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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 preg-

nancy. Pregnancy is associated with enormous hormonal, circulatory, and mechani-

cal 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 out-

put 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 com-

bination 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 hor-

monal 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 preg-

nancy 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].

0889-8561/06/$ see front matterD 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.iac.2005.10.004 immunology.theclinics.com

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: [email protected] (R.A. Wise).

Immunol Allergy Clin N Am

26 (2006) 112
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Effect of pregnancy on ventilation and gas exchange

Resting minute ventilation increases during pregnancy [79]. This is primarilydue 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 respiratorydrive that causes the hyperpnea of pregnancy is the elevation of serum pro-

gesterone, 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 loadimposed 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 venti-lation 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 par-

ticularly susceptible to develop hypoxemia in the presence of respiratory depres-

sion 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 mon-oxide (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 exercisecauses 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 non-

pregnant 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 per-

ceived 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 dys-pnea 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 un-

changed compared with the postpartum state [35]. Similarly, exercise efficiency

respiratory physiologic changes in pregnancy 3


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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 ab-normal 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 to0.5 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 pre-

served 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 theuterus 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 in-

creasing the abdominal pressure, because the reduction in FRC is correlated with

the increase in end-expiratory abdominal pressure, but not end-expiratory pleuralpressure [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.

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The rib cage undergoes structural changes during pregnancy from the changes

in the hormonal milieu [52]. Progressive relaxation of the ligamentous attach-

ments of the ribs causes the subcostal angle of the rib cage to increase from 688

to1038 early in pregnancy, before the uterus is enlarged substantially. This change

persists for months after the end of pregnancy when the uterus returns to nor-

mal 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 sig-nificant, 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]. Smallairway 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 bio-chemical and physical changes. The American Academy of Sleep Medicine

defines a clinical entity of pregnancy-associated sleep disorder as the occur-

rence of insomnia or excessive sleepiness that develops in the course of preg-

nancy [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 pro-

tection during pregnancy to rest. Cortisol level is increased during pregnancy, and

is associated with clinical depression and its associated sleep changes (increasedrapid 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 re-

duced sleep efficiency and increased nocturnal awakenings.

Pregnant women have increased complaints of insomnia and daytime sleepi-

ness. 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 efficiencyalso 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 pregnancy-

induced 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 hypo-

ventilation, is uncommon in otherwise healthy young women, but changes inpregnancy alter the risk of developing sleep disordered breathing. Weight gain

and increased upper airway resistance that are due to estrogen effects may pre-

cipitate or worsen preexisting sleep apnea; increased minute ventilation, prefer-

ence 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 finaltrimester [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 oxy-genation, FEV1, FVC, diffusing capacity, and respiratory rate indicate patho-

logic conditions. In contrast, a normal nongravid value of 40 mm Hg for the

Paco2 in a pregnant patient should be considered evidence of respiratory fail-

ure 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.

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Sarcoidosis is the classic example of a disease that tends to stabilize or im-

prove during pregnancy [7176]. It is the most common of the interstitial lung

diseases to complicate pregnancy. The observed increase in circulating free cor-tisol in pregnant women has been postulated as the explanation for the im-

provement 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 cortico-steroids 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, lymphangio-

leiomyomatosis (LAM), an uncommon interstitial lung disease that occurs ex-

clusively in fertile women, typically is worsened by pregnancy [8084]. This is

not surprising given the hypothesis that disease progression in LAM is estrogen-

mediated. Consequently, most women who have LAM are advised to avoid

pregnancy [85].

The mean age of survival of patients who have cystic fibrosis has increasedprogressively over the last several decades. With this change, an increasing num-

ber 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 pulmo-

nary 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 ofliterature has described the problems that are induced by the increased cardiac

output demands of pregnancy in patients who have primary and secondary pul-

monary 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 preg-

nancy. 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 immunocompro-mised state, several chronic infections, most notably tuberculosis [98,99] and coc-

cidioidomycosis [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 lympho-

cytes [102104], but hormonal alterations also may play a role. For example, es-

trogen 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 thromboembolicdisease and amniotic fluid embolism [106]. Pregnancy increases the risk of ve-

nous thromboembolism formation by the hypercoagulable effects of estrogen

and venous stasis that are due to increased intra-abdominal pressure [107]. Am-

niotic fluid embolism may result in acute lung injury by causing pulmonary vas-

cular 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 respiratoryinsufficiency from parenchymal or neuromuscular disease.

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