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Clinical Pharmacology During Pregnancy
Clinical Pharmacology
During Pregnancy
Second Edition
Edited by
Donald R. Mattison
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Academic Press in an imprint of Elsevier
Clinical Pharmacology
During Pregnancy
Second Edition
Edited by
Donald Mattison
University of South Carolina,
Arnold School of Public Health,
Columbia, SC, United States
Risk Sciences International, Ottawa, ON, Canada
School of Epidemiology and Public Health,
University of Ottawa, Ottawa, ON, Canada
Lee-Ann Halbert
Associate Professor of Nursing
University of South Carolina
Beaufort, Bluffton
SC, United States
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This book is dedicated to all the individuals who have added to
and benefit from the collective knowledge and wisdom presented
within this book. The chapter authors share their insights with the
express goal of helping health care practitioners and their clients
make the best clinical decisions when it comes to the use of
medications in pregnancy.
This page intentionally left blank
Contributors
Mahmoud Abdelwahab
Ohio State University, Columbus, OH, United States
Mahmoud S. Ahmed
Department of Obstetrics & Gynecology, University of Texas Medical Branch,
Galveston, TX, United States
Sarah Armstrong
Frimley Park Hospital, Surrey, United Kingdom
Cheston M. Berlin, Jr.
Department of Pediatrics/Division of Academic General Pediatrics, Penn State
College of Medicine, Penn Statae Children’s Hospital, Hershey, PA, United States
Brookie M. Best
University of California, Skaggs School of Pharmacy and Pharmaceutical
Sciences, San Diego, CA, United States
Carolyn Bottone-Post
University of Northern Colorado, Greeley, CO, United States
Shannon M. Clark
Department of ObGyn, Division of Maternal-Fetal Medicine, University of Texas
Medical Branch-Galveston, Galveston, TX, United States
Maged M. Costantine
Ohio State University, Columbus, OH, United States
Kala R. Crobarger
Tanner Health System School of Nursing, University of West Georgia, Carrollton,
GA, United States
Cara D. Dolin
Department of Obstetrics and Gynecology, University of Pennsylvania, Perelman
School of Medicine, Philadelphia, PA, United States
Jeffrey W. Fisher
Division of Biochemical Toxicology, National Center for Toxicological Research,
Food and Drug Administration, Jefferson, AR, United States; ScitoVation, LLC,
Durham, NC, United States
David A. Flockhart
Indiana University School of Medicine, Indianapolis, IN, United States
Jeffrey S. Fouche-Camargo
School of Health Sciences, Georgia Gwinnett College, Lawrenceville, GA, United
States
xxi
xxii Contributors
William D. Fraser
Department of Obstetrics and Gynecology, Université de Sherbrooke,
Sherbrooke, QC, Canada
Jennifer L. Grasch
David M. Haas
Lee-Ann Halbert
University of South Carolina Beaufort, Bluffton, SC, United States
Isabelle Hardy
Department of Obstetrics and Gynecology, Université de Sherbrooke,
Sherbrooke, QC, Canada
Carmen V. Harrison
School of Nursing, Simmons University, Boston, MA, United States
Mary F. Hebert
Departments of Pharmacy and Obstetrics & Gynecology, University of
Washington, Seattle, WA, United States
Henry M. Hess
Emeritus Professor of Obstetrics and Gynecology, University of Rochester School
of Medicine, Rochester, NY
Janelle Komorowski
Department of Nurse-midwifery, Frontier Nursing University, Versailles, KY,
United States
Miao Li
Food and Drug Administration, Jefferson, AR, United States
Megan Lutz
University of Wisconsin School of Medicine and Public Health, Department of
Medicine, Madison, WI, United States
Donald R. Mattison
University of South Carolina, Arnold School of Public Health, Columbia, SC,
United States; Risk Sciences International, Ottawa, ON, Canada; School of
Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada
Contributors xxiii
Darshan Mehta
Food and Drug Administration, Jefferson, AR, United States
Jeremiah D. Momper
University of California, Skaggs School of Pharmacy and Pharmaceutical
Sciences, San Diego, CA, United States
Luis A. Monsivais
Department of ObGyn, Division of Maternal-Fetal Medicine, University of Texas
Medical Branch-Galveston, Galveston, TX, United States
Jennifer A. Namazy
Scripps Clinic, San Diego, CA, United States
Luis Pacheco
University of Texas Medical Branch, Galveston, TX, United States
Maria P. Ramirez-Cruz
Department of Obstetrics and Gynecology, University of New Mexico School of
Medicine, Albuquerque, NM, United States
William F. Rayburn
Obstetrics and Gynecology, University of New Mexico School of Medicine,
Albuquerque, NM, United States
Michael D. Reed
Professor Emeritus of Pediatrics, Department of Pediatrics, School of Medicine,
Case Western Reserve University, Cleveland, United States
Sharon E. Robertson
Department of Obstetrics and Gynecology, Indiana University School of
Medicine, Indianapolis, IN, United States
Erik Rytting
Department of Obstetrics & Gynecology, University of Texas Medical Branch,
Rachel Ryu
Department of Pharmacy, University of Washington, Seattle, WA, United States
Sumona Saha
University of Wisconsin School of Medicine and Public Health, Department of
Medicine, Madison, WI, United States
Michael Schatz
Kaiser Permanente, San Diego, CA, United States
xxiv Contributors
Jeanne M. Schilder
Department of Obstetrics and Gynecology, Indiana University School of
Medicine, Indianapolis, IN, United States
Steven A. Seifert
Department of Emergency Medicine, University of New Mexico School of
Medicine, Albuquerque, NM, United States; Medical, New Mexico Poison and
Drug Information Center, Clinical Toxicology, Albuquerque, NM, United States
Harry Soljak
Frimley Park Hospital, Surrey, United Kingdom
Kimberly K. Trout
Department of Family and Community Health, University of Pennsylvania, School
of Nursing, Philadelphia, PA, United States
Jennifer Waltz
School of Medicine, University of Texas Medical Branch, Galveston, TX, United
States
Xiaoxia Yang
Division of Infectious Disease Pharmacology, Center for Drug Evaluation and
Research, Food and Drug Administration, Silver Spring, MD, United States
Andrew Youmans
University of Michigan School of Nursing, MI, United States
Acknowledgment
Although each chapter author is acknowledged by having his/her/their name

associated with the chapters, the timing of this book necessitates an additional thank
you to each author. Research and writing for this book started before anyone was
aware that a pandemic would change the world and raise concerns about therapeutic
interventions during pregnancy.
As the authors became involved with the challenges of working in healthcare, a
world turned upside downdlong hours in uncertain times, isolation, trying to
understand and predict the impact of coronavirus on pregnancy, shortages of
equipment and staff, and countless other trials of the timesdthe authors continued
their research and writing for these chapters.
Under normal times, completing a book chapter takes dedication and commit-
ment, and during pandemic, it goes beyond measure. For this, we are appreciative.
xxv
CHAPTER
Introduction
1
1
Donald R. Mattison1, 2, 3, Lee-Ann Halbert 4
University of South Carolina, Arnold School of Public Health, Columbia, SC, United States;
2
Risk Sciences International, Ottawa, ON, Canada; 3School of Epidemiology and Public Health,
University of Ottawa, Ottawa, ON, Canada; 4University of South Carolina Beaufort, Bluffton,
SC, United States
Over the past decade, attention to clinical therapeutics during pregnancy has grown
substantially [1e3]. Examples of these advances are summarized in many different
chapters in this edition Despite these advances, there is increasing concern that
discovery and development of new drugs for these important populations is lagging
[4e9]. For example, while there are many advances in treating depression and mood
disorders, we are still struggling with questions concerning whether these diseases
should be treated during pregnancy [Chapter 14]. Clearly, select populations are
excluded from drug development, especially women and children [5,10e12]. One
consequence of this failure to develop drugs for maternal and child health is to disso-
ciate therapeutic opportunities for women and children from the drugs and treat-
ments currently available. This distancing of women and children from drug
development and therapeutic knowledge produces a host of clinical challenges for
the concerned practitioner. In the absence of sufficient therapeutic knowledge,
appropriate dosing is not known [[13e17], see Chapter 26]. Without the understand-
ing of appropriate dosing, the clinician does not know if the dose recommended on
the product label will produce the desired drug concentration at the site of action, or
if the concentration produced will be above or below the needed concentration,
producing toxicity or inadequate response, respectively. Similarly, without thought-
ful therapeutic development in women and children, it is not known if differences in
pharmacodynamics will produce different treatment goals and needs for monitoring
effectiveness and safety [14,18e21].
A consequence of the failure to develop drugs for use in pregnancy is that most
drugs are not tested for use during pregnancy [4,22]; consequently, labeling, which
may include extensive information about fetal safety [10,23], includes nothing about
dosing, appropriate treatment, efficacy, or maternal safety [3e5,10,11,22,23]. Yet,
these are concerns of health care providers considering treatment during pregnancy.
Therefore, the practitioner treats the pregnant woman with the same dose recom-
mended for use in adults (typically men) or may decide not to treat the disease at
all. However, is the choice of not treating a woman during pregnancy better than
dealing with the challenges which accompany treatment? Clearly, treatment of
Clinical Pharmacology During Pregnancy. https://doi.org/10.1016/B978-0-12-818902-3.00012-9 1

