasselbach more than a century ago. Progesterone causes profound stimulation of ventilation from early in the first trimester in pregnancy due to central mechanisms whereby it decreases the threshold and increases the sensitivity of the respiratory centre to carbon dioxide. Each incremental increase of PaCO2 by 1 mmHg increases minute volume by 6 L per minute in pregnancy vs 1.5 L per minute outside pregnancy.25,26 This is similar in magnitude to the adaptive response seen in males after 20 days acclimatization at 14 000 feet high altitude. Oestrogen contribution to enhanced CO2 sensitivity in pregnancy is likely, given that oestrogens modulate central and peripheral progesterone receptors. Higher plasma progesterone levels during the luteal phase of the menstrual cycle also cause cyclical hyperventilation in females, as does exogenous administration in both male and female volunteers.27–29 Mechanistically, progesterone is associated with the hyperventilation seen in liver cirrhosis, and has been used therapeutically to treat disease states associated with hypoventilation (e.g. obesity hypoventilation syndrome).30,31 The hypoxic ventilatory response is also increased in pregnancy because of similar hormonal influences.32 Although it is understood that progesterone influences central and peripheral ventilatory responses to both CO2 and O2 in pregnancy, it is not clear why most of the ventilatory change is effected in the first trimester even though progesterone levels continue to increase through the remainder of pregnancy (without parallel changes in ventilation parameters). Nor is it clear why twin pregnancies with greater potential ‘mechanical’ compromise of respiratory function (because of increased uterine size and intra-abdominal pressure) demonstrate no clear differences in respiratory function compared to singleton pregnancies.33
Respiratory rate and pattern are only marginally changed with resting rate increasing by only one to two breaths per minute. The major change driving the 20–50% increase in minute ventilation (by term pregnancy) is a 30–35% increase in tidal volume. This is facilitated by the anatomic reconfiguration of the chest wall and improved diaphragmatic excursion discussed above. The ratio of dead space to tidal volume is unchanged in pregnancy so there is an increase in alveolar ventilation to 30–50% above pre-pregnancy values. The relationship of changes in basal metabolic rate, oxygen consumption and minute ventilation at monthly intervals in pregnancy is depicted in Figure 4.1
Figure 4.1 Changes in basal metabolic rate, oxygen consumption and minute ventilation in pregnancy.40
Changes in Blood Gases
The substantial increase in alveolar ventilation changes alveolar and arterial partial pressures of oxygen and carbon dioxide, and acid–base balance. There is a small increase from the first trimester in PaO2, which facilitates O2 transfer across the placenta from mother to fetus. This arises directly from the increase in alveolar ventilation, but also from the associated decrease in partial pressure of CO2 and a decrease in arterio-venous oxygen difference. Later in pregnancy, PaO2 drops somewhat (although still remaining higher than non-pregnant values) – a phenomenon that is exaggerated in the supine position and is reversible with head-up tilt.34,35,19 It is likely that this effect is caused by closing volume encroaching on FRC. Closing volume describes the lung volume at which small airway closure in dependent lung stops ventilating, and contributes instead to shunt fraction. It may have particular clinical relevance for pregnant patients with critical oxygenation for themselves or the fetus. The fetus has almost no oxygen storage and little margin for safety with regard to oxygenation despite the maternofetal physiologic changes of pregnancy. In summary, although there is increased maternal PaO2 (especially in early pregnancy) to augment fetal and maternal systemic oxygen delivery, metabolic demands remain higher than normal and functional stores of oxygen (for both mother and dependent fetus) are lower, so vulnerability to hypoxia remains. Hypoxaemia is more likely in a supine position, especially near term, and is partially reversible with more upright posture.
As a consequence of increased alveolar ventilation, alveolar partial pressure of carbon dioxide (PACO2) and arterial partial pressure of carbon dioxide (PaCO2) decrease to 27 and 32 mmHg respectively, starting from early in gestation.15 The lower maternal CO2 facilitates transfer of CO2 from fetal to maternal circulation and ultimately, maternal pulmonary excretion. Fetal growth and development then occurs with PaCO2 in utero similar to the (non-pregnant) adult.36 So pregnancy-related hypocarbia assists fetal oxygenation (indirectly) and fetal carbon dioxide removal (directly). However, excessive hyperventilation and profound alkalosis (whether during the additional stresses of labour or by iatrogenic means such as overzealous mechanical ventilation) can cause vasoconstriction of uterine arteries and reduced utero-placental perfusion, with adverse consequences for fetal wellbeing.37
Sustained hypocarbia in pregnancy causes a state of primary respiratory alkalosis. Renal excretion of bicarbonate attempts to redress this, but metabolic compensation is incomplete. Base excess becomes more negative by up to 5 mEq/L and total buffer base also decreases.38,39 These changes have a number of significant clinical consequences in the setting of maternal critical illness. The extent of acidosis (for example, representing tissue hypoperfusion) may be underestimated if the ‘normal’ alkalotic state is not considered. Additionally, pH is a logarithmic scale and the accumulation of hydrogen ions from relatively small changes in pH can be underestimated. Hypocarbia and a decrease in bicarbonate decreases buffering capacity of blood and makes acidosis more likely as a manifestation of evolving critical illness. Maintenance of ‘normal’ hypocarbia facilitates fetal metabolism so some clinical contexts create conflict between maternal and fetal best interests, e.g. permissive hypercapnia as a strategy of lung-protective ventilation is likely to compromise fetal gas exchange. Although the short-term consequences of this in an experimental setting do not seem to be too detrimental, we do not know if maternal hypercapnia is safe for the fetus.40 Interpretation of laboratory results and targets for treatment require knowledge of expected values in normal pregnancy for a particular gestational stage. Changes in PaO2 and PaCO2, and acid–base balance are summarized in Table 4.2.
