Pregnancy is a normal but altered physiologic state that results in significant hormonal, mechanical, and circulatory changes. The increases in progesterone and estrogen associated with pregnancy contribute to vascular and central nervous system effects, changes in the balance of bronchoconstrictor and bronchodilator prostanoids, and increases in peptide hormones that alter connective tissue characteristics. 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. Cardiac output, pulmonary blood flow, and circulating blood volume are all increased due to increased metabolic demands. This increase in blood volume without an increase in red cell mass results in a decreased hemoglobin concentration. Keywordslung mechanics, oxygenation, ventilation, respiratory physiology, pregnancy

.1 Normal respiratory physiologic changes in pregnancy.

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Preface

Pregnancy is associated with physiologic changes that help compensate for the

increasing demands of the fetus and placenta. Clinically, pregnancy acts as a stress

test that unmasks maternal disease and may have long term implications for

maternal and fetal health. General obstetricians are often hesitant to care for

complex medical problems, and internists to care for pregnant patients, which

may create a gap into which sick pregnant women will fall at a time when they

are most vulnerable.

Investigation and treatment of pregnant patients with pulmonary disorders is

often hindered by both a fear of doing harm to the fetus and by the paucity of data

needed to make recommendations. At Women and Infants Hospital, the tertiary

women's teaching hospital at Brown University, 10,000 deliveries occur every year.

The editors of this textbook are members in the division of obstetric and

consultative medicine, a group of obstetric internists and medical specialists that

provide consultation to obstetricians on complex medical and pulmonary

problems. Most pulmonary and critical care training programs provide little

exposure to this population. Despite this, pulmonologists and intensivists are

often called upon to provide consultation to critically ill pregnant women.

As editors, our hope was to gather pulmonologists, intensivists, obstetric

internists, high risk obstetricians and obstetric anesthesiologists from across the

globe to shed light on some common or complex pulmonary issues occurring in

pregnancy. The book is divided into three parts. The first few chapters introduce

the reader to the normal physiologic changes that occur during pregnancy. The

chapter on high altitude is included to illustrate the consequences of chronic

hypoxia on maternal and fetal outcomes, to help extrapolate to the effects of

chronic pulmonary conditions. The second part reviews general management

principles, including diagnostic imaging and prescribing in pregnancy. The final,

longest part includes multiple chapters on specific pulmonary disorders. The

specific chapters are intended to summarize the available literature, linking

science to bedside, and make management recommendations whenever possible.

Our goal is that the careful reading of this text will stimulate further investigation

into this fascinating and under explored area of medicine.

Ghada Bourjeily, MD

Karen Rosene-Montella, MD

v

2

Respiratory Physiology in Pregnancy

Meredith C. McCormack and Robert A. Wise

Keywords: lung mechanics, oxygenation, ventilation, respiratory physiology,

pregnancy

Introduction

Pregnancy is a normal but altered physiologic state that results in significant hormo-

nal, mechanical, and circulatory changes. The increases in progesterone and estrogen

associated with pregnancy contribute to vascular and central nervous system effects,

changes in the balance of bronchoconstrictor and bronchodilator prostanoids, and

increases in peptide hormones that alter connective tissue characteristics. 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.

Cardiac output, pulmonary blood flow, and circulating blood volume are all

increased due to increased metabolic demands. This increase in blood volume with-

out an increase in red cell mass results in a decreased hemoglobin concentration.

There is a reduction in plasma oncotic pressure due to both increased blood volume

and a 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. Given

the dramatic physical and hormonal alterations of pregnancy, perhaps the most

remarkable aspect of respiratory physiology is the relatively minor impact that

pregnancy has on the function of the lung. To be able to accurately identify and

diagnose respiratory abnormalities in pregnant patients, the clinician must first

understand normal physiologic changes of pregnancy. Over the years, there have

been several excellent reviews of the effects of pregnancy on the respiratorysystem in

health and disease (1–6) . This chapter provides an updated overview of respiratory

physiology in healthy pregnant women (6).