2 CHAPTER 1 Introduction
depression poses risks for both mother and fetus, as does stopping treatment
[24e26]. This is also the case with respect to influenza during pregnancy
[13,27,28]. All combined, the state of therapeutics during pregnancy underscores
the continued tension that exists between maternaleplacentalefetal health and
maternal quality of life during pregnancy and the lack of critical study of “gesta-
tional therapeutics.” This book hopes to address many of these imbalances.
A second and equally important aspect of this edition is the focus on collabora-
tive practice. Physicians and their students, nurses (advanced practice and gener-
alist) and their students, and physician assistants (and their students) are all
involved in the care of the pregnant woman. The American College of Nurse-
Midwives and the American College of Obstetricians and Gynecologists formalized
support of the collaborative practice between midwives and physicians in statements
dating back to 2011 [29]. The American College of Obstetricians and Gynecologists
2016 Executive Summary on collaborative practice extends interdisciplinary prac-
tice support to include not only physicians and nurses but also pharmacists and
physician assistants [30]. This edition reflects this goal of collaborative practice,
with an editorial team comprised of a physician and certified nurse-midwife.
Medical and health care providers caring for women during pregnancy have
many excellent resources describing the safety of medications for the fetus
[10,23]. However, none of these references provide information on appropriate
dosing as well as the efficacy of the various medications used during pregnancy
for maternal/placental therapeutics. We are all familiar with the potential/actual
costs, financial and psychosocial, of having treatments which produce develop-
mental toxicity; however, how many of us ever think critically about the costs of
having inadequate therapeutic options to treat the major diseases of pregnancy,
growth restriction, pregnancy loss, and preeclampsia/eclampsia? Where we have
effective treatments for maternal diseases, infection, depression, diabetes, and
hypertension, we are recognizing that continuation of treatment during pregnancy
carries benefit for mother, placenta, and baby. In the end what is important for the
mother, baby, and family is the appropriate balancing of benefit and riskdas indeed
is the important balancing for all clinical therapeutics [11,12]. This book provides
medical and health professionals involved in the care of pregnant women with
contemporary information on clinical pharmacology for pregnancy. It covers an
overview of the impact of pregnancy on drug disposition, summarizing current
research about the changes of pharmacokinetics and pharmacodynamics during
pregnancy. This is followed by specific sections on the treatment, dosing, and clin-
ical effectiveness of medications during pregnancy, providing health care providers
with an essential reference on how to appropriately treat women with medications
during pregnancy. At one level, the question is simple: how to treat, how to monitor
for benefit and risk, or how to know if treatment is successful? This book was devel-
oped to explore that question for women during pregnancy. The book is meant to be
a guide to clinicians who care for women during pregnancy. We hope the busy
clinician and student of obstetrics will find this a useful guide.
References 3
References
[1] Zajicek A, Giacoia GP. Obstetric clinical pharmacology: coming of age. Clin Pharma-
col Ther 2007;81(4):481e2.
[2] Schwartz JB. The current state of knowledge on age, sex, and their interactions on clin-
ical pharmacology. Clin Pharmacol Ther 2007;82(1):87e96.
[3] Kearns GL, Ritschel WA, Wilson JT, Spielberg SP. Clinical pharmacology: a discipline
called to action for maternal and child health. Clin Pharmacol Ther 2007;81(4):463e8.
[4] Malek A, Mattison DR. Drug development for use during pregnancy: impact of the
placenta. Expet Rev Obstet Gynecol 2010;5(4):437e54.
[5] Thornton JG. Drug development and obstetrics: where are we right now? J Matern Fetal
Neonatal Med 2009;22(Suppl. 2):46e9.
[6] Woodcock J, Woosley R. The FDA critical path initiative and its influence on new drug
development. Annu Rev Med 2008;59:1e2.
[7] The PME. Drug development for maternal health cannot be left to the whims of the
market. PLoS Med 2008;5(6):e140.
[8] Hawcutt DB, Smyth RL. Drug development for children: how is pharma tackling an
unmet need? IDrugs 2008;11(7):502e7.
[9] Adams CP, Brantner VV. Estimating the cost of new drug development: is it really $802
million? Health Aff 2006;25(2):420e8.
[10] Lo WY, Friedman JM. Teratogenicity of recently introduced medications in human
pregnancy. Obstet Gynecol 2002;100(3):465e73.
[11] Fisk NM, Atun R. Market failure and the poverty of new drugs in maternal health. PLoS
Med 2008;5(1):e22.
[12] Thornton J. The drugs we deserve. BJOG 2003;110(11):969e70.
[13] Beigi RH, Han K, Venkataramanan R, Hankins GD, Clark S, Hebert MF, et al. Pharma-
cokinetics of oseltamivir among pregnant and nonpregnant women. Am J Obstet
Gynecol 2011;204(6 Suppl. 1):S84e8.
[14] Rothberger S, Carr D, Brateng D, Hebert M, Easterling TR. Pharmacodynamics of
clonidine therapy in pregnancy: a heterogeneous maternal response impacts fetal
growth. Am J Hypertens 2010;23(11):1234e40.
[15] Eyal S, Easterling TR, Carr D, Umans JG, Miodovnik M, Hankins GD, et al. Pharma-
cokinetics of metformin during pregnancy. Drug Metab Dispos 2010;38(5):833e40.
[16] Hebert MF, Ma X, Naraharisetti SB, Krudys KM, Umans JG, Hankins GD, et al. Are we
optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for
better clinical practice. Clin Pharmacol Ther 2009;85(6):607e14.
[17] Andrew MA, Easterling TR, Carr DB, Shen D, Buchanan ML, Rutherford T, et al.
Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage
strategies. Clin Pharmacol Ther 2007;81(4):547e56.
[18] Na-Bangchang K, Manyando C, Ruengweerayut R, Kioy D, Mulenga M, Miller GB,
et al. The pharmacokinetics and pharmacodynamics of atovaquone and proguanil for
the treatment of uncomplicated falciparum malaria in third-trimester pregnant
women. Eur J Clin Pharmacol 2005;61(8):573e82.
[19] Hebert MF, Carr DB, Anderson GD, Blough D, Green GE, Brateng DA, et al. Pharma-
cokinetics and pharmacodynamics of atenolol during pregnancy and postpartum. J Clin
Pharmacol 2005;45(1):25e33.
4 CHAPTER 1 Introduction
[20] Meibohm B, Derendorf H. Pharmacokinetic/pharmacodynamic studies in drug product

development. J Pharmacol Sci 2002;91(1):18e31.
[21] Lu J, Pfister M, Ferrari P, Chen G, Sheiner L. Pharmacokinetic-pharmacodynamic
modelling of magnesium plasma concentration and blood pressure in preeclamptic
women. Clin Pharmacokinet 2002;41(13):1105e13.
[22] Feghali MN, Mattison DR. Clinical therapeutics in pregnancy. J Biomed Biotechnol
2011;2011:783528.
[23] Adam MP, Polifka JE, Friedman JM. Evolving knowledge of the teratogenicity of med-
ications in human pregnancy. Am J Med Genet C Semin Med Genet 2011;157(3):
175e82.
[24] Markus EM, Miller LJ. The other side of the risk equation: exploring risks of untreated
depression and anxiety in pregnancy. J Clin Psychiatr 2009;70(9):1314e5.
[25] Marcus SM, Heringhausen JE. Depression in childbearing women: when depression
complicates pregnancy. Prim Care 2009;36(1):151e65 [ix].
[26] Marcus SM. Depression during pregnancy: rates, risks and consequences e Motherisk
Update 2008. Can J Clin Pharmacol 2009;16(1):e15e22.
[27] Mirochnick M, Clarke D. Oseltamivir pharmacokinetics in pregnancy: a commentary.
Am J Obstet Gynecol 2011;204(6 Suppl. 1):S94e5.
[28] Greer LG, Leff RD, Rogers VL, Roberts SW, McCracken Jr GH, Wendel Jr GD, et al.
Pharmacokinetics of oseltamivir according to trimester of pregnancy. Am J Obstet
Gynecol 2011;204(6 Suppl. 1):S89e93.
[29] Statement of policy: joint statement of practice relations between obstetrician-
gynecologists and certified nurse-midwives/certified midwives, vol. 129; 2017. p.
e117ee122.
[30] Executive summary: collaboration in practice: implementing team-based care. Obstet
Gynecol 2016;127:612e7.
CHAPTER
Physiologic changes
during pregnancy
1
Mahmoud Abdelwahab1, Maged M. Costantine1, Luis Pacheco2
2
Ohio State University, Columbus, OH, United States; 2University of Texas Medical Branch,
2.1 Physiologic changes during pregnancy

Human pregnancy is characterized by profound anatomic and physiologic changes
that affect virtually all systems and organs in the body. Many of these changes begin
in early gestation. Understanding of the various physiologic adaptations in preg-
nancy is vital to the clinician and the pharmacologist as many of these alterations
will have a significant impact on pharmacokinetics and pharmacodynamics of
different therapeutic agents. A typical example involves the increase in glomerular
filtration rate (GFR) during pregnancy leading to increased clearance of heparins,
thus requiring the use of higher doses during pregnancy. This chapter discusses
the most relevant physiologic changes that occur during human gestation.
2.2 Cardiovascular system

Profound changes in the cardiovascular system characterize human pregnancy and
are likely to affect the pharmacokinetics of different pharmaceutical agents.
Table 2.1 summarizes the main cardiovascular changes during pregnancy.
Cardiac output (CO) increases by 30%e50% during pregnancy, secondary to an
increase in both heart rate and stroke volume; the increase in CO in early pregnancy
is thought to be mainly mediated by an increase in stroke volume, whereas later in
gestation the increase is attributed to elevated heart rate [1]. Most of the increase in
CO occurs early in pregnancy such that by the end of the first trimester 75% of the
increase has already occurred. In addition, CO is expected to be 15% more in a twin
pregnancy compared to a singleton [2]. CO plateau at 28e32 weeks and afterward
remains relatively stable until delivery. At 32 weeks, CO increased to about 7.21
l/min vs 4.88 l/min prior to conception [3].
As CO increases, pregnant women experience a significant decrease in both
systemic and pulmonary vascular resistances [4]. Systemic vascular resistance
decreases in early pregnancy, reaching a nadir (5e10 mm below baseline) at 14e
24 weeks. Subsequently, vascular resistance starts rising, progressively approaching
the prepregnancy value at term [4]. Blood pressure tends to fall toward the end of the
Clinical Pharmacology During Pregnancy. https://doi.org/10.1016/B978-0-12-818902-3.00008-7 5

