Immunol Allergy Clin N Am 26 (2006) 1 12

Respiratory Physiologic Changes in Pregnancy

Robert A. Wise, MDT, Albert J. Polito, MD, Vidya Krishnan, MD, MHS
Department of Medicine (Pulmonary and Critical Care Medicine), Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA

This article reviews the respiratory functional changes that accompany pregnancy. Pregnancy is associated with enormous hormonal, circulatory, and mechanical alterations. The pregnant state is accompanied by increases in progesterone and estrogen with vascular and central nervous system effects, alterations in the balance of bronchoconstrictor and bronchodilator prostanoids, and increased levels of peptide hormones that alter connective tissue characteristics. Cardiac output and pulmonary blood flow are increased because of the metabolic demands of the products of conception, the increase in blood volume, and the decrease in hemoglobin concentration. The plasma oncotic pressure is decreased because of the increase in blood volume and decrease in albumin concentration. The combination of increased pulmonary blood flow, increased pulmonary capillary blood volume, and decreased oncotic pressure all promote the formation of edema in the periphery and in the lung. The course of pregnancy is accompanied by structural changes to the ribcage and abdominal compartments as a consequence of the hormonal changes and the enlarged uterus. Given the dramatic physical and hormonal alterations of pregnancy, perhaps the most remarkable aspect of respiratory physiology is the minor impact that pregnancy has on the function of the lung. Over the years, there have been several excellent reviews of the effects of pregnancy on the respiratory system in health and disease. [15]. This article is an update of a previous paper that appeared in this journal in 2000 [6].

Portions of this article were previously published in Wise RA, Polito AJ. Respiratory physiologic changes in pregnancy. Immunol Allergy Clin North Am 2000;20(4):66372. T Corresponding author. E-mail address: rwise@jhmi.edu (R.A. Wise). 0889-8561/06/$ see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2005.10.004 immunology.theclinics.com

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Effect of pregnancy on ventilation and gas exchange Resting minute ventilation increases during pregnancy [79]. This is primarily due to an increase in tidal volume with a constant breathing rate and pattern. Because the dead space/tidal volume ratio remains normal during pregnancy, the increased tidal volume leads to increased alveolar ventilation [10]. Most studies find that this hyperventilation occurs early in pregnancy during the first trimester, and stays constant or increases slightly as pregnancy progresses [11]. Typically, resting minute ventilation is increased about 30% during pregnancy compared with the postpartum value. In part, the increase in minute ventilation is caused by an increase in metabolic rate and carbon dioxide (CO2) production. During pregnancy, CO2 production at rest increases by about 30% to 300 mL/minute. The increase in minute ventilation exceeds that which is required to maintain a normal arterial carbon dioxide level. As a result, the Paco2 decreases from 40 mm Hg in the nonpregnant state to 32 to 34 mm Hg in pregnancy [12]. The kidney excretes excess bicarbonate to compensate for the respiratory alkalosis, and maintains a serum bicarbonate level of about 15 to 20 mEq/L to preserve a normal arterial pH. The respiratory alkalosis causes a rightward shift in the oxyhemoglobin dissociation curve that favors the unloading of oxygen in the periphery, and presumably aids oxygen transfer across the placenta [13]. There is general agreement that the main cause of the increased respiratory drive that causes the hyperpnea of pregnancy is the elevation of serum progesterone, a direct respiratory stimulant. The progesterone-induced increase in chemosensitivity results in an increase in the slope and a leftward shift of the CO2 ventilatory response curve. The increase in chemosensitivity occurs early in pregnancy and remains constant up until delivery. The respiratory center output, which integrates chemical and mechanical stimuli, is measured by the mouth pressure 100 milliseconds after airway occlusion. This measure increases progressively throughout pregnancy, and is compatible with the idea that the hyperpnea of pregnancy is the result of increased chemosensitivity and the load imposed by the gravid uterus. Shortly after delivery, the respiratory drive returns to normal with the decrease in progesterone levels and the reduction in metabolic and mechanical loads that were induced by pregnancy. The evidence that progesterone is a respiratory stimulant is strong [14]. When progesterone is administered to nonpregnant individuals, it increases minute ventilation, CO2 chemosensitivity, and airway occlusion pressure [1517]. It has been debated whether progesterone acts through a direct stimulatory effect on the respiratory center or through an increase in the gain of the chemoreceptors [18]. The most recent evidence shows that the threshold for hypercapnic ventilation and the gain in ventilation is increased in pregnancy, which suggests that intrinsic and chemically driven responses are more sensitive in the pregnant hormonal milieu [19]. The hypoxic ventilatory response is increased in pregnancy to about twice the normal level [20]. This occurs despite the blood and cerebrospinal fluid alkalosis that tends to suppress hypoxic drive. In contrast to the response to