Chest Wall and Lung Mechanics in Pregnancy

During pregnancy, the ribcage undergoes structural changes in response to hor-

monal changes (7) . Progressive relaxation of the ligamentous attachments of the

ribs cause the subcostal angle of the rib-cage to increase from 688 to 1038 early in

G. Bourjeily, K. Rosene-Montella (eds.), Pulmonary Problems in Pregnancy , Respiratory Medicine,

DOI 10.1007/978-1-59745-445-2_2 Ó Humana Press, a part of Springer Scienceþ Business Media, LLC 2009

19

pregnancy before the uterus is substantially enlarged. This change persists for

months after the end of pregnancy when the uterus returns to normal size. The

increased elasticity of the rib-cage is probably the result of the same factors that

induce changes in the elastic properties of the pelvis. One of the important media-

tors is thought 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 (8 , 9).

Pregnancy causes the diaphragm to elevate about 4 cm and the circumference of

the lower rib-cage to increase about 5 cm (10) . 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 (11) .Thus,the

increased tidal volume in pregnancy is achieved without an increase in the respiratory

excursion of the diaphragm. The enlarging uterus results in increasing abdominal

pressure which decreases chest wall compliance, which falls about 35–40% (12).

The decrease in chest wall compliance causes a reduction in functional residual

capacity (FRC). Reductions in the FRC and the expiratory reserve volume are the

most consistent changes in static lung volumes with pregnancy. As the uterus

enlarges, FRC falls by 10–25% of the previous value, starting about the 12th

week of pregnancy (13) . The normal reduction in FRC in the supine position is

further accentuated in pregnancy (14 , 15) . By contrast, the total lung capacity is

usually preserved or minimally decreased as a result of the mild increase in the

inspiratory capacity. The residual volume tends to fall slightly, leading to a small

increase or stability of the vital capacity (16 , 17 , 10 , 13 , 18 – 21). The lung

compliance remains normal during pregnancy but chest wall compliance is slightly

reduced because of the effect of the enlarging uterus leading to a distention of the

abdominal cavity. Expiratory muscle strength is in the low-normal range (19).

Airflow Mechanics

Pregnancy has no significant effect on FEV

1

or the FEV

1

/FVC ratio (22 ,23 ,24) .

Peak expiratory flow rates remain close to the normal range and do not change during

pregnancy (25) . The shape of the flow-volume curve and absolute flow rates at low

lung volumes are normal in pregnant women (17 ,26) . Thus, it is possible to use non-

pregnant reference values to evaluate lung function in pregnant women. A reduction in

FEV

1

or FVC should not be attributed to pregnancy alone. This is important for

clinicians to understand, particularly as they are following patients with underlying

lung diseases, such as asthma (27 ,28) . Measurement of airway conductance by

several methods demonstrates normal or increased large airway conductance (19 ,

23). A relatively recent epidemiologic study has raised the possibility that pregnancy

may induce changes in the lung that improve airway function and persist throughout

life (29) . Small airway function as measured by closing volume is normal (30 –32).

However, because the FRC is low, airways may close during tidal breathing and

increase the alveolar-arterial oxygen gradient in the supine position.

Ventilation and Gas Exchange

Resting minute ventilation increases during pregnancy (33 – 35) . This is primarily

due to an increase in tidal volume with a relatively constant breathing rate and

pattern. Because the dead space-tidal volume ratio remains normal during

20 M.C. McCormack and R.A. Wise

pregnancy, the increased tidal volume leads to increased alveolar ventilation (36).

Dead space may be decreased in pregnancy because of increased cardiac output

and better perfusion to the apices, so ratio of VD/VT is even more advantageous.

Most studies find that this hyperventilation (increase in tidal volume) is a

progesterone effect that occurs early in pregnancy during the first trimester, and

stays constant or increases slightly as pregnancy progresses (37) . Typically, resting

minute ventilation is increased about 30% during pregnancy compared to the post-

partum value. This primary increase in minute ventilation is enhanced secondarily,

by an increase in metabolic rate and carbon dioxide production. During pregnancy,

carbon dioxide production at rest increases by about 30–300 ml/min. Despite this

increase in production, overcompensation results in a low to normal CO

2

during

pregnancy.