6 CHAPTER 2 Physiologic changes during pregnancy
Table 2.1 Summary of cardiovascular changes during pregnancy.

Variable Change
Mean arterial pressure No significant change
Central venous pressure No change
Pulmonary arterial occlusion No change
pressure
Systemic vascular Decreased by 21% (nadir at 14e24 weeks)
resistance
Pulmonary vascular Decreased by 34%
resistance
Heart rate Increased by 10e20 bpm maximum in third trimester
Stroke volume Increases to a maximum of 85 mL at 20 weeks of
gestation
Colloid osmotic pressure Decreased by 14% (associated with a decrease in serum
osmolarity noticed as early as the first trimester of
pregnancy)
Hemoglobin concentration Decreased (maximum hemodilution is achieved
at 30e32 weeks)
first trimester and then rises again in the third trimester to prepregnancy levels [5].
Physiologic hypotension may be present between weeks 14 and 24, likely due to the
decrease in the systemic vascular resistance observed during pregnancy.
Maternal blood volume increases in pregnancy by 40%e50%, reaching
maximum values at 32 weeks [6]. Despite the increase in blood volume, central
filling pressures like the central venous and pulmonary occlusion pressures remain
unchanged secondary to an increase in compliance of the right and left ventricles [7].
The precise etiology of the increase in blood volume is not clearly understood. How-
ever, increased mineralocorticoid activity with water and sodium retention does
occur [8]. Production of arginine vasopressin (resulting in increased water absorp-
tion in the distal nephron) is also increased during pregnancy and thought to further
contribute to hypervolemia. Secondary hemodilutional anemia and a decrease in
serum colloid osmotic pressure (due to a drop in albumin levels) are observed.
Finally, left ventricular wall thickness and left ventricular mass increase by 28%
and 52% above pregnancy values [9]. Despite the multiple changes in cardiovascular
parameters, left ventricular ejection fraction does not appear to change during
pregnancy [10].
The latter physiological changes could have theoretical implications on the phar-
macokinetics of drugs in pregnancy. The increase in blood volume, increased capil-
lary hydrostatic pressure, and decrease in albumin concentrations would be expected
to increase significantly the volume of distribution of hydrophilic substances. In
addition, highly protein-bound compounds may display higher free levels due to
decreased protein binding availability.
2.3 Respiratory system 7
2.3 Respiratory system

The respiratory system undergoes both mechanical and functional changes during
pregnancy. Table 2.2 summarizes these changes.
The sharp increase in estrogen concentrations during pregnancy leads to hyper-
vascularity and edema of the upper respiratory mucosa [11]. These changes result in
an increased prevalence of rhinitis and epistaxis in pregnant individuals. Theoreti-
cally, inhaled medications such as steroids used in the treatment of asthma could
be more readily absorbed in the pregnant patient. Despite this theoretical concern,
however, there is no evidence of increased toxicity with the use of these agents
during pregnancy.
Progesterone acts centrally to increase the sensitivity of respiratory center to car-
bon dioxide [12]. This drives an increase in minute ventilation by 30%e50% sec-
ondary to an increase in tidal volume. As a result of in the increase in ventilation,
there in an increase in the arterial partial pressure of oxygen to 101e105 mmHg
and a diminished arterial partial pressure of carbon dioxide (PaCO2), with normal
values of PaCO2 of the range 28e31 mmHg during pregnancy. This decrement al-
lows for a gradient to exist between the PaCO2 of the fetus and the mother so that
carbon dioxide can diffuse freely from the fetus into the mother through the placenta
and then be eliminated through the maternal lungs. Of note, maternal respiratory rate
remains unchanged during pregnancy [13].
The normal maternal arterial blood pH in pregnancy is between 7.4 and 7.45,
consistent with a mild respiratory alkalosis. The latter is partially corrected by an
Table 2.2 Summary of respiratory changes during pregnancy.

Variable Change
Tidal volume Increased by 30%e50% (increase starts as early as the first
trimester)
Respiratory rate No change
Minute ventilation Increased by 30%e50% (increase starts as early as the first
trimester)
Partial pressure of Increased (increase starts as early as the first trimester)
oxygen
Partial pressure of carbon Decreased (decrease starts as early as the first trimester)
dioxide
Arterial pH Slightly increased (increase starts as early as the first
trimester)
Vital capacity No change
Functional residual Decreased by 10%e20% (predisposes pregnant patients to
capacity hypoxemia during induction of general anesthesia)
Total lung capacity Decreased by 4%e5% (maximum diaphragmatic elevation
happens during the third trimester of pregnancy)
increased renal excretion of bicarbonate to allow for a normal serum bicarbonate

between 18 and 21 meq/L during gestation [14]. As pregnancy progresses, the
increased intraabdominal pressure (likely secondary to uterine enlargement, bowel
dilation, and third-spacing of fluids into the peritoneal cavity secondary to decreased
colloid osmotic pressure) displaces the diaphragm upward by 4e5 cm leading to alve-
olar collapse in the bases of the lungs. Bibasilar atelectasis results in a 10%e20%
decrease in the functional residual capacity and increased right to left vascular shunt
[15,16]. The decrease in expiratory reserve volume is coupled with an increase in
inspiratory reserve volume. As a result, no change is seen in the vital capacity [15].
An increase in the transverse diameter of the rib cage occurs to accommodate the
upward shit of the diaphragm due to the enlarging gravid uterus and upward
displacement of intraabdominal contents, in order to allow space for the lung and
preserve total lung capacity. The average subcostal angle of the ribs at the xiphoidal
level increases from 68.5 degrees at the beginning of pregnancy to 103.5 degrees at
term [17].
Changes in respiratory physiology may impact the pharmacokinetics of certain
drugs. Topical drugs administered into the nasopharynx and upper airway could
be more readily available to the circulation as local vascularity and permeability
of the mucosa are increased. As discussed earlier, the latter assumption is theoret-
ical, and no evidence of increased toxicity from inhaled or topical agents during
pregnancy has been demonstrated.
2.4 Renal system

Numerous physiologic changes occur in the renal system during pregnancy. These
changes are summarized in Table 2.3.
The relaxing effect of progesterone on smooth muscle and mechanical effects of
the enlarging uterus leads to dilation of the urinary tract with subsequent urinary sta-
sis. It is estimated that the dilated collecting system seen in pregnancy can hold
200e300 mL of urine [18]. Hydronephrosis affects 43%e100% of pregnant women
and is more prevalent with advancing gestation. However, studies have shown that
exogenous administration of progesterone in nonpregnant women fails to cause
hydronephrosis. The changes observed in the urinary tract predispose pregnant
women to infectious complications, most notably urinary tract infections [19].
The 50% increase in renal blood flow during early pregnancy leads to a parallel
increase in the GFR of approximately 50%. This massive elevation in GFR is present
as early as 14 weeks of pregnancy [20]. As a direct consequence of increased GFR,
creatinine clearance increases and serum values of creatinine and blood urea nitro-
gen decrease. In fact, a serum creatinine above 0.8 mg/dL may be indicative of un-
derlying renal dysfunction during pregnancy.
Besides detoxification, one of the most important functions of the kidney is to
regulate sodium and water metabolism. Progesterone favors natriuresis, while
2.4 Renal system 9
Table 2.3 Summary of renal changes during pregnancy.

Variable Change
Renal blood flow Increased by 50%. Increase noticed as early as 14 weeks
of gestation
Glomerular filtration rate Increased by 50%. Increase noticed as early as 14 weeks
of gestation
Serum creatinine Decreased (normal value is 0.5e0.8 mg/dL during
pregnancy)
Renineangiotensine Increased function leading to sodium and water retention
aldosterone system noticed from early in the first trimester of pregnancy
Total body water Increased by up to 8 L. 6 L gained in the extracellular
space and 2 L in the intracellular space
Ureterebladder muscle tone Decreased secondary to increases in progesterone.
Smooth muscle relaxation leads to urine stasis with
increased risk for urinary tract infections
Urinary protein excretion Increased secondary to elevated filtration rate. Values up
to 260 mg of protein in 24 h are considered normal in
pregnancy
Serum bicarbonate Decreased by 4e5 meq/L. Normal value in pregnancy is
18e22 meq/L (24 meq/L in nonpregnant individuals)
estrogen favors sodium retention [21]. Although the increase in GFR leads to more
sodium wasting, it is counterbalanced by an elevated level of aldosterone which re-
absorbs sodium in the distal nephron [21]. Relaxin may also play a role in water
retention since it stimulates ADH production in animal studies and is normally
elevated in pregnancy [22]. The net effect during pregnancy is a state of avid water
and sodium retention leading to a significant increase in total body water with up to
6 L of fluid gained in the extracellular space and 2 L in the intracellular space. This
“dilutional effect” leads to a mild decrease in both serum sodium (concentration of
135e138 meq/L) and serum osmolarity (normal value in pregnancy w280 mOsm/
L) [23]. In comparison, in the nonpregnant state, normal serum osmolarity is
286e289 mOsm/L with a concomitant normal serum sodium concentration of
135e145 meq/L.
Changes in renal physiology have profound repercussions on drug pharmacoki-
netics. Agents cleared renally are expected to have shorter half-lives, and fluid reten-
tion is expected to increase the volume of distribution of hydrophilic agents. A
typical example involves lithium. Lithium is mainly cleared by the kidney, and dur-
ing the third trimester of pregnancy, clearance is doubled compared to the nonpreg-
nant state [24]. However, not all renally cleared medications undergo such dramatic
increases in excretion rates. For example, digoxin clearance is only increased by
30% during the third trimester of pregnancy.
2.5 Gastrointestinal system

The gastrointestinal tract is significantly affected during pregnancy secondary to
progesterone-mediated inhibition of smooth muscle motility [25]. Table 2.4 summa-
rizes these changes.
Gastric emptying and small bowel transit time are considerably prolonged during
pregnancy. The increase in intragastric pressure (secondary to delayed emptying and
external compression from the gravid uterus) together with a decrease in resting
muscle tone of the lower esophageal sphincter favors gastroesophageal regurgita-
tion. Of note, studies have shown that gastric acid secretion is not affected during
pregnancy [26]. However, overall gastric acidity might be increased due to increased
serum levels of gastrin [27]. Finally, constipation commonly affects pregnant
women and is multifactorial in nature. The combination of increased bowel transit
time, mechanical obstruction by gravid uterus, decreased maternal activity,
decreased motilin, increased colonic water and sodium absorption, and routine
iron supplementation all contribute to constipation in pregnancy [28].
Conflicting data exist regarding liver blood flow during pregnancy. Recently,
with the use of Doppler ultrasonography, investigators found that blood flow in
the hepatic artery does not change during pregnancy, but portal venous return to
the liver was increased [29].
Most of the liver function tests are not altered. Specifically, serum transaminases,
bilirubin, lactate dehydrogenase, and gamma-glutamyl transferase are all unaffected
by pregnancy. Serum alkaline phosphatase is elevated secondary to production from
the placenta and levels two to four times higher than that of nonpregnant individuals
may be seen [30]. Other liver products that are normally elevated include
serum cholesterol, fibrinogen, and most of the clotting factors, ceruloplasmin,
Table 2.4 Summary of gastrointestinal changes during pregnancy.