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CO2, the hypoxic ventilatory response in pregnancy does not correlate well with progesterone levels. It is believed that the increased sensitivity to hypoxia is due to the increases in estrogen and progesterone [21,22]. Arterial oxygen tensions are increased slightly in pregnancy as a result of the pregnancy-induced hyperpnea, with a normal pregnant level of 100 to 105 mm Hg [10]. This higher level of oxygen tension may facilitate oxygen transfer across the placenta by diffusion; however, the increased metabolic rate and the low oxygen reservoir in the lung at end expiration make the pregnant woman particularly susceptible to develop hypoxemia in the presence of respiratory depression or apnea [23,24]. In some women, the low end-expiratory lung volume may predispose them to decreasing oxygen tensions in the supine position [25]. The overall effect of pregnancy on the diffusing capacity for carbon monoxide (Dco) is determined by the relative contributions of opposing physiologic changes. Pulmonary blood volume and cardiac output are increased in pregnancy, which should recruit capillary surface area, and thereby, increase Dco. This is offset by the dilutional reduction in hemoglobin concentration that occurs, and leads to a constant or slightly diminished Dco in most pregnant patients [26]. The normal increase in Dco that occurs in the supine position is absent in pregnancy, which might indicate that the gravid uterus prevents the normal increase in systemic venous return, or that the pulmonary capillary bed is already fully recruited [27]. The latter explanation is less plausible because exercise causes a normal increase in Dco in pregnant women [28]. One study suggests that there are different effects of pregnancy on Dco in high-altitude dwellers. Pregnant women who dwell at high altitude have a higher Dco than those who live at sea level; however, during the third trimester they have a lower Dco than nonpregnant women who live at high altitude. At sea level, the Dco is similar throughout pregnancy compared with nonpregnant controls [29].

Physiologic dyspnea of pregnancy The increase in minute ventilation that accompanies pregnancy often is perceived as shortness of breath. Approximately 75% of pregnant women have exertional dyspnea by 30 weeks of gestation [3033]. Shortness of breath at rest or with mild exertion is so common that it often is referred to as physiologic dyspnea. The proposed causes of dyspnea are the increased drive to breath and the increased respiratory load. The increase in minute ventilation and the load that is imposed by the enlarging uterus cause an increase in the work of breathing. Other factors that are believed to contribute to the sensation of dyspnea include increased pulmonary blood volume, anemia, and nasal congestion. Studies of the psycho-physiology of dyspnea in pregnancy indicate that the dyspnea can be accounted for by the increased effort of breathing, rather than an increased sensitivity to mechanical loads [34]. The cardiovascular response to endurance exercise in late pregnancy is unchanged compared with the postpartum state [35]. Similarly, exercise efficiency

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(change in oxygen consumption per change in work load) is unchanged [36]; however, ventilation at any level of oxygen consumption or CO2 production is increased in pregnancy, which leads to increased perception of respiratory effort. This excess exercise ventilation and sensation of breathlessness can be reduced by aerobic training [37]. It can be challenging for a physician to differentiate the normal dyspnea of pregnancy from that which is due to disease pathology. Findings that raise the question of pathologic dyspnea include increased respiratory rate greater than 20 breaths per minute, Paco2 that is less than 30 mm Hg or greater than 35 mm Hg, or abnormal measures on forced expiratory spirometry or cardiac echocardiography. The time course of symptoms also is helpful in differentiating pathologic conditions. Abrupt or paroxysmal episodes of dyspnea suggest an abnormal condition.

Lung and chest wall mechanics in pregnancy Lung volumes have been measured in several case series of pregnant women, in comparison with nonpregnant women or with the postpartum state. At term, helium dilution lung volumes may underestimate the true lung volume by 0.2 to 0.5 L because the low end-expiratory lung volume may impinge upon the closing volume, and thereby, prevent equilibration with the helium. If accurate measures of lung volume are required in term pregnancy, then body plethysmography is the preferred technique [38]. The consensus of many studies is that lung volumes mostly are well preserved in pregnancy. The total lung capacity usually is preserved or is decreased minimally. The residual volume tends to decrease slightly, which leads to a small increase or stability of the vital capacity [3946]. The most consistent change in static lung volumes with pregnancy is the reduction in functional residual capacity (FRC) and the expiratory reserve volume. As the uterus enlarges, FRC decreases by 10% to 25% of the previous value, starting about the twelfth week of pregnancy [39]. The normal reduction in FRC in the supine position is accentuated further in pregnancy [47,48]. The reduction in FRC is due to a decrease in chest wall compliance, which decreases about 35% to 40% [49]. The lung compliance remains normal during pregnancy, whereas expiratory muscle strength is in the low-normal range [40]. The decreased chest wall compliance is the result of the enlarging uterus increasing the abdominal pressure, because the reduction in FRC is correlated with the increase in end-expiratory abdominal pressure, but not end-expiratory pleural pressure [50]. The diaphragm elevates about 4 cm and the circumference of the lower rib cage increases about 5 cm [41]. The lower end-expiratory lung volume leads to an increased area of apposition of the diaphragm to the chest wall, which improves the coupling of the diaphragm and chest wall [51]. Thus, the increased tidal volume of pregnancy is achieved without an increase in the respiratory excursions of the diaphragm.