The increase in minute ventilation exceeds that which is required to maintain a

normal arterial carbon dioxide level. As a result, the arterial PaCO

2

falls from

40 mmHg in the non-pregnant state to 32–34 mmHg in pregnancy (38) . The

kidney excretes excess bicarbonate to compensate for the respiratory alkalosis and

maintains a serum bicarbonate level of about 15–20 meq/L to preserve a normal

arterial pH. Likely contributes to a rightward shift in the oxyhemoglobin dissocia-

tion curve the chronic alkalosis stimulates 2,3-diphosphoglycerate synthesis and

this, in conjunction with anemia, that favors the unloading of oxygen in the

periphery, presumably aiding oxygen transfer across the placenta (39) . 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 CO

2

ventilatory

response curve. The increase in chemosensitivity occurs early in pregnancy and

remains constant up until delivery. The respiratory center output, which integrates

both chemical and mechanical stimuli, is measured by the mouth pressure 100 ms

following airway occlusion (P

0.1

). This measure increases progressively throughout

pregnancy, compatible with the idea that the hyperpnea of pregnancy is the result

of both increased chemosensitivity and the metabolic and mechanical loads

imposed by the gravid state. Shortly after delivery, the respiratory drive returns

to normal with the fall in progesterone levels and the reduction in metabolic and

mechanical loads induced by pregnancy.

The evidence that progesterone is a respiratory stimulant is strong (40) . When

administered to non-pregnant individuals, progesterone increases minute ventila-

tion, CO

2

chemosensitivity, and airway occlusion pressure (41 – 43) . 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 (44).

The most recent evidence shows that both the threshold for hypercapnic ventilation

as well as the gain in ventilation is increased in pregnancy, suggesting that both

intrinsic and chemically-driven responses are more sensitive in the pregnant hor-

monal milieu (45).

The hypoxic ventilatory response is increased in pregnancy to about twice the

normal level (46) . This occurs despite the blood and cerebrospinal fluid alkalosis

that tends to suppress hypoxic drive. In contrast to the response to carbon dioxide,

the hypoxic ventilatory response in pregnancy is not well correlated with proges-

terone levels. It is thought that the increased sensitivity to hypoxia is due to the

increases in both estrogen and progesterone (47 , 48).

Arterial oxygen tensions are slightly increased in pregnancy as a result of the

pregnancy-induced hyperpnea, with a normal pregnant level of 100–105 mmHg

2 Respiratory Physiology in Pregnancy 21

(36). This high 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 (49 , 50) . In some women, the low end-expiratory lung volume may predis-

pose them to decreasing oxygen tensions in the supine position in the late stages of

pregnancy (51).

The overall effect of pregnancy on 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 preg-

nancy, which should recruit capillary surface area and thereby increase Dco.

This is offset by the dilutional reduction in hemoglobin concentration that

occurs, leading to a constant or slightly diminished Dco in the majority of

pregnant patients (22) . 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 (26) . The latter explanation is less

plausible because exercise causes a normal increase in Dco in pregnant people

(52). One study suggests that there are different effects of pregnancy on Dco in

high-altitude dwellers. Pregnant women dwelling at high altitude have a higher

Dco than those at sea-level, but during the third-trimester they have a lower Dco

than non-pregnant altitude dwellers. At sea-level, the Dco is similar throughout

pregnancy compared to non-pregnant controls (53) . High altitude also acts

additively with progesterone and ventilation is increased to a greater extent in

high altitude residents compared to low altitude residents. The increase in venti-

lation, along with increased hemoglobin concentrations, appears to raise arterial

oxygen saturation to levels similar to those of low altitude dwellers (54) .