Variable Change
Gastric emptying time Prolonged, increasing the risk of aspiration in pregnant
women. Intragastric pressure is also increased
Gastric acid secretion Unchanged
Liver blood flow Unchanged in the hepatic artery; however, more venous
return in the portal vein has been documented with
ultrasound Doppler studies
Liver function tests No change during pregnancy except for alkaline
phosphatase (increases in pregnancy secondary to
placental contribution)
Bowel/gallbladder motility Decreased, likely secondary to smooth muscle
relaxation induced by progesterone
Pancreatic function enzymes Unchanged
(amylase and lipase)
2.6 Hematologic and coagulation systems 11
thyroid-binding globulin, and cortisol-binding globulin (CBG). The observed

increase in all of these proteins is likely estrogen mediated [30]. Progesterone, on
the other hand, decreases gallbladder motility rendering the pregnant woman at
increased risk for cholelithiasis.
These observed physiologic changes can clearly affect pharmacokinetics of
orally administered agents, with delayed absorption and onset of action resulting.
For example, the pharmacokinetics of antimalarial agents undergo significant
changes at the gastrointestinal level during pregnancy that could decrease their
therapeutic efficacy [31].
2.6 Hematologic and coagulation systems

Pregnancy is associated with an increased white cell count, mainly consisting of an
increase in neutrophils. On the contrary, lymphocyte count decreases during the
first and second trimesters with return to baseline in the third trimester. The rise
in white cell count is thought to be related to increased bone marrow granulopoiesis
and may make a diagnosis of infection difficult at times. However, it is usually not
associated with significant elevations in immature forms like bands. There is also an
absolute monocytosis and increase in the monocyte-to-lymphocyte ratio, which is
thought to aid in preventing fetal allograft rejection by infiltrating decidual tissue
at 7e20 weeks of gestation [32].
An increase in red cell mass by 30% during pregnancy is likely secondary to an
increase in renal erythropoietin production. Placental lactogen may also enhance the
effect of erythropoietin on erythropoiesis [32]. This occurs simultaneously with a
much higher (around 45%) increase in plasma volume leading to what is referred
to as “physiologic anemia” of pregnancy which peaks early in the third trimester
(30e32 weeks) [33,34]. This hemodilution is thought to confer maternal and fetal
survival advantage as the patient will lose more dilute blood during delivery. In addi-
tion, the decreased blood viscosity improves uterine perfusion, while the increase in
red cell mass serves to optimize oxygen transport to the fetus. As an example,
patients with preeclampsia, despite having fluid retention, suffer from reduced intra-
vascular volume (secondary to diffuse endothelial injury and resultant third-
spacing), which makes them less tolerant to peripartum blood loss [35,36].
Pregnancy is also associated with changes in the coagulation and fibrinolytic
pathways that favor a hypercoagulable state. Plasma levels of fibrinogen, clotting
factors (VII, VIII, IX, X, and XII), and von Willebrand factor increase during preg-
nancy leading to a hypercoagulable state. Factor XI decreases and levels of
prothrombin and factor V remain the same. Protein C is usually unchanged, but pro-
tein S is decreased in pregnancy. There is no change in the levels of antithrombin III.
The fibrinolytic system is suppressed during pregnancy as a result of increased levels
of plasminogen activator inhibitor (PAI-1) and reduced plasminogen activator levels.
Platelet function remains normal in pregnancy. Routine coagulation screen panel
will show values around normal.
Table 2.5 Hemoglobin values during pregnancy.

Gestational age Mean hemoglobin value (g/dL)
12 weeks 12.2
28 weeks 11.8
40 weeks 12.9
Table 2.6 Summary of hematological changes during pregnancy.

Variable Change
Fibrinogen level Increased (elevation starts in the first trimester of
pregnancy and peaks during the third trimester)
Factors VII, VIII, and X Increased
Von Willebrand factor Increased
Factors II, IX, and V No change
Clotting times (prothrombin and No change
activated partial thromboplastin times)
Protein C, antithrombin III No change
Protein S Decreased. Free antigen levels above 30% in the
second trimester and 24% in the third trimester
are considered normal during pregnancy
Plasminogen activator inhibitor Levels increase 2e3 times leading to a decrease
in fibrinolytic activity
White blood cell count Elevated. This increase results in a “left shift” with
granulocytosis. Increased peaks at 30 weeks of
gestation. May see values of 20,000e30,000/
mm3 during labor
Platelet count No change
This hypercoagulable state predisposes the pregnant patient to a higher risk of

thromboembolism. However, it is also thought to offer survival advantage in mini-
mizing blood loss after delivery [37]. Tables 2.5 and 2.6 summarize some of the most
relevant changes discussed previously.
2.7 Endocrine system

Pregnancy is defined as a “diabetogenic” state. Increased insulin resistance is due
to elevated levels of human placental lactogen, progesterone, estrogen, and
cortisol. Carbohydrate intolerance that occurs only during pregnancy is known
2.7 Endocrine system 13
as gestational diabetes. Most gestational diabetes patients are managed solely with
a modified diet. Approximately 10% of patients will require pharmacological treat-
ment, mainly in the form of insulin, glyburide, or even metformin. Available liter-
ature suggests that glyburide and metformin may be as effective as insulin for the
treatment of gestational diabetes.
Pregnancy is also associated with higher glucose levels following a carbohydrate
load. In contrast, maternal fasting is characterized by accelerated starvation,
increased lipolysis, and faster depletion of liver glycogen storage [38]. This is
thought to be related to the increased insulin resistance state of pregnancy induced
by placental hormones such as human placental lactogen. Pancreatic b-cells undergo
hyperplasia during pregnancy resulting in increased insulin production leading to
fasting hypoglycemia and postprandial hyperglycemia. All of these changes facili-
tate placental glucose transfer, as the fetus is primarily dependent on maternal
glucose for its fuel requirements [39].
Leptin is a hormone primarily secreted by adipose tissues. Maternal serum levels
of leptin increase during pregnancy and peak during the second trimester. Leptin in
pregnancy is also produced by the placenta.
When considering changes in certain endocrine glands during pregnancy, the
thyroid gland faces a particular challenge. Due to the hyperestrogenic milieu,
thyroid-binding globulin (the major thyroid hormone (TH)ebinding protein in
serum) increases by almost 150% from a prepregnancy concentration of
15e16 mg/L to 30e40 mg/L in mid-gestation. This forces the thyroid gland to in-
crease its production of THs to keep their free fraction in the serum constant
[40,41]. The increase in THs production occurs mostly in the first half of gestation
and plateaus around 20 weeks until term.
Other factors that influence THs in pregnancy include a minor thyrotropic action
of human chorionic gonadotropin hormone (hCG), higher maternal metabolic rate as
pregnancy progresses, in addition to increase in transplacental transport of TH to the
fetus early in pregnancy, inactivity of placental type III monodeiodinase (which con-
verts T4 to reverse T3), and in maternal renal iodine excretion.
Although the free fraction of T4 and T3 concentrations declines somewhat dur-
ing pregnancy (but remains within normal values), these patients remain clinically
euthyroid [40,41]. Thyroid-stimulating hormone (TSH) decreases during the first
half of pregnancy secondary to a negative feedback from peripheral THs secondary
to thyroid gland stimulation by hCG. During the first half of pregnancy, the upper
limit of normal value of TSH is 2.5 mIU/L (as compared to 5 mIU/L in the nonpreg-
nant state).
Serum cortisol levels are increased during pregnancy. Most of this elevation is
secondary to increased synthesis of CBG by the liver. Free cortisol levels are also
increased by 30% during gestation.
Serum parathyroid hormone and 1, 25 dihydroxy vitamin D increase to favor an
environment of calcium accumulation in the fetus. The placenta forms a calcium
Table 2.7 Summary of endocrine changes during pregnancy.

Variable Change
Leptin Increases
Free T4 and T3 levels Unchanged
Total T4 and T3 levels Increased secondary to increased levels of thyroid-binding
globulin (TBG) induced by estrogen. This elevation begins as
early as 6 weeks and plateaus at 18 weeks of pregnancy
Thyroid-stimulating Decreases in the first half of pregnancy and returns to normal in
hormone (TSH) the second half of gestation. During the first 20 weeks of
pregnancy, a normal value is between 0.5 and 2.5 mIU/L
Parathyroid hormone Increases to favor calcium accumulation in the fetus (PTH) and
1, 25 dihydroxy vitamin D
Total calcium Decreases
Ionized calcium Unchanged
Prolactin Increases
Total cortisol levels Increased, mainly driven by increased liver synthesis of cortisol-
binding globulin (CBG)
Free serum cortisol Increased by 30% in pregnancy
pump in which a gradient of calcium and phosphorus is established which favors