respiratory physiologic changes in pregnancy

The rib cage undergoes structural changes during pregnancy from the changes in the hormonal milieu [52]. Progressive relaxation of the ligamentous attachments of the ribs causes the subcostal angle of the rib cage to increase from 688 to 1038 early in pregnancy, before the uterus is enlarged substantially. This change persists for months after the end of pregnancy when the uterus returns to normal size. The increased elasticity of the rib cage probably is the result of the same factors that induce changes in the elastic properties of the pelvis. One of the important mediators is believed to be the polypeptide hormone, relaxin, which is increased during pregnancy. This substance is responsible for the softening of the cervix and the relaxation of the pelvic ligaments [53,54].

Airflow mechanics Forced expiratory spirometry is useful to follow patients who have asthma. Therefore, it is important that clinicians understand that pregnancy has no significant effect on the forced expiratory volume in 1 second (FEV1) or the FEV1/forced vital capacity (FVC) ratio [26,55,56]. Peak expiratory flow rates have been reported to remain close to the normal range and be unchanged during pregnancy [57]. A more recent study described a small, but statistically significant, decrease in peak expiratory flow rates with advancing pregnancy, especially in the supine position [58]. The shape of the flow-volume curve and absolute flow rates at low lung volumes are normal in pregnant women [27]. Thus, it is possible to use nonpregnant reference values to evaluate lung function in pregnant women. A reduction in FEV1 or FVC should not be attributed to pregnancy alone. Measurement of airway conductance by several methods demonstrates normal or increased large airway conductance [40,55]. A recent epidemiologic study raised the possibility that pregnancy may induce changes in the lung that improve airway function and persist throughout life [59]. Small airway function, as measured by closing volume, is normal [6062]; however, because the FRC is low, airways may close during tidal breathing and increase the alveolararterial oxygen gradient in the supine position.

Sleep and pregnancy Sleep disturbances are common during pregnancy as the result of biochemical and physical changes. The American Academy of Sleep Medicine defines a clinical entity of pregnancy-associated sleep disorder as the occurrence of insomnia or excessive sleepiness that develops in the course of pregnancy [63]. Estrogen causes alterations in the upper airway, including mucosal edema, hyperemia, and mucus hypersecretion, which can increase upper airway resis-

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tance. Progesterone has a strong sedating effect, which may be a teleologic protection during pregnancy to rest. Cortisol level is increased during pregnancy, and is associated with clinical depression and its associated sleep changes (increased rapid eye movement [REM] density and decreased REM latency). Physical changes in pregnancy, including abdominal distension, fetal movement, bladder distention, urinary frequency, backache, and heartburn, all contribute to the reduced sleep efficiency and increased nocturnal awakenings. Pregnant women have increased complaints of insomnia and daytime sleepiness. Sleep quality reportedly is worsened in the first and third trimesters, with frequent nocturnal awakenings. Polysomnography reveals reduced slow wave and REM phases of sleep, and increased total sleep time and wake after sleep onset, all of which progress during the course of the pregnancy. Sleep efficiency also is reduced, and remains poor up to 3 months post partum [64,65]. Snoring is common during pregnancy; it occurs in 14% to 23% of pregnant women by the third trimester, as compared with 4% of nonpregnant, age-matched controls [66]. Of concern is that snoring during pregnancy may be associated with pregnancyinduced hypertension and intrauterine growth retardation [67]. Sleep disorders may occur more frequently in the gravid female patient. Sleep disordered breathing, a spectrum of respiratory disorders during sleep, including obstructive and central sleep apnea, periodic breathing, and nocturnal hypoventilation, is uncommon in otherwise healthy young women, but changes in pregnancy alter the risk of developing sleep disordered breathing. Weight gain and increased upper airway resistance that are due to estrogen effects may precipitate or worsen preexisting sleep apnea; increased minute ventilation, preference for the lateral sleep posture, and decreased REM sleep time can decrease the risk of sleep apnea [64]. Restless leg syndrome (RLS), a sensory disorder in which patients describe an uncontrollable urge to move the legs while in the recumbent position at night, can disrupt sleep significantly. In one large study from Japan, prevalence of RLS in pregnant women (who did not have RLS before pregnancy) ranged from 15% in the first trimester to 23% by the final trimester [68]. This increased prevalence may reflect relative iron or folate deficiency during pregnancy [69,70].