Physiologic Dyspnea of Pregnancy

The increase in minute ventilation that accompanies pregnancy is often perceived

as shortness of breath. About 75% of pregnant women have exertional dyspnea

by 30 weeks of gestation (55 – 58) . Shortness of breath at rest or with mild

exertion is so common that it is often referred to as ''physiologic dyspnea.'' The

proposed causes of dyspnea are the increased drive to breathe and the increased

respiratory load. The increase in minute ventilation and the load imposed by the

enlarging uterus cause an increase in the work of breathing. Other factors that are

thought 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 (59) .

The cardiovascular response to endurance exercise in late pregnancy is

relatively unchanged compared to the post-partum state (60) . Similarly,

exercise efficiency (change in oxygen consumption per change in work load)

is unchanged (61 ,62). However, ventilation at any level of oxygen consump-

tion or carbon dioxide production is increased in pregnancy which leads to

increased perception of respiratory effort. This excess exercise ventilation and

sensation of breathlessness can be somewhat reduced by aerobic training

(63). In general, fetal responses to short duration of exercises are usually

22 M.C. McCormack and R.A. Wise

moderateandreturntobaselineint he post-exercise state and moderate

prenatal physical conditioning does not significantly affect fetal growth (6) .

It can be challenging for a physician to differentiate the normal dyspnea of

pregnancy from that due to disease pathology. Findings that raise the question

of pathologic dyspnea include: increased respiratory rate greater than 20 breaths

per minute, arterial PCO

2

less than 30 or greater than 35, hypoxemia or abnor-

mal measures on forced expiratory spirometry, or cardiac echocardiography.

The time course of symptoms is also helpful in differentiating pathologic

conditions. Abrupt or paroxysmal episodes of dyspnea suggest an abnormal

condition.

Summary and Conclusions

In summary, an understanding of the normal changes that occur in respiratory

physiology during pregnancy (Table 2.1) is fundamental to recognizing how the

presentation of lung diseases is altered by pregnancy. Although these changes in

cardiovascular and respiratory physiology are remarkably well tolerated, there is

diminished reserve capacity to deal with intercurrent respiratory insults. Thus,

prompt recognition and treatment of altered respiratory function is needed to

protect the health of the mother and fetus.

Table 2.1 Normal respiratory physiologic changes in pregnancy.

Chest Wall/Lung Mechanics

Chest wall compliance Decreased

Thoracic diameter Increased

Diaphragm Elevated

Lung compliance Unchanged

Lung Volumes

Total Lung Capacity Unchanged or slightly decreased

Vital capacity Unchanged or slightly increased

Inspiratory capacity Slightly increased

Functional residual capacity Decreased

Residual volume Slightly decreased

Expiratory reserve volume Decreased

Spirometry

FEV

1

Unchanged

FVC Unchanged

FEV

1

/FVC Unchanged

Gas Exchange

D

CO

Unchanged or slightly decreased

Ventilation

Minute ventilation Increased

Tidal volume Increased

Respiratory rate Unchanged

Blood gas

pH Normal (7.39–7.42)

PaO

2

Slightly elevated (100–105 mmHg)

PaCO

2

Slightly decreased (32–34 mmHg)

Bicarbonate Slightly decreased (15–20 meq/L)

2 Respiratory Physiology in Pregnancy 23

Abbreviations

cm Centimeters

Dco Diffusing capacity for carbon monoxide

FEV

1

Forced expiratory volume in one second

FRC Functional residual capacity

FVC Forced vital capacity

PaCO

2

Partial pressure of carbon dioxide in arterial blood

PaO

2

Partial pressure of oxygen in arterial blood

RV Residual volume

TLC Total lung capacity

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26 M.C. McCormack and R.A. Wise

... [3] During pregnancy, the rib cage undergoes structural changes in response to progressive relaxation of the ligamentous attachments of rib increasing the subcostal angle from 68° to 103°. [4] In pregnancy, the diaphragm is elevated by about 4 cm, and the lower rib cage circumference is increased by about 5 cm. [4] Hence, the functional residual capacity (FRC) and residual volume are reduced in pregnancy. ...