the fetus. The total level of calcium decreases, but ionized calcium remains the
same [42].
Finally, the anterior pituitary enlarges 2e3-fold in pregnancy primarily due to
hyperplasia and hypertrophy of lactotrophs, which causes increase in serum prolac-
tin as pregnancy progress. The increase in pituitary size is thought to cause hypophy-
seal artery compression and predisposes the pituitary to infarction in cases of
hypotension secondary to postpartum (i.e., Sheehan syndrome) [43]. The endocrine
changes during pregnancy are summarized in Table 2.7.
2.8 Summary
Pregnancy is associated with profound changes in human physiology. Virtually
every organ in the body is affected and the clinical consequences of these changes
are significant. Unfortunately, our knowledge of how these changes affect the phar-
macokinetics and pharmacodynamics of therapeutic agents is still very limited.
Future research involving pharmacokinetics of specific agents during pregnancy is
desperately needed.
References 15
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apparently, in the case of solemn vows of perpetual chastity. It will be
observed that this heaven is moved by the Angels, who are severally
assigned to individuals as guardians, and who are the bearers of
tidings of God’s bounty to men; and, corresponding to this, the
questions solved relate to the salvation and guidance of individual
souls, and to the great gift of liberty, whereby God’s bounty is
specially shown.
The Heaven of Mercury.—In the second sphere, the heaven of
Mercury, appear the souls of those who did great things for humanity
or for special nations, but who were actuated by mixed motives;
personal ambition, desire of fame and honour, made “the rays of true
love mount upwards less vividly” (Par. vi. 117); and they have thus
the next lowest mansion of beatitude to the spirits that appeared in
the inconstant Moon. The Emperor Justinian recites the proud
history of the Roman Eagle, and shows how Divine Providence
established the sway of the Roman people over all the earth, made
the Eagle the instrument of the Atonement offered by Christ for all
mankind, the avenger of His death, the protector of His Church. As
the monarch who reformed and codified Roman Law, of which he is
for Dante the personification, and who restored Italy to the Empire
(the work which the Veltro is to renew under altered conditions of
Christendom), Justinian lifts the imperial ideal far above the factious
politics of the Middle Ages, condemning Guelfs and Ghibellines alike
as traitors and sowers of discord. Here, too, is Romeo of Villanova,
who did in a lesser degree for Provence what Justinian did for the
Empire, thus appearing with him in the sphere that is moved by the
Archangels, whose function is to guide and protect particular nations.
The figure of Romeo—unjustly accused of corrupt practices in office,
supporting with magnanimous heart the poverty and humiliations of
voluntary exile—is perhaps an unconscious portrait of Dante himself.
Even as the Archangels announce messages of special import and
sacredness, as Gabriel did to Mary, so Beatrice explains to Dante
the mystery of man’s redemption by the Incarnation and Crucifixion,
the supremest work at once of Divine Justice and Divine Mercy (Par.
vii.), and touches somewhat upon the immortality of the soul and the
resurrection of the body.
The Heaven of Venus.—The third heaven, the sphere of Venus,
is moved by the celestial Principalities, whose office is to influence
earthly rulers to imitate the principality of God, by uniting love with
their lordship. They are those, according to St. Bernard, “by whose
management and wisdom all principality on earth is set up, ruled,
limited, transferred, diminished, and changed.” Into this sphere
descend the souls of purified lovers, brilliant lights moving circle-wise
and hidden in the rays of their own joy. Carlo Martello, son of
Charles II. of Naples, and son-in-law of Rudolph of Hapsburg, who,
by reason of his marriage with Clemenza, might have healed the
feuds of Guelfs and Ghibellines, pictures the realms over which he
should have ruled, denounces the misgovernment of his own house,
and explains the influence of the celestial bodies for the constitution
of society and the government of states (Par. viii.). Cunizza da
Romano, the famous sister of Ezzelino, rebukes the anarchy of the
March of Treviso; a “modern child of Venus,” she here appears as
the type of a perfect penitent (Par. ix.). Like her, Folco of Marseilles,
poet then prelate, but here recorded only as troubadour, remembers
the love sins of his youth, not with sorrow, but with gratitude to the
Divine Mercy and wonder at the mysteries of Providence. Rahab of
Jericho, the highest spirit of this sphere, is a type of the Church,
saved by Christ’s blood from the ruin of the world; and, with a fine
thrust at the loveless avarice of the Pope and his cardinals, Dante
passes with Beatrice beyond the shadow of the earth.
The Heaven of the Sun.—To mark this higher grade of bliss and
knowledge, Dante pauses on his entrance into the fourth sphere, the
heaven of the Sun, to sing again of the Creation, the work of the
Blessed Trinity, and the order of the Universe, the visible expression
of the perfection of Divine art (Par. x. 1-21). The Sun is ruled by the
celestial Powers, the angelic order that represents the Divine
majesty and power, combats the powers of darkness, and stays
diseases. Here, in two garlands of celestial lights surrounding Dante
and Beatrice, appear the glorious souls of twenty-four teachers and
doctors, who illuminated the world by example and doctrine; the
twofold work of co-operation with the celestial Powers, which is seen
in its supereminent degree in the lives of St. Francis and St.
Dominic, the champions who led the armies of Christ against the
powers of darkness and healed the spiritual diseases of the Christian
world. St. Thomas Aquinas, the great light of the Dominicans, after
naming the other eleven spirits of his circle (Albertus Magnus,
Gratian, Peter Lombard, Solomon, Dionysius, Orosius, Boëthius,
Isidore, Bede, Richard of St. Victor, and Siger), sings the glorious
panegyric of St. Francis, the seraphic bridegroom of Poverty,
laments the backsliding of the Dominicans (Par. xi.). St.
Bonaventura, once minister-general of the Franciscans, extols the
marvellous life of St. Dominic, the cherubical lover of Faith, the great
paladin in Holy Church’s victorious battle where St. Francis bore the
standard of the Crucified (Par. xii.). Lamenting the degenerate state
of the Franciscans, he names the eleven spirits that accompany him;
two of the followers of St. Francis, Illuminato and Agostino; Hugh of
St. Victor; Peter Comestor, Peter of Spain (the logician whose
elevation to the papacy as John XXI. may be ignored in Paradise),
Nathan, Chrysostom, St. Anselm, Aelius Donatus (the Latin
grammarian), Rabanus Maurus, and the Calabrian abbot Joachim.
Lovers of poverty, rebukers of corruption, historians, mystics,
theologians, writers of humble text-books are here associated in the
same glory, as servants of truth in the same warfare against the
powers of darkness. They illustrate what St. Bonaventura calls the
broadness of the illuminative way. Each group closes with a spirit
whose orthodoxy had been at least questioned. Siger of Brabant, the
champion of Averroism at the university of Paris, had “syllogised
invidious truths,” and met with a violent death at the Papal Court at
Orvieto about 1284. Joachim of Flora, “endowed with prophetic
spirit,” had foretold the advent of the epoch of the Holy Ghost, in
which the Everlasting Gospel, the spiritual interpretation of the
Gospel of Christ, would leave no place for disciplinary institutions;
his later followers among the Franciscans had been condemned at
the Council of Anagni in 1256.
St. Thomas further explains to Dante the grades of perfection in
God’s creatures, from the Angels downwards; whereby His Divine
light is more or less imperfectly reflected, and the likeness of the
Divine ideas more or less imperfectly expressed—perfectly only
when the Trinity creates immediately, as in the case of Adam and the
humanity of Christ (Par. xiii.). Solomon, whose peerless wisdom St.
Thomas had explained as “royal prudence,” instructs Dante
concerning the splendour of the body after the resurrection, when
human personality will be completed and the perfection of beatitude
fulfilled (Par. xiv.). In a mysteriously beautiful apparition of what
seems to be another garland of spirits in the Sun, this vision of the
fourth heaven closes; and Beatrice and her lover are “translated to
more lofty salvation” in the glowing red of Mars.
The Heaven of Mars.—The fifth heaven, the sphere of Mars, is
ruled by the angelic Virtues. This is the order which images the
Divine strength and fortitude; their name, according to Dionysius,
signifies “a certain valiant and unconquerable virility.” According to
St. Bernard, they are those “by whose command or work signs and
prodigies are wrought among the elements, for the admonition of
mortals,” and it is through them that the sign of the Son of Man shall
appear in heaven as foretold in the Gospel.[39] Therefore, in Mars,
Dante beholds a great image of the Crucified, blood-red, formed by
stars which are the souls of the warrior saints, whom the Virtues
impressed at their birth with the influence of the planet (Par. xvii. 76-
78), to be strongly and manfully valiant, and to do notable things on
earth (ibid. 92, 93), even as the Virtues, according to St. Bernard,
work signs and prodigies among the elements.
Cacciaguida passes from the right arm of the Cross to greet his
descendant, like Anchises to Aeneas in Elysium. In his long
discourse with the poet (Par. xv. and xvi.) we dimly discern a
splendidly ideal picture of a free Italian commune of the twelfth
century, before what Dante regards as the corrupting influence of
wealth and illegitimate extension of its boundaries had fallen upon it,
and before the hostility of the Church to the Empire, with the
resulting confusion of persons in the city, had involved the
Florentines in the feuds of Guelfs and Ghibellines. Then, having
bitterly lamented the decay of the old Florentine families and the
corruption of their successors, Cacciaguida co-operates with the
Virtues by inspiring Dante with endurance and fortitude to suffer
unjust exile and perform his life’s work (Par. xvii.). In the famous and
most noble lines, to which reference has already been made in
touching upon this epoch of Dante’s life, Cacciaguida foretells the
poet’s banishment, the calumnies of his enemies, his sufferings in
exile, his forming a party to himself, the future greatness of Can
Grande, Dante’s own certainty of eternal fame. And let him be no
timid friend to truth, but make manifest his whole vision, and
especially assail corruption in highest places (cf. Mon. iii. 1). It is
Dante’s apologia for his own life, first as citizen, then as poet. The
keynote of the closing years of his life is struck at the opening of
Canto xviii.: “And that Lady who was leading me to God said:
‘Change thy thought; think that I am near to Him who unburdens
every wrong.’” Gazing upon her, his affection “was free from every
other desire.” Then, with a charge of celestial chivalry across the sky,
this vision of warriors closes; Joshua and Judas Maccabaeus,
Charlemagne and Orlando, William of Orange still with Renoardo,
Godfrey de Bouillon and Robert Guiscard, flash through the Cross,
and are rejoined by Cacciaguida in their motion and their song.
The Heaven of Jupiter.—The silvery white sphere of Jupiter, the
sixth heaven, is ruled by the Dominations, the angelic order which
images the archetypal dominion in God as the source of true
dominion. “We must consider in the Dominations,” writes St.
Bernard, “how great is the majesty of the Lord, at whose bidding
empire is established, and of whose empire universality and eternity
are the bounds.” This, then, is the sphere of ideal government, the
heaven of the planet that effectuates justice upon earth (Par. xviii.
115-117). The souls of faithful and just rulers appear as golden
lights, singing and flying like celestial birds. They first form the text,
Diligite iustitiam que iudicatis terram, “Love justice, you that are the
judges of the earth” (Wisdom, i. 1, Vulgate), tracing successively the
letters until they rest in the final golden M, the initial letter of
Monarchy or Empire, under which alone can justice be paramount on
earth, and then, with further transformations, become the celestial
Eagle (Par. xviii. 100-114). This is the “sign which made the Romans
reverend in the world” (xix. 101); no emblem of material conquest,
but the image of the sempiternal justice of the Primal Will, the type of
dominion on earth ordained by God. It is the allegorical
representation of the doctrines of the Monarchia. And, since justice
is obscured and good government rendered abortive by the simony
of the pastors of the Church, which leads them to oppose the
Empire, Dante has a bitter word in season for the reigning pontiff,
John XXII (Par. xviii. 130-136).
In the perfect concord of its component spirits the Eagle, speaking
with one voice, discourses upon the immutability and absolute justice
of the Divine Will, which is inscrutable and incomprehensible to
mortals (Par. xix.). Having rebuked the wickedness of all the kings
and princes then reigning, from the Emperor-elect (Albert of Austria
in 1300) to the King of Cyprus, it sets forth in contrast to them the
example of just and righteous monarchs and rulers of olden time, the
six noblest of whom now form its eye—David, Trajan, Hezekiah,
Constantine, the Norman William II. of Sicily, and Rhipeus the Trojan
(Par. xx.). Three exquisite lines (73-75)—introduced as a mere
image—render the flight and song of the skylark with a beauty and
fidelity to nature which even Shelley was not to surpass. The
salvation of Trajan, through the prayers of St. Gregory, and Rhipeus,
by internal inspiration concerning the Redeemer to come, unveils yet
more wondrous mysteries in the treasury of Divine Justice, which
suffers itself to be overcome by hope and love. Rhipeus, the justest
among the Trojans and the strictest observer of right (Virgil, Aen. ii.
426, 427; cf. Acts x. 35), by his presence solves Dante’s doubt
concerning the fate of the just heathen who die without baptism, and
indicates that the race which gave the ancestors to the Roman
people was not without Divine light.
Heaven of Saturn.—The last of the seven heavens of the
planets is the sphere of Saturn, over which the Thrones preside.
According to Dionysius, the Thrones are associated with
steadfastness, supermundane tendency towards and reception of
the Divine. They represent, according to St. Bernard, supreme
tranquillity, most calm serenity, peace which surpasses all
understanding; and upon them God sits as judge (cf. Par. ix. 61, 62).
In Saturn appear the contemplative saints, and the monks who kept
firm and steadfast in the cloister. They pass up and down the
celestial Ladder of Contemplation (Par. xxi. and xxii.), the stairway by
which the soul mystically ascends to the consideration of the
impenetrable mysteries of God which transcend all reason. In this
high stage of progress towards the suprasensible Beatrice does not
smile, for Dante’s human intellect could not yet sustain it, and the
sweet symphonies of Paradise are silent. St. Peter Damian
discourses upon the impenetrable mysteries of Divine
predestination, and rebukes the vicious and luxurious lives of the
great prelate and cardinals. St. Benedict describes the foundation of
his own great order, and laments the shameless corruption of
contemporary Benedictines. Thus in this, and, above all, in the cry
like thunder which bursts from the contemplatives at the conclusion
of Peter Damian’s words, threatening the Divine vengeance which is
to fall upon the corrupt pastors of the Church, the saints of the
seventh sphere unite themselves with the celestial Thrones, whose
office is purification, and who are the mirrors of the terrible
judgments of God.
The Gemini.—At Beatrice’s bidding, Dante follows the
contemplatives up the celestial ladder, entering the Firmament at the
sign of the Gemini or Twins, beneath which he was born (Par. xxii.
112-123). To his natal stars, and thus to the Cherubim with whose
virtue they are animated, he appeals for power to complete the work
for which they have inspired him. In a momentary vision, with the
capacity of his inward soul enlarged, he looks down upon the whole
Universe, and estimates aright the relative value of all things in
heaven and earth, now that he is prepared to witness the true glories
of Paradise.
The Stellar Heaven.—The Firmament or stellar heaven, the
eighth sphere, is ruled by the Cherubim, who represent the Divine
Wisdom; it is the celestial counterpart of the Garden of Eden. Here
the fruit of man’s redemption is mystically shown in a vision of the
triumph of Christ, the new Adam, surrounded by myriads of shining
lights which draw their light from Him and represent the souls of the
blessed whom He has sanctified (Par. xxiii.). After Christ has
ascended from this celestial garden, where Mary is the rose and the
Apostles the lilies, the Archangel Gabriel descends with ineffable
melody and attends upon the new Eve, “the living garden of delight,
wherein the condemnation was annulled and the tree of life
planted,”[40] in her Assumption.
The four spheres of the higher planets had set forth a celestial
realisation of the four cardinal virtues, Prudence, Fortitude, Justice,
and Temperance, with perfect man according to the capacity of
human nature; now, in this sphere of the Cherubim whose name
indicates plenitude of the knowledge of God, Dante is examined
upon the three theological virtues, which have God for their object as
He transcends the knowledge of our reason, and which put man on
the way to supernatural happiness. “If we would enter Paradise and
the fruition of Truth,” writes St. Bonaventura, “the image of our mind
must be clothed with the three theological virtues, whereby the mind
is purified, illumined, and rendered perfect, and thus the image is
reformed and made fit for the Jerusalem which is above.” Dante’s
answers to St. Peter upon Faith (Par. xxiv.), to St. James upon Hope
(Par. xxv.), to St. John upon Charity (Par. xxvi.), contain the essence
of the devout wisdom of the schoolmen upon those three divine gifts,
whereby man participates in the Deity, and “we ascend to
philosophise in that celestial Athens, where Stoics and Peripatetics
and Epicureans, by the art of the eternal Truth, harmoniously concur
in one will” (Conv. iii. 14). For the object of Faith and Love alike
Dante, even in Paradise, can appeal to the Metaphysics of Aristotle
(Par. xxiv. 130-132, xxvi. 37-39); and all the celestial music cannot
quite drown the poet’s sigh for that fair Florentine sheepfold, from
which he is still barred out, though Hell and Heaven have opened for
him their eternal gates (Par. xxv. 1-12). Within a fourth light the soul
of Adam appears, to instruct Dante upon the proper cause of his fall
and upon his life in the Earthly Paradise, now that the poet has seen
the triumph and ascent of the new Adam. Adam, in whom was
directly infused all the light lawful to human nature to have (Par. xiii.
43), is the last soul that appears to Dante until the consummation of
the vision in the Empyrean. On the close of his discourse, a hymn of
glory to the Blessed Trinity resounds through Paradise, a laugh of
the Universe in joy of the mystery of Redemption (Par. xxvii. 1-9).
Then, while all Heaven blushes and there is a celestial eclipse as at
the Crucifixion, St. Peter utters a terrible denunciation of the
scandals and corruption in the Papacy and the Church, wherein
Dante, as in the Epistle to the Italian Cardinals, takes his stand as
the Jeremiah of Roman Catholicity.
The Ninth Heaven.—When the saints have returned to their
places in the Empyrean, Dante, after a last look to earth, passes up
with his lady into the ninth sphere, the Crystalline heaven. Beatrice
discourses upon the order of the heavens and the want of
government upon earth, prophesying that, before very long,
deliverance and reformation will come, even as St. Peter had
announced in the sphere below. Here, where nature begins, Dante
has a preparatory manifestation of the nine angelic orders, the
ministers of Divine Providence, who ordain and dispose all things by
moving the spheres. They appear as nine circles of flame, revolving
round an atomic Point of surpassing brilliancy, which symbolises the
supreme unity of God, the poet again having recourse to the
Metaphysics of Aristotle: “From that Point depends heaven and all
nature” (Par. xxviii. 41, 42). Each angelic circle is swifter and more
brilliant as it is nearer to the centre, each hierarchy striving after the
utmost possible assimilation to God and union with Him. Swiftest and
brightest of all are the Seraphim, who move this ninth sphere; the
angelic order that, representing the Divine Love, loves most and
knows most. “In the Angels,” says Colet on Dionysius, “an intensity
of knowledge is love; a less intense love is knowledge.” The relation
of the Seraphim to the Cherubim is that of fire to light; their special
office is perfecting, as that of the Cherubim is illumination. All the
orders contemplate God, and manifest Him to creatures to draw
them to Him. Receiving from God the Divine light and love that
makes them like to Him, the higher orders reflect this to the lower,
like mirrors reflecting the Divine rays; and these lower orders reflect
it to men, so rendering all things, as far as possible to each nature,
like to God and in union with Him. After distinguishing between the
different orders according to Dionysius, Beatrice speaks of their
creation as especially illustrating the Divine Love, which the
Seraphim represent (Par. xxix.), and their place in the order of the
Universe, the fall of the rebellious, the reward of the faithful, and their
immeasurable number. Each Angel belongs to a different species,
and each differs from every other in its reception of Divine light and
love.
The Empyrean.—Dante and Beatrice now issue forth of the last
material sphere into the Empyrean, the true Paradise of vision,
comprehension, and fruition, where man’s will is set at rest in union
with universal Good, and his intellect in the possession of universal
Truth. In preparation for this Divine union, Dante is momentarily
blinded by the Divine light which overpowers him with its radiance—
a blindness followed by a new celestial sight and new faculties for
comprehending the essence of spiritual things. The first empyreal
vision is still a foreshadowing preface: a river of light, the stream
which makes the city of God joyful, the wondrous flowers of celestial
spring, the living sparks of angelic fire. This river of Divine grace is
the fountain of wisdom from which, according to Bernard, the
Cherubim drink, to pour out the streams of knowledge upon all God’s
citizens; and of this fountain Dante, too, drinks with his eyes, that he
may more fully see the vision of God which he has to relate, to
diffuse His knowledge upon earth as the Cherubim do from Heaven.
By the light of glory his mind is rendered capable of seeing those
spiritual things which the blessed behold with immediate intuition,
and of ultimate union with the Divine Essence (Par. xxx. 100-102).
The river seems to change to a circular ocean of light; the saints and
Angels appear in their true forms, all united in the sempiternal Rose
of Paradise. Even at this height of ecstatic alienation from terrestrial
things, Dante can turn in thought to Pope and Emperor who should
be leading men to beatitude; a throne is prepared for Henry in this
convent of white stoles, while the hell of the simoniacs is gaping for
Boniface and Clement.
Eternity, as defined by Boëthius, is “the complete and perfect
simultaneous possession of unlimited life”; and Dante is one who
has come from time to the eternal: a l’etterno dal tempo era venuto
(Par. xxxi. 38).[41] Beatrice has returned to her throne, her allegorical
mission ended; and for this supreme revelation of the Divine beauty
in the mystical Rose, where there is no medium to impede the poet’s
sight of the Divine light (for his is now that of a separated spirit), but
blessed souls and flying Angels are absorbed in love and vision, St.
Bernard completes her work, even as that of Virgil had been
completed by Matelda in the Earthly Paradise. St. Bernard may
represent the glorified contemplative life in our heavenly country, as
Matelda may symbolise the glorified active life in the state of
restored Eden; or, perhaps better, if Matelda is taken as the love
rightly ordered to which the Purgatorio leads, Bernard represents the
loving contemplation or contemplative love, attained by the mystic in
brief moments here and now, in which the eternal and unchanging
life of the soul in the hereafter consists. In an exquisite lyrical inter-
breathing Dante addresses Beatrice for the last time, thanking her
for having led him from servitude to liberty, praying to her for final
perseverance (Par. xxxi. 79-90). Under the guidance of Bernard, he
prepares himself for the vision of the Divine Essence, by disciplining
his spiritual sight in contemplation of the glory of the saints and of
the ineffable beauty of Mary, surrounded by her Angels, and clothed,
as Bernard himself puts it elsewhere, in the Sun by whose fire the
prophet’s lips were cleansed and the Cherubim kindled with love.
Throughout the Rose two descending lines divide the redeemed of
the old law from the redeemed under the new. The one line passes
down from Mary’s throne, composed of holy women, ancestresses of
Christ or types of His Church: Eve, Rachel, Sarah, Rebecca, Judith,
Ruth (Par. xxxii.). With Rachel, in the third row, Beatrice is seated.
The opposite line passes down from the seat of the Baptist, Christ’s
precursor; and begins with St. Francis, His closest and most perfect
imitator, St. Benedict (in the third row opposite to Rachel and
Beatrice), St. Augustine. The lower sections of each half of the Rose
are occupied by the little children who died before attaining use of
reason; and who yet have different degrees of bliss, according to the
inscrutable mysteries of predestination and Divine Justice, which
willed to give grace differently to each. Another vision of Mary, the
supreme of created things, “the face that is most like to Christ,
whose beauty alone can dispose thee to see Christ” (Par. xxxii. 85-
87), is the prelude to the vision of the Deity. Before her hovers her
chosen knight, Gabriel, the “strength of God,” the pattern of celestial
chivalry, leggiadria. Round her are Adam and St. Peter, Moses and
St. John the Divine; opposite the two latter are St. Anne and St.
Lucy. Thus the three Ladies who took pity upon Dante in the dark
wood, when the mystical journey opened, have been seen in their
glory at its close.
Mary and the Divine Essence.—And the poet turns finally to the
Primal Love, by Mary’s grace and Bernard’s intercession, in the
lyrical prayer that opens the wonderful closing canto of the
Commedia:
Vergine madre, figlia del tuo figlio,
“Virgin Mother, daughter of thy Son.” Setting forth her predestination