Table 4.2 Changes in pH and blood gases during pregnancy
| Parameter | Non-pregnant | First trimester | Second trimester | Third trimester |
|---|---|---|---|---|
| pH | 7.40 | 7.44 | 7.44 | 7.44 |
| PaO2 (mmHg) | 100 | 107 | 105 | 103 |
| PaCO2 (mmHg) | 40 | 30 | 30 | 30 |
| HCO3– (mEq/L) | 24 | 21 | 20 | 20 |
From reference 39.
The alkalosis and hypocarbia of pregnancy (along with physiologic anaemia) will tend to shift the oxyhaemoglobin dissociation curve to the left, therefore increasing haemoglobin affinity for oxygen and reducing P50. However, this effect is offset by an increase in 2,3-diphosphoglycerate in maternal plasma during pregnancy, shifting the curve to the right, lowering maternal haemoglobin affinity for oxygen, and facilitating oxygen offload to the fetus.41
Gas Exchange at the Alveolar Interface
The diffusing capacity of the lung for carbon monoxide (DLCO) describes gas transfer from lung alveoli to pulmonary capillaries (carbon monoxide is used in place of oxygen because it diffuses rapidly, binds avidly with haemoglobin and its diffusing capacity is easily measured). Early studies of DLCO in pregnancy found no difference between first, second and third trimester of pregnancy values compared to post-partum. Other studies have found that there is a small decrease in gas transfer from the first trimester to post-partum (although this is likely offset by hyperventilation of pregnancy and of little clinical significance).42 Overall, pregnancy does not seem to adversely affect gas exchange at the alveolar–capillary interface unless disease states intervene.
Cardiovascular Changes to Facilitate Increased Oxygen Delivery in Pregnancy
Pregnancy hormones are the mediators of physiological change for the cardiovascular as well as respiratory systems.43,44 High plasma levels of oestrogen and progesterone modulate vasoconstrictor tone in endothelial smooth muscle, both by a direct effect and by enhanced production of nitric oxide. Along with other pregnancy hormones (prostaglandins and relaxin), a blunted maternal renin–angiotensin–system (RAS)-mediated vasoconstrictor response and the down-regulation of alpha-adrenergic receptors, there is a substantial reduction in systemic vascular resistance (SVR).45 The utero-placental unit contributes to decreased SVR because it functions as a high-flow, low-resistance vascular bed.46
Hypervolaemia ensues: the reduction in SVR and increase in compliance of the vasculature leads to an increase in plasma volume via RAS-mediated retention of salt and water in the kidney. The trigger for this is increased renin release from extra-renal sources available in pregnancy, including the ovaries and maternal decidua.47 Total body water increases by approximately 8500 ml and total body sodium by 1000 mmol/L.48,49 This mismatch between the gain of free fluid and electrolytes decreases plasma osmolality.50 Colloid oncotic pressure is reduced by approximately 14% from pre-pregnancy levels, which may predispose to increased extravascular lung water and non-cardiogenic pulmonary oedema with overzealous fluid challenge.51
Red cell mass is increased due to the secretion of erythropoietin (stimulated by human placental lactogen). Due to the greater relative increase in plasma volume (40–50%) over that of red cell mass (20–30%), there is a reduction in haematocrit to 33%.52 Therefore, an advantageous circulatory reserve is created in anticipation of haemorrhage at delivery, with less red cell mass loss per unit of blood loss. This is why anaemia of pregnancy is termed ‘physiological’ and although lower haemoglobin decreases the O2 carrying-capacity of blood, overall O2 delivery is maintained by an increase in cardiac output (CO). Increased preload due to high volume status and a decrease in left ventricular afterload are contributors to improved cardiac functional performance. Echocardiography-derived data demonstrate an increase in cardiac output from five weeks after the last menstrual period to 24 weeks’ gestation, with mean CO 45% above non-pregnant values.53 Both heart rate and stroke volume contribute. An increase in heart rate occurs from five weeks until 34 weeks, whereas stroke volume begins to increase from eight weeks and reaches a maximum at 20 weeks. The increase in heart rate shortens diastolic filling time – this may be pathogenic in the presence of co-existing cardiovascular disease. Physiological myocardial remodelling during pregnancy (eccentric hypertrophy), in contrast to pathogenic (e.g. hypertensive) remodelling, is reversible and is not associated with fibrosis or dysfunction.54 There is an increase in ventricular myocardial tissue mass and these structural adaptations can take six months to resolve after delivery.
Maternal supine position has the potential to adversely affect cardiac output from about 20 weeks’ gestation by compression of the aorta and vena cava opposed between the lordotic spine and the gravid uterus. This is called supine hypotension syndrome or aortocaval compression. Compression of the vena cava decreases venous return to the right side of the heart, reducing CO. Utero-placental perfusion is directly related to maternal perfusion pressure because placental blood flow is passive and is therefore pressure-dependent.55 Aortocaval compression can cause fetal hypoxia and acidaemia due to a fall in CO by as much as 24% at term. Maternal compensatory mechanisms comprise an increase in sympathetic tone, with resulting vasoconstriction and tachycardia, and diversion of blood through the vertebral venous plexus and the azygos veins to reach the right heart.56 Diagnosis is based on clinical assessment of the mother and interpretation of fetal heart rate pattern. Uterine blood flow may be compromised even if the mother is asymptomatic. Treatment involves placing the patient into the lateral position or manual displacement of the uterus off the midline – left uterine displacement (LUD).57 This is a critical intervention in the setting of low cardiac output states or maternal cardiac arrest to maximize maternal CO and minimize fetal asphyxia. Important cardiovascular changes of pregnancy related to gestation and their impact on clinical care are summarized in Figure 4.2 and Table 4.3.