... [4] In pregnancy, the diaphragm is elevated by about 4 cm, and the lower rib cage circumference is increased by about 5 cm. [4] Hence, the functional residual capacity (FRC) and residual volume are reduced in pregnancy. [4] National Journal of Physiology, Pharmacy and Pharmacology 2 Volume 2 | Issue 4 | Sep-Oct 2015 2017 | Vol 7 | Issue 10 (Online First) Decreased FRC with increased oxygen demand lowers oxygen reserve of the mother. ...

... [4] Hence, the functional residual capacity (FRC) and residual volume are reduced in pregnancy. [4] National Journal of Physiology, Pharmacy and Pharmacology 2 Volume 2 | Issue 4 | Sep-Oct 2015 2017 | Vol 7 | Issue 10 (Online First) Decreased FRC with increased oxygen demand lowers oxygen reserve of the mother. [5] The increased metabolic rate and low oxygen reservoir in the lung at end expiration make the pregnant women particularly susceptible to develop hypoxemia. ...

  • Prema Joshi
  • Milind Chitale

Background: Pregnancy is a stressful condition with considerably altered physiological and metabolic functions. Several authors have reported that oxygen consumption increases by 30-40% during pregnancy. Maternal ventilation and blood gases undergo substantial changes in pregnancy. During pregnancy, the rib cage undergoes structural changes in response to progressive relaxation of the ligamentous attachments of rib increasing the subcostal angle from 68° to 103°. In pregnancy, the diaphragm is elevated by about 4 cm, and the lower ribcage circumference is increased by about 5 cm. Hence, the functional residual capacity (FRC) and residual volume are reduced in pregnancy. Decreased FRC with increased oxygen demand lowers oxygen reserve of the mother. The increased metabolic rate and low oxygen reservoir in the lung at end expiration make the pregnant women particularly susceptible to develop hypoxemia. The blood gas analyzers require blood sample from the patient, hence invasive and painful. Whereas, pulse oximetry is a non-invasive, inexpensive, bedside technique and an alternative for arterial blood gas measurement. There is conflicting evidence concerning arterial oxygen saturation during pregnancy, hence the present study was done. Aims and Objectives: The aim of this study is to assess and compare the arterial oxygen saturation in pregnant and non-pregnant women. Material and Methods: This study was done on 60 non-pregnant women and 60 pregnant women in each trimester of the age group 20-35 years. The arterial oxygen saturation was measured with pulse oximeter. Result: The arterial oxygen saturation did not show any statistically significant difference in pregnant women in any trimester as compared to non-pregnant women. Conclusion: The decreased FRC and increased oxygen demand does not affect the arterial oxygen saturation in pregnant women as progesterone mainly lowers the threshold of respiratory center and increases their sensitivity to carbon dioxide.

... The effects of N95 FFR use on the normally higher HR of pregnancy (owing to metabolic demands 10 ) was not significantly different from those in the nonpregnant subjects in the present series and in other investigations with similar workloads. 21,22 RR RR is relatively stable during pregnancy, 10 and no significant differences were noted between pregnant and nonpregnant subjects. The significant (P = .001) ...

... PtcCO 2 declines with pregnancy to 32-34 mm Hg owing to increased minute ventilation necessitated by the added metabolic demands, ventilatory stimulant effects of elevated progesterone, and need to develop a fetal/maternal CO 2 gradient. 10 No significant differences in PtcCO 2 were found between the pregnant and nonpregnant subjects (Table 1). No subject was hypercapneic, and none had an increase in baseline PtcCO 2 >3 mm Hg (Table 2). ...

  • Raymond J Roberge
  • Jung-Hyun Kim Jung-Hyun Kim
  • Jeffrey B Powell

Background To determine the physiological and subjective effects of wearing an N95 filtering facepiece respirator (N95 FFR) in advanced stages of pregnancy. Methods Healthy pregnant women (n = 22) and nonpregnant women (n = 22) had physiological and subjective measurements taken with and without wearing an N95 FFR during exercise and postural sedentary activities over a 1-hour period. Results There were no differences between the pregnant and nonpregnant women with respect to heart rate, respiratory rate, oxygen saturation, transcutaneous carbon dioxide level, chest wall temperature, aural temperature, and subjective perceptions of exertion and thermal comfort. No significant effect on fetal heart rate was noted. Conclusions Healthy pregnant women wearing an N95 FFR for 1 hour during exercise and sedentary activities did not exhibit any significant differences in measured physiological and subjective responses compared with nonpregnant women.

