Nathematical Noueling

anu Biological Systems

The Effects of Smoking on
Fetal anu Nateinal Ciiculation

ByRachelM.Marano

UnderthesupervisionofProfessorCharlesS.Peskin

S0N u9 NER 0NBERu PERIENCE 2u
C00RANT INS AL SCIENCES
RAB0ATE RESEARCB EX
TIT0TE 0F NATBENATIC
NEW Y0RK 0NIvERISTY

Abstract

The effects of smoking on maternal and fetal circulation are not well researched
in the United States. This project attempts to effectively model the repercussions of
smoking during pregnancy on the circulatory pathways of the fetus and the mother. By
applying a mathematical model to this scientific inquiry, we aim to offer a different
approach to and thus a broader perspective on the subject matter. We have created a
functional model of the healthy symbiosis of exchanges between mother and baby, and
then altered the model to account for the effects of nicotine and carbon monoxide.
Throughout this project, gas exchange across the placenta has been mathematically
simulated.

2

1 Introduction

For this project, MATLAB, a numerical computing environment and programming
language, which is a tool for doing numerical computations with matrices and vectors,
and can also display information graphically, is used. Using this program, we simulated
the effects of smoking on the blood and oxygen circulation via the placenta. Through
this we study acute hemodynamic alterations in the fetal-placental maternal system
immediately after maternal exposure to nicotine.
First, we have modeled a healthy system of maternal and fetal circulation. To do
this the parameters for normal fetal and maternal heart rate, diastolic and systolic
blood pressure, and uterine blood flow are needed. Using these parameters, a model is
constructed of the healthy system to serve as means for comparison.
Next, we modeled the effects of smoking in the fetal-maternal circulation via
acute hemodynamic alterations. To understand the immediate effects of smoking on
the circulation, the consequences of nicotine and other compounds inherent in cigarette
smoke on the placenta and circulation have been researched. Using MATLAB, we
modeled these changes and used graphs to compare the results to the healthy model.
In doing so, we have been able to graphically display the immediate consequences of
smoking on both fetal and maternal circulation. Using a mathematical model to study
the repercussions of smoking during pregnancy is an ethical and valuable investigative
tool.
Below are a brief description of the interactions between fetus and mother during
pregnancy and the implications of smoking during this period.

1.1 Mother and Fetus

The growing fetus receives oxygen directly from its mother through a specialized
circulatory system, which supplies oxygen and nutrients to the fetus as well as removes
carbon dioxide and metabolic wastes. The two components of this system are the
placenta and the umbilical cord, which both develop in the first few weeks following
fertilization. The placenta is the site of nutrition, respiration and waste disposal for the
fetus. Water, glucose, amino acids, vitamins and inorganic salts diffuse across
maternal capillaries into fetal blood. Fetal hemoglobin has a greater affinity for oxygen
than adult hemoglobin does, so oxygen diffuses into fetal blood. The placenta is
permeable to viruses, alcohol and many drugs and toxins, which can adversely affect
fetal development. Gas exchange does not occur in the fetal lungs, it occurs in the
placenta.
The umbilical vein carries oxygenated blood from the placenta to the fetus. The
deoxygenated blood is returned to the placenta via umbilical arteries.

1.2 Smoking and its effects

Cigarette smoking is the largest known modifiable risk factor for low birth weight
and infant death. Cigarette smoke contains over 1000 different compounds including
carbon monoxide, hydrogen cyanide, carcinogens and trace elements such as lead,
3

nickel and cadium. The two main compounds suspected of causing the harmful effects
on the developing fetus during pregnancy are carbon monoxide and nicotine. Carbon
monoxide has a higher affinity for hemoglobin than oxygen, quickly forming the
compound carboxyhemoglobin which is unable to carry oxygen. The formation of this
molecule leads to a potential for decreased oxygen delivery to the fetus and fetal
hypoxia.
Nicotine is generally regarded as the pharmacologically active ingredient in
tobacco responsible for the majority of its effects. Nicotine is known to cross the
placenta reaching levels in the amniotic fluid and fetus that exceed those of the mother.
Nicotine has been shown to be a potent vasoconstrictor reducing uterine and placental
blood flow.
The proposed mechanism for development of placental abruption in smoking
women is explained by reduction in blood flow to the placenta resulting in decidual
necrosis at the periphery of the placenta. The increase in placenta previa, where the
placenta is attached over or near the cervix, in smoking women may be explained by
placental enlargement, which may be a compensatory mechanism for reduction in
oxygen transport to the fetus caused by carbon monoxide in cigarette smoke. Placental
changes consistent with impairment in the placentas ability for gaseous exchange are a
thickening of the trophoblastic basal lamina and a reduction in the size of the fetal
capillaries.
Effects include vasoconstrictive properties of nicotine on uterine blood or the
decreased oxygen availability due to carbon monoxide and the formation of
carboxyhemoglobin. Cigarette smoking is unequivocally the largest and most important
known modifiable risk factor for low birth weight and infant death, and I believe that
studying the effects on circulation will investigate its dire implications and increase
awareness of such.