from eternity to bring the Redeemer into the world, her office of love
and hope to Heaven and earth, her infinite excellence and dignity,
her power and never-failing love, St. Bernard implores of her grace
for Dante to rise to the vision of the Divine Essence now, in ecstatic
contemplation, and then for his final perseverance that, on his return
to earth, her loving protection may strengthen him against the
assaults of passion, until he rejoice once more in the Beatific Vision
for all eternity. Human love becomes one with the divine where
Beatrice—joined with him now in the union of fruition—is named for
the last time in the poem as he draws near to his mystical goal.
In answer to Mary’s intercession, an anticipation is granted to
Dante of the vision wherein the last and perfect beatitude of man
consists. The supreme experience of the soul, recognised by the
great mystics from Plotinus and Augustine to Richard of St. Victor
and Bonaventura, is rendered into unsurpassable poetry with the
impassioned conviction that it has been the writer’s own. All ardour
of desire dies away. Entering into the Divine light, uniting his
intellectual gaze with the Divine Essence, he actualises all
potentialities of spiritual vision therein. In the Divine light, he beholds
all nature, all Being scattered in leaves throughout the Universe here
united by love into one volume; the vision of the First Cause which
satisfies the understanding becomes that of the Supreme Goodness
which fulfils the will; and this First Cause, this Supreme Goodness,
itself remaining unchanged, becomes revealed to the poet’s ever
strengthening intuition as the mystery of the Blessed Trinity, in which
the Person of the Word took Human Nature.
A l’alta fantasia qui mancò possa;
“Here power failed the lofty phantasy”—the inspired imagination of