  • Shivakumar Iyer Shivakumar Iyer
  • Jignesh Shah

Pregnancy is associated with various physiological adaptations. Respiratory monitoring is of primary importance in obstetric patients. Even a transient inadequacy in oxygenation and ventilation may be life threatening to both mother and fetus. Bedside clinical monitoring of vital signs is currently largely supplemented by availability of pulse oximetry, capnography, and easy availability of blood gas analysis. Proper understanding of these monitored parameters and their pitfalls is crucial in the management of respiratory failure and acid-base disorders in pregnancy.

  • Jung-Hyun Kim Jung-Hyun Kim
  • Raymond J Roberge
  • Jeffrey B Powell

To determine the impact of wearing an N95 filtering facepiece respirator (N95 FFR) on tympanic temperature measurements. TMT measurements, with and without wearing an N95 filtering facepiece respirator (N95 FFR) were obtained at the onset and termination of 1 h of treadmill exercise in 21 subjects, and at staggered time intervals (0, 20, 40, 60 min) during combined sedentary activity and exercise of another 46 subjects, to determine any effect on TMT. A total of 877 TMT measurements were obtained that demonstrated a mean TMT increase of 0.05 °C in the first study group (p = 0.04) and a 0.19 °C decrease in the second study group (p < 0.001) with the wearing of an N95 FFR, both of which were lower than controls. Wearing an N95 FFR for 1 h, at different levels of activity, results in significantly lower TMT values than not wearing an N95 FFR, but the magnitude of the changes would likely have minimal clinical significance.

  • Nuala J Meyer
  • Gregory A Schmidt Gregory A Schmidt

Critical illness invariably elicits special trepidation and concern whenever a pregnant patient is involved. Not only must providers struggle to restore normal physiology to the mother, but they must do so whilst providing adequate circulation, oxygenation, and ventilation to the growing fetus. Few disease processes present as great a challenge to this delicate maternal-fetal balance as Acute Lung Injury (ALI) and its most severe form, the Acute Respiratory Distress Syndrome (ARDS). While the past decade has finally produced clinical trials demonstrating a reduced mortality when patients with ARDS are treated with careful ventilator strategies, investigational trials almost invariably exclude pregnant patients, leaving us to hypothesize how the application of various strategies will differ in a pregnant patient. In this chapter, we will review the definitions, clinical features, and epidemiology of ALI/ARDS in the pregnant patient, discuss the specific challenges that pregnancy imposes upon a patient with ALI, and present our therapeutic approach to the gravida with ALI. Keywordsacute respiratory distress syndrome–acute lung injury–hypoxemia–pulmonary edema–mechanical ventilation

Background: Pregnancy is associated with considerable changes in the physiological, anatomical and biochemical attributes in women. These may alter the exposure to xenobiotics between pregnant and non-pregnant women who receive similar doses, with implications for different susceptibility to environmental pollutants or therapeutic agents. Physiologically based pharmacokinetic (PBPK) models together with in vitro in vivo extrapolation (IVIVE) of absorption, distribution, metabolism and excretion (ADME) characteristics may capture the likely changes. However, such models require comprehensive information on the longitudinal variations of PBPK parameter values; a set of data that are as yet not available from a singular source. Aim: The aim of this article was to collect, integrate and analyse the available time-variant parameters that are needed for the PBPK modelling of xenobiotic kinetics in a healthy pregnant population. Methods: A structured literature search was carried out on anatomical, physiological and biochemical parameters likely to change in pregnancy and alter the kinetics of xenobiotics. Collated data were carefully assessed, integrated and analysed for trends with gestational age. Algorithms were generated to describe the changes in parameter values with gestational age. These included changes in maternal weight, the individual organ volumes and blood flows, glomerular filtration rates, and some drug-metabolising enzyme activities. Results: Articles were identified using relevant keywords, quality appraised and data were extracted by two investigators. Some parameters showed no change with gestational age and for others robust data were not available. However, for many parameters significant changes were reported during the course of pregnancy, e.g. cardiac output, protein binding and expression/activity of metabolizing enzymes. The trend for time-variant parameters was not consistent (with respect to direction and mono-tonicity). Hence, various mathematical algorithms were needed to describe individual parameter values. Conclusion: Despite the limitations identified in the availability of some values, the collected data presented in this paper provide a potentially useful singular resource for key parameters needed for PBPK modelling in pregnancy. This facilitates the risk assessment of environmental chemicals and therapeutic drug dose adjustments in the pregnant population.