2 The Placenta

The placenta is described as a pancake-shaped organ that connects the blood
supplies of the mother and the fetus. The placenta achieves its definitive form 8 to 10
weeks after conception and is fully formed by the end of the fourth month or early in the
fifth month of gestation. At term, the placenta weighs 400 to 600 grams. It is round or
oval and approximately 16 to 20 centimeters in diameter and 1.5 to 3 centimeter thick.
The placenta produces pregnancy-related hormones, including chorionic gonadotropin
(hCG), estrogen, and progesterone.
It attaches to the uterus and is connected to the fetus by the umbilical cord. On
one side of the placenta is the maternal deciduas and spiral arteries, which perfuse the
fetal basal or basement membrane and chorionic villi. On the fetal side are fetal
arterioles, venules and capillaries. The placenta is full of maternal blood, and has small
blood vessels that carry fetal blood. Nutrients, such as glucose, and oxygen from the
mothers blood are transferred to the fetal blood, as waste products, such as lactate and
carbon dioxide, from the fetal blood are transferred to the maternal blood, without the
two blood supplies mixing.
Placental transport of gases and nutrients depends on placental surface area,
rate of blood flow on maternal and fetal sides of the placenta, diffusion distance gases
4

must travel, vascular volume in maternal and fetal capillary beds and the affinity of
hemoglobin for oxygen.

2.1 Oxygen Saturation Curves

The placenta serves as the fetal respiratory organ. Oxygen is able to move from
the maternal blood to the fetal blood because of the conformational differences in the
two types of hemoglobin. Fetal hemoglobin has a higher affinity for oxygen than
maternal hemoglobin does, and thus can extract it from the mothers blood supply.
We can display this by modeling the oxygen saturation curves for both types of
hemoglobin. For this we must first know what P50 is for both fetal and maternal
hemoglobin. P50 (called Pstar in our program) refers to the partial pressure of oxygen
when the hemoglobin is 50% saturated. P50 is a standard measure of hemoglobin
affinity for oxygen. For a healthy adult, P50 is usually about 26.8 mmHg. For a healthy
fetus, P50 is approximately 19 mmHg. With a change in the oxygen affinity of
hemoglobin, there is consequently a shift in the oxygen saturation curve. A higher P50
indicates a rightward shift of the standard curve, meaning a larger partial pressure is
required to maintain 50% oxygen saturation, and thus hemoglobin has a decreased
affinity for oxygen. A lower P50 indicates a leftward shift and a higher affinity of
hemoglobin for oxygen. By compare those of fetal and maternal hemoglobin we can
easily deduce that fetal hemoglobin has a higher affinity for oxygen, and thus is capable
of extracting oxygen from the mothers blood supply.
Our equation for saturation is modeled after Professor Peskins equation for
concentration as a function of partial pressure when modeling gas exchange in the
lungs. Fraction saturated is the fraction of hemoglobin binding sites in the bloodstream
that are occupied by oxygen. It is equivalent to the concentration of oxygen in
hemoglobin divided by the total c n tra oglobin delivered to the placenta
through the maternal artery.
o cen tion of hem
c
-
= c
mu
= 4 - |Eb]
m
P
-]
= 19 mmEg
P
-m
= 26.8 mmEg
The equations for fetal and maternal saturation are as follows:
s =
c
c
-
=
_
P
P
-]
]
3
1 +
P
-]
_
P
]
3

ms =
c
c
-
=
[
P
P
-m

3
1 + [
P
P
-m

3

Using these equations, we can graph the oxygen saturation curve with MATLAB:

5

We can see the higher affinity of fetal hemoglobin for oxygen in the graph, as it is more
saturated with oxygen at each given partial pressure.
0 10 20 30 40 50 60 70 80 90 100
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Partial Pressure of Oxygen (mmHg)
F
r
a
c
t
i
o
n

s
a
t
u
r
a
t
e
d
Fetal Hemoglobin
Maternal Hemoglobin

2.2 The General Model

The amount of oxygen consumed by the uterus and placenta affects fetal oxygen
availability or delivery. Uteroplacental oxygen consumption is measured in mol/minute.
The amount of oxygen consumed by the uterus and placenta depends on maternal
cardiac output (=stroke volume * heart rate), which determines uterine blood flow.
The umbilical cord is the life-line that attaches the placenta to the fetus. The
umbilical cord is made up of three blood vessels: two smaller arteries which carry blood
to the placenta and a larger vein which returns blood to the fetus. It can grow to be 60
cm long, allowing the baby to safely move around without causing damage to the cord
or the placenta.