Effect of pregnancy on chronic pulmonary diseases Clinicians who care for pregnant women who have underlying pulmonary disorders should understand that deviations from normal values of arterial oxygenation, FEV1, FVC, diffusing capacity, and respiratory rate indicate pathologic conditions. In contrast, a normal nongravid value of 40 mm Hg for the Paco2 in a pregnant patient should be considered evidence of respiratory failure and be treated accordingly. The effect of pregnancy on asthma and allergic diseases is treated extensively elsewhere in this issue. Other chronic respiratory diseases also may be affectedbeneficially and adverselyby pregnancy.

respiratory physiologic changes in pregnancy

Sarcoidosis is the classic example of a disease that tends to stabilize or improve during pregnancy [7176]. It is the most common of the interstitial lung diseases to complicate pregnancy. The observed increase in circulating free cortisol in pregnant women has been postulated as the explanation for the improvement that is seen in some patients [77]. This also may explain why patients who have autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus with their attendant pulmonary involvement, frequently stabilize during pregnancy [7779]. Cytotoxic agents that might be used for autoimmune disorders are contraindicated in pregnancy because of their teratologic and abortifacient effects. Corticosteroids have been used in pregnancy, although they may lead to preterm delivery or intrauterine growth retardation [79]. As with asthma, however, the effect of the use of higher doses of corticosteroids cannot be separated clearly from the impact of increased disease activity that prompts the use of these agents. In contrast to the immune-mediated interstitial lung diseases, lymphangioleiomyomatosis (LAM), an uncommon interstitial lung disease that occurs exclusively in fertile women, typically is worsened by pregnancy [8084]. This is not surprising given the hypothesis that disease progression in LAM is estrogenmediated. Consequently, most women who have LAM are advised to avoid pregnancy [85]. The mean age of survival of patients who have cystic fibrosis has increased progressively over the last several decades. With this change, an increasing number of women who have cystic fibrosis are choosing to become pregnant. With careful management, such patients are generally able to tolerate pregnancy well [8688]. An FVC of more than 50% of predicted has been offered as a safe threshold for pregnancy; however, other factors, including frequency of pulmonary exacerbations, nutritional status, and presence of pulmonary hypertension, must be taken into account [89,90]. The physiologic changes in the cardiovascular and respiratory systems during pregnancy are tolerated poorly by certain groups of patients. A large body of literature has described the problems that are induced by the increased cardiac output demands of pregnancy in patients who have primary and secondary pulmonary hypertension [9194]. Chronic obstructive pulmonary disease [95,96] and neuromuscular disease [97] also generally predispose to poor outcomes because they add to the increased work of breathing that is imposed by pregnancy. Among the neuromuscular disorders, myasthenia gravis presents a special case. Two thirds of myasthenic women remain the same or show improvement in their disease during pregnancy, whereas one third worsen [76]. Although pregnancy generally is not considered to be an immunocompromised state, several chronic infections, most notably tuberculosis [98,99] and coccidioidomycosis [100,101], may reactivate or worsen in the gravid setting. This may be due, in part, to changes in the number and function of T and B lymphocytes [102104], but hormonal alterations also may play a role. For example, estrogen was demonstrated to enhance the growth of Coccidioides immitis in vitro [105]. Antituberculous and antifungal chemotherapy are useful in these settings.

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Pulmonary embolic disease in pregnancy The two leading causes of unexpected maternal deaths are thromboembolic disease and amniotic fluid embolism [106]. Pregnancy increases the risk of venous thromboembolism formation by the hypercoagulable effects of estrogen and venous stasis that are due to increased intra-abdominal pressure [107]. Amniotic fluid embolism may result in acute lung injury by causing pulmonary vascular endothelial damage, complement activation, and direct platelet aggregation effects of amniotic fluid [108110]. Air embolism is an uncommon complication of pregnancy in which air enters the venous circulation through the subplacental myometrial veins, and results in endothelial damage and mechanical obstruction.

Summary In summary, the major physiologic changes that occur in pregnancy are the increased minute ventilation, which is caused by increased respiratory center sensitivity and drive; a compensated respiratory alkalosis; and a low expiratory reserve volume. The vital capacity and measures of forced expiration are well preserved. Patients who have many lung diseases tolerate pregnancy well, with the exception of those who have pulmonary hypertension or chronic respiratory insufficiency from parenchymal or neuromuscular disease.

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