  • Chao Sheng
  • Yan-Hong Yu
  • Ke-Seng Zhao Ke-Seng Zhao
  • Ding-Sheng Zha

The acute respiratory distress syndrome may complicate postpartum hemorrhagic shock and resuscitation, but its mechanisms are not yet well defined. We studied the lung inflammatory response to postpartum hemorrhagic shock and resuscitation in a rabbit model and the role of the nuclear factor-κB pathway. Randomized, controlled, prospective study. University hospital laboratory. Nonobstetric (not pregnant nor postpartum) and obstetrical (within 2 hrs postpartum) rabbits. Nonobstetric and obstetric female New Zealand white rabbits underwent fixed-pressure or fixed-volume hemorrhagic shock for 30 mins and then were rapidly resuscitated with the shed blood and Ringer's solution. Finally, they were either monitored for survival time or euthanized by exsanguination for lung tissue examination 24 hrs after hemorrhage. After hemorrhagic shock and resuscitation, median survival time in obstetric rabbits (3 days) was significantly shorter (p<.05) than that in nonobstetric rabbits (5 days). Compared with nonobstetric rabbits, obstetric rabbits had more severe lung injury as indicated by alveolar and interstitial fluid accumulation and marked neutrophil sequestration and greater lung injury score, myeloperoxidase activity, expression of intercellular adhesion molecule-1, serum tumor necrosis factor-α levels, and nuclear factor-κB activation, and lower serum interleukin-10 levels (p<.05 for all). After hemorrhage and resuscitation, obstetric rabbits had significantly shorter survival time and more severe lung injury than nonobstetric rabbits. The mechanism may be through upregulation of the signal transductions of the nuclear factor-κB pathways.

Asthma is one of the most common diseases complicating pregnancy and a risk factor for several maternal and fetal complications, posing a special challenge for physicians treating asthmatic pregnant women. Asthma influences the outcome of pregnancy and - vice versa - pregnancy affects asthma severity with bidirectional immunological interactions that are currently being examined. Supporting pregnancy-induced immunotolerance is the observation that attenuation of allergic responses can be detected in controlled asthmatic pregnant patients. However, uncontrolled asthmatic pregnant women show significant asthma-associated immune reactions, such as diminished pregnancy specific regulatory T cell proliferation, that may - besides other factors - influence fetal growth. Uncontrolled, symptomatic asthma may increase the risk of adverse perinatal outcomes; thus adequate regular anti-asthmatic treatment resulting in optimal asthma control represents a vital need during pregnancy. This review summarizes immunological changes characterizing pregnancy in asthmatic women together with the clinical implications of asthma management during pregnancy.

The ventilatory management of patients with acute respiratory failure is supported by good evidence, aiming to reduce lung injury by pressure limitation and reducing the duration of ventilatory support by regular assessment for discontinuation. Certain patient groups, however, due to their altered physiology or disease-specific complications, may require some variation in usual ventilatory management. The present manuscript reviews the ventilatory management in three special populations, namely the patient with brain injury, the pregnant patient and the morbidly obese patient.