the prophet; but it left the desire and will assimilated in perfect
harmony with the will of God—the Divine will revealed as universal,
all-pervading, and all-moving love, “the love that moves the sun and
the other stars”:
L’amor che move il sole e l’altre stelle.
FOOTNOTES:
[28] “Della insufficienza del titolo è prova ed effetto il pronto e
universale accoglimento, che, messo una volta sul frontespizio,
trovò l’epiteto divina, che al generico Commedia diede
determinatezza e colore” (P. Rajna, Il titolo del poema dantesco,
in Studi danteschi diretti da M. Barbi, vol. iv.).
[29] For details of structure and scansion, the reader should
consult P. E. Guarnerio, Manuale di versificazione italiana; G.
Federzoni, Dei versi e dei metri italiani; F. D’Ovidio, Versificaizone
italiana e arte poetica medioevale.
[30] Cf. G. Livi, op. cit., pp. 26, 27.
[31] Traces of an earlier design have been tentatively found in
various places of the first seven cantos, and associated with
Boccaccio’s story of Dante having begun the poem before his
exile and resumed it after the recovery of his manuscript when the
guest of Moroello Malaspina. In Boccaccio’s commentary upon
the opening of Inf. viii., Andrea Poggi and Dino Perini are
represented as rival claimants for the honor of having recovered
the manuscript for Dante.
[32] Cf. Conv. ii. 5.
[33] Cf. Inf. xxxiii. 79-84 with Phars. viii. 827-830.
[34] See Moore’s Time-References.
[35] Cf. Sonnets lx. and lxi. of The House of Life.
[36] See in particular Parodi, “L’Albero dell’Impero,” in his
Poesia e storia nella Divina Commedia.
[37] In Purg. xxx. 109-117, Dante thus distinguishes between
the ovra de le rote magne and the larghezza di grazie divine in his
own case. St. Gregory the Great, speaking of the correspondence
of men with the angelic orders, uses the phrase: divinae largitatis
munere refecti (Hom. in Evangelia, ii. 34).
[38] I venture to retain this reading, although the testo critico
now gives: E’n la sua volontade.
[39] The Vulgate has virtutes caelorum, in Matt. xxiv. and Luke
xxi., where the English Bible reads “the powers of the heavens.”
[40] St. John of Damascus.
[41] Note the scansion of the previous line (37): Io che al divino
da l’umano. There is no syneresis in ïo, no elision of the e in che;
thus emphasising Dante’s personal experience, his wonder that it
should be vouchsafed to him, and producing the slow movement,
the solemn intonation of the line.
BIBLIOGRAPHICAL APPENDIX
The following notes do not attempt to give a full bibliography, but
merely a selection of works that will be found useful by the readers
of this Primer.
A. Text of Complete Works of Dante,

Dictionaries and Concordances
Le Opere di Dante, testo critico della Società Dantesca Italiana, a
cura di M. Barbi, E. G. Parodi, F. Pellegrini, E. Pistelli, P. Rajna, E.
Rostagno, G. Vandelli. Con indice analitico dei nomi e delle cose di
Mario Casella. Florence, 1921. The “Sexcentenary Dante.”
Le Opere di Dante Alighieri, a cura del Dr. E. Moore, nuovamente
rivedute nel testo dal Dr. Paget Toynbee. Fourth edition. Oxford,
1923.
A Dictionary of Proper Names and Notable Matters in the Works of
Dante, by Paget Toynbee. Oxford, 1898.
A Concise Dictionary of Proper Names and Notable Matters in the
Works of Dante, by Paget Toynbee, Oxford, 1914.
Concordance of the “Divina Commedia.” By E. A. Fay. Boston,
1888.
Concordanza delle opere italiane in prosa e del Canzoniere di
Dante Alighieri. By E. S. Sheldon and A. C. White. Oxford, 1905.
Dantis Alagherii Operum Latinorum Concordantiae. By E. K. Rand
and E. H. Wilkins, Oxford, 1912.
B. History and Literature of Dante’s Times

Caggese, R., Firenze dalla decadenza di Roma al Risorgimento
d’Italia. Vols. i. and ii. Florence, 1912-1913.
Casini, T., Letteratura italiana: storia ed esempi. Vols. i. and ii.
Rome, 1909.
Dino Compagni, La Cronica con introduzione e commento di G.
Luzzatto. Milan, 1906. (English translation of the Chronicle by E.
Benecke and A. G. F. Howell in the “Temple Classics,” London.)
D’Ancona, A., and Bacci, O., Manuale della letteratura italiana, vol.
i. Florence.
Gaspary, A., History of Early Italian Literature to the Death of
Dante, translated by H. Oelsner. London, 1901.
Del Lungo, I., Dino Compagni e la sua Cronica (Florence, 1879-
1887); I Bianchi e i Neri (second edition. Milan, 1921).
Piccioni, L., Da Prudenzio a Dante. Turin, 1916.
Rossi, V., Storia della Letteratura Italiana per uso dei Licei. Voi. i.
(Il Medio Evo). Milan, sixth edition, 1914.
Salvemini, G., Magnati e Popolani in Firenze dal 1280 al 1295.
Florence, 1899.
Villani, Giovanni, Croniche (Istorie) fiorentine. (Best edition at
present, Florence, 1823.)
Villani, Giovanni, Selections from the first Nine Books, translated
by Rose Selfe and edited by P. H. Wicksteed. London. 1906.
Villari, P., I primi due secoli della storia di Firenze, new edition,
Florence, 1905. (English translation by Linda Villari from the first
edition.)
For the expedition of Henry of Luxemburg, the reader should study
Caggese, Roberto d’Angiò e i suoi tempi, vol. i. chap. ii. (Florence,
1922).
C. Biography, Etc.
Codice Diplomatico Dantesco: i documenti della vita e della
famiglia di Dante, ed. G. Biagi and G. L. Passerini. Florence (in
course of publication).
Barbadoro, B., La condanna di Dante e le fazioni politiche del suo
tempo. In Studi danteschi, ed. M. Barbi, vol. ii. Florence, 1920.
Boccaccio, Il comento alla Divina Commedia e gli altri scritti
intorno a Dante, a cura di D. Guerri. Three vols. Bari, 1918. Vol. i.
contains the Vita di Dante and the Compendio.
Bruni, Leonardo, Vita di Dante (in Le vite di Dante, Petrarca e
Boccaccio scritte fino al secolo decimosesto, ed. A. Solerti. Milan,
1904).
Foligno, C., Dante. Bergamo, 1921.
Howell, A. G. F., Dante (in “The People’s Books,” London).
Del Lungo, I., Dell’esilio di Dante. Florence, 1881.
Ricci, C., L’ultimo rifugio di Dante. Second edition. Milan, 1921.
Scherillo, M., Alcuni capitoli della biografia di Dante. Turin, 1896.
Toynbee, P., Dante Alighieri, his Life and Works. Fourth edition.
London, 1910.
Wicksteed, P. H., The Early Lives of Dante (translated). London,
1904.
Zingarelli, N., Dante (Milan, 1903); Vita di Dante in compendio
(Milan, 1905).
D. The Minor Works