  • G.W. Archer Jr
  • G.F. Marx

The decrease in arterial oxygen tension, during 60 sec of apnea with exposure to room air, was studied in twelve healthy parturient women undergoing Caesarean section under endotracheal fluoroxene oxygen anaesthesia. Eight young gynecological patients, anaesthetized in an identical manner, served as controls. The reduction in oxygen tension was significantly greater in the pregnant women than in the controls and was greatest in women in labour. The results confirm the presence of a markedly increased oxygen consumption at term and emphasize the importance in obstetric anaesthesia of preoxygenation before and of prompt reoxygenation following endotracheal intubation.

  • Frank Dibrell Sutton Frank Dibrell Sutton

10 patients with the Pickwickian syndrome characterized by obesity hypoxemia hypercapnia polycythemia and cor pulmonale underwent long-term treatment as outpatients with (MPA) medroxyprogesterone acetate. Although there was no significant weight change in the group PaO2 rose 12.6 +or- 2.7 mm Hg (SEM) from 49 +or- 2.6 mm Hg to 62 +or-2.3 mm Hg (P<0.001) while PaCO2 fell 13 +or- 2.6 mm Hg from 51 +or- 1.9 mm Hg to 38 +or- 1.2 mm Hg (P<0.001). Hematocrit fell from 56 +or- 2.5% to 50 +or- 1.2% a mean fall of 6% (P<0.01) duringMPA therapy. In the 2 patients who had cardiac catheterization before and during MPA therapy mean pulmonary arterial pressure fell 13 and 19 mm Hg. There were no recurrences of cor pulmonale during treatment. These effects on arterial blood gas values and clinical state were sustained during therapy. On withdrawal of MPA during a 1-month period arterial oxygen and carbon dioxide tensions deteriorated to their previous pretreatment values. Reinstitution of MPA caused improvement in both the oxygen and carbon dioxide tensions. We conclude that sublingual MPA therapy is useful in the management of the Pickwickian syndrome. (authors)

This article reviews the respiratory functional changes that accompany pregnancy. Pregnancy induces 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 prostenoids, 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 rib cage 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 relatively 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.23, 44, 86 and 88

  • A. B. Alaily Clinical Tutor and Honorary Senior Registrar in Obstetrics and Gynaecology
  • K. B. Carr

Serial tests of ventilatory function were made in 38 normal primigravidae during and after pregnancy. During pregnancy all patients showed major changes in tidal volume, functional residual capacity and residual volume. Minor changes were found in many other measurements, all of which occurred at an early stage of pregnancy. Most of the obvious alterations cannot be accounted for adequately by mechanical disturbance from the gravid uterus.

  • Kuddusi Gazioglu
  • Nolan L. Kaltreider
  • Mortimer Rosen
  • Paul N. Yu

Pulmonary function studies were carried out during pregnancy in 8 normal women, in 8 patients with valvular (either mitral or aortic) heart disease, and in 8 patients with chronic pulmonary disease (either emphysema or sarcoidosis). In healthy pregnant women, changes in lung volumes and maximal expiratory flow rates were not significant. Diffusing capacity tended to decrease associated with unchanged pulmonary capillary blood volume. In patients with valvular heart disease, ventilation and oxygen consumption increased toward the term. The patients with mitral valve lesions showed a significant decrease in diffusing capacity with an increase in pulmonary capillary blood volume. In patients wth emphysema, characteristic changes were increasing obstructive functional abnormalities associated with an increase in pulmonary diffusing capacity and pulmonary capillary blood volume. None of these patients, however, had clinical evidence of deterioration of their disease. Patients with sarcoidosis had no appreciable alteration in pulmonary function tests. The influence of various factors, such as increased ovarian hormones, ventilation-perfusion relationships, intra-abdominal distension, and cardiac haemodynamics, are discussed in relation to the change in pulmonary diffusing capacity and pulmonary capillary blood volume. From the standpoint of pulmonary function studies we think that patients with mitral heart disease and those with pulmonary emphysema tolerate pregnancy less favourably than normal subjects and patients with sarcoidosis.