The Convivio or Convito was first printed at Florence in 1490.
Eighteen canzoni (erroneously numbered as fourteen) were
published at the end of a Venetian edition of the Commedia in
November, 1491. Fifteen genuine Dantesque canzoni, with others
wrongly ascribed to him, are contained in a collection printed at
Milan and at Venice in 1518. The first partially complete edition of
Dante’s lyrical poetry is contained in the first four books of Sonetti e
canzoni di diversi antichi autori toscani in dieci libri raccolte, edited
by Bernardo di Giunta at Florence in 1527. The Vita Nuova was first
printed at Florence in 1576; but its lyrics had been given in the first
book of the 1527 Sonetti e canzoni. The De Vulgari Eloquentia was
published in Trissino’s Italian translation at Vicenza in 1529, and in
the original Latin at Paris in 1577; the Monarchia in 1559 at Basle.
The latter work had been translated into Italian by Marsilio Ficino in
the latter half of the fifteenth century. The Letter to Henry VII. was
first published in an old Italian version in 1547; in its original Latin by
Witte in 1827.
The Epistle to Can Grande was first published in 1700, the
Eclogues in 1719. The Letters as a whole were edited by Witte in
1827 and by Torri in 1842.
Special editions and studies. (a) Vita Nuova. Critical edition by M.
Barbi (Florence, 1907); with notes and commentary by M. Scherillo
(Milan, 1911, reprinted with the Canzoniere); G. Salvadori, Sulla vita
giovanile di Dante (Rome, 1906); Vita Nuova and Canzoniere, text,
translation, and notes by P. H. Wicksteed and T. Okey (“Temple
Classics”). For the “dolce stil nuovo,” V. Rossi, in Lectura Dantis, Le
Opere Minori (Florence, 1906), and Parodi, Poesia e storia nella
D.C. A new edition of the Vita Nuova is published by K. McKenzie
(London, 1923). (b) Rime or Canzoniere. M. Barbi, Studi sul
Canzoniere di Dante (Florence, 1915); G. Zonta, La lirica di Dante
(in Miscellanea dantesca, supplement 18-21 of Giornale storico della
letteratura italiana, Turin, 1922); E. G. Gardner, The Lyrical Poetry of
Dante (in preparation). For the tenzone with Forese F. Torraca, Nuovi
studi danteschi (Naples, 1921), and A. F. Massèra, Sonetti burleschi
e realistici dei primi due secoli (Bari, 1920); for the tenzone with
Dante da Maiano, S. Santangelo, Dante Alighieri e Dante da Maiano
(in Bullettino della Società Dantesca Italiana, N. S., XXVII., 1920); for
the canzone of the Tre donne, Torraca, op. cit., and Carducci, Opere
xvi (“Poesia e Storia”). The majority of the Rime are translated by
Wicksteed in the “Temple Classics” volume cited above. (c)
Convivio. Translation by W. W. Jackson (Oxford, 1909); translation
and commentary by Wicksteed in the “Temple Classics”; Wicksteed,
From Vita Nuova to Paradiso (Manchester University Press, 1922).
(d) De Vulgari Eloquentia. Critical edition by P. Rajna (Florence,
1896); facsimile reproduction of Berlin MS., L. Bertalot, Il Codice B
del “De Vulgari Eloquentia” (Florence, 1923); studies by F. D’Ovidio,
Versificazione italiana e arte poetica medioevale (Milan, 1910);
translation and commentary by A. G. F. Howell in “Temple Classics
Latin Works of Dante”; C. Foligno, Dante, the Poet (Brit. Acad.
Annual Italian Lecture, 1921). (e) Monarchia. C. Cipolla, Il trattato
“De Monarchia” di D. A. e l’opuscolo “De potestate regia et papali” di
Giovanni da Parigi (reprinted in Gli studi danteschi di Carlo Cipolla,
Verona, 1921); F. Ercole, L’unità politica della nazione italiana e
l’Impero nel pensiero di Dante (in Archivio storico italiano, LXXV.,
Florence, 1917), and Per la genesi del pensiero politico di Dante (in
Giornale storico della letteratura italiana, LXXII., Turin, 1918); E. G.
Parodi, Del concetto dell’Impero in Dante e del suo averroismo (in
Bull. d. Soc. Dantesca Italiana, N.S., XXVI., Florence, 1919); A.
Solmi, Il pensiero politico di Dante (Florence, 1922); C. Foligno, The
Date of the Monarchia (in Dante, Essays in Commemoration,
University of London Press, 1921); translation and commentary by P.
H. Wicksteed in “Temple Classics Latin Works of Dante.” (f)
Epistolae. P. Toynbee, Dantis Alagherii Epistolae (The Letters of
Dante, emended text, with introduction, translation, notes, etc.,
Oxford, 1920); F. Torraca, Le lettere di Dante (in Nuovi studi
danteschi); E. Moore, The Genuineness of the Dedicatory Epistle to
Can Grande (in Studies in Dante, Series III.). (g) Eclogae. P. H.
Wicksteed, Dante and Giovanni del Virgilio (London, 1902); G.
Albini, Dantis Eclogae, etc. (Florence, 1903). (h) Quaesto de Aqua
et Terra. Edited and translated by C. L. Shadwell (Oxford, 1909);
ed. V. Biagi, with critical dissertation (Modena, 1907); E. Moore,
Studies in Dante, Series II. (Oxford, 1899); Wicksteed, translation
and commentary in “Temple Classics Latin Works of Dante.”
E. The “Divina Commedia”

Editions with Notes and Commentaries
[The first three editions of the Divina Commedia were printed in
1472, at Foligno, Mantua, and Jesi. They were reprinted, together
with the Neapolitan edition of 1477, by Lord Vernon and Panizzi: Le
Prime Quattro Edizioni della Divina Commedia letteralmente
ristampate (London, 1858). The first Venetian edition is dated 1477,
the first Florentine 1481. There were about fifteen editions of the
Divina Commedia published before the end of the fifteenth century.
The first Aldine was printed in 1502. The two earliest dated
manuscripts, the Landiano (1336) and the Trivulziano (1337), have
been published in facsimile: Il Codice Trivulziano 1080 della D.C.,
with introduction by L. Rocca (Milan, 1921); Il Codice Landiano with
preface by A. Balsamo and introduction by G. Bertoni (Florence,
1921).]
La Divina Commedia nuovamente commentata da F. Torraca.
Milan and Rome, third edition 1915.
La Divina Commedia commentata da G. A. Scartazzini. Seventh
edition revised by G. Vandelli, Milan, 1914.
La Divina Commedia con il commento di Tommaso Casini. Sixth
edition renovated and augmented by S. A. Barbi. Florence, 1923.
Inferno, Purgatorio, and Paradiso, Italian text with English prose
translation on opposite pages, maps and notes, three vols., “Temple
Classics” (London). Inferno, Carlyle’s translation with notes by H.
Oelsner; Purgatorio, translation and notes by T. Okey; Paradiso,
translation and notes by P. H. Wicksteed.
Vernon, W. W., Readings on the Inferno, Purgatorio, and Paradiso,
chiefly based upon the Commentary of Benvenuto da Imola. Six
vols. (two on each part). London, new edition, 1906-1909.
La Divina Commedia, edited and annotated by C. H. Grandgent.
London, 1914.
La Divina Commedia nella figurazione artistica e nel secolare
commento, a cura di Guido Biagi. Turin, 1921, et seq.
F. Subsidiary to the “Commedia” and General.

Clinical Pharmacology During Pregnancy 2Nd Edition Donald Mattison Editor Full Chapter

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Clinical Pharmacology During

Pregnancy 2nd Edition Donald Mattison

AMSTERDAM • BOSTON • HEIDELBERG • LONDON

No part of this publication may be reproduced or transmitted in any form or by any

Library of Congress Cataloging-in-Publication Data

For information on all Academic Press publications visit our

Publisher: Andre Gerhard Wolff

Typeset by TNQ Technologies

Although each chapter author is acknowledged by having his/her/their name

Clinical Pharmacology During Pregnancy. https://doi.org/10.1016/B978-0-12-818902-3.00012-9 1

[20] Meibohm B, Derendorf H. Pharmacokinetic/pharmacodynamic studies in drug product

2.1 Physiologic changes during pregnancy

2.2 Cardiovascular system

Clinical Pharmacology During Pregnancy. https://doi.org/10.1016/B978-0-12-818902-3.00008-7 5

Table 2.1 Summary of cardiovascular changes during pregnancy.

2.3 Respiratory system

Table 2.2 Summary of respiratory changes during pregnancy.

increased renal excretion of bicarbonate to allow for a normal serum bicarbonate

2.4 Renal system

Table 2.3 Summary of renal changes during pregnancy.

2.5 Gastrointestinal system

Table 2.4 Summary of gastrointestinal changes during pregnancy.

thyroid-binding globulin, and cortisol-binding globulin (CBG). The observed

2.6 Hematologic and coagulation systems

Table 2.5 Hemoglobin values during pregnancy.

Table 2.6 Summary of hematological changes during pregnancy.

This hypercoagulable state predisposes the pregnant patient to a higher risk of

2.7 Endocrine system

Table 2.7 Summary of endocrine changes during pregnancy.

pump in which a gradient of calcium and phosphorus is established which favors

Vergine madre, figlia del tuo figlio,

“Virgin Mother, daughter of thy Son.” Setting forth her predestination

“Here power failed the lofty phantasy”—the inspired imagination of

L’amor che move il sole e l’altre stelle.

A. Text of Complete Works of Dante,

B. History and Literature of Dante’s Times

D. The Minor Works

E. The “Divina Commedia”

F. Subsidiary to the “Commedia” and General.

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