Qm [Hb]m
ma mv

Rate of O2 consumption by fetus
~~~~~~~~~~~~~~~~~~~~~~~~~ Placenta

Qf
fa fv
[Hb]f


6

Using the above diagram and the previous section, we have several parameters, which
can be measured, and unknowns, which are dependent upon the parameters.

First let us define the following abbreviations we use:
Qm = maternal flow to placenta
Qf = fetal flow to placenta (umbilical blood flow)
ma = maternal artery
mv = maternal vein
fa = fetal artery
fv = fetal vein
c = concentration of oxygen
P = partial pressure of oxygen
Vp = amount of O2 consumed per unit time in placenta
Vf = amount of O2 consumed per unit time in fetus

Parameters: Vp, Vf, Qm, Qf, [Hb]m, [Hb]f, Pstarm, Pstarf

We were able to obtain values for these parameters through research.
Vp = .00002232 mol/min per kg placenta
Vf = .001098 mol/min per kg fetal weight
Qm = .700 L/min
Qf = .350 L/min
[Hb]m = .00189270533 mol/L
[Hb]f = .00178410748 mol/L
Pstarm = 26.8 mmHg
Pstarf = 19 mmHg

Unknowns: cma, cmv, Pv, cfv, cfa, Pfa

To solve for these un e knowns, we use th f g t ns:

m
(c
mu
- c
m
) = +I
]
- c
]u
)
e ollowin qua io
I
p ]
= I
p
+
]
(c
because I
]
=
]
(c
]
- c
]u
).
We are able to derive these equations due to the assumption that there is a steady state
and equilibrium between the partial pressures. The number of molecules of gas
entering the placenta per unit time from the maternal side is equal to the number of
molecules consumed per unit time b the ere is a conservation of molecules. y fetus. Th
c
m
= 4 - | b
u
E ]
m

c
I
p
+ I
We are also given that:
With this, we can solve for c
m
:
m
= c
mu
-
]

m

c
m
= 4 - |Eb]
m
-
I
p
+ I
]

m

Using our equations for saturation from the previous section, we can solve for Pmv, Pfv,
and Pfa.
7

c
c
-
=
[
P
P
-

3
1 + [
P
P
-

3
, wbcrc c
-
= 4 - |Eb]
P
m
= _
c
m
4 - |Eb]
m
1 -
c
m
b]
m
Thus,
4 - |E
_
1
3
- P
-m

P
]
= _
c
]
4 - |Eb]
]
1 -
c
]
4 - |Eb]
]
_
1
3
- P
-]

P

= P
m
= = partial pressure of O2 in ma l or fetal vein, respectively P
]
rna
We can solve for c
]
using our equation obtained :
te
for P
]
c
]
= 4 - |Eb]
]
-
_
P

P
-]
]
3
1 + _
P

P
-]
]
3

We also know the relation between c
]
an use I
]
=
]
(c
]
- c
]u
)
u
d c
]
beca
c
]u
= c
]
-
I
]

]

P
]u
= _
c
]u
4 - |Eb]
]
1 -
c
]u
4 - |Eb]
]
_
1
3
- P
-]

Finally,

Now that we have created equations for all of our unknowns, we can create a function
to solve for each of them.

We call this function pfa_value, ultimately solving for Pfa using all of our parameters and
equations.

Under standard conditions, we find from running our program that:
cma = 0.0076 mol/
cmv = 0.0060 mol/L
Pv = 41.5643 mmHg
cfv = 0.0065 mol/L
cfa = 0.0034 mol/L
Pfa = 18.3327 mmHg

8

3 The Effects of Smoking

It has been observed that smokers have smaller placentas then non smokers,
more fibrin deposits and fewer fetal capillaries. We know that carbon monoxide has a
higher affinity for hemoglobin than oxygen, which forms the compound
carboxyhemoglobin, thus decreasing the concentration of oxyhemoglobin. Also, blood
flow to the placenta is reduced by smoking, which can result in the development of
placental abruption and decidual necrosis, which is a placental lesion, at the periphery
of the placenta.
In order to evaluate the effects of altering blood flow and hemoglobin
concentration, we varied Qm, Qf, [Hb]m, and [Hb]f, and plotted Pfa versus each of these
values separately. We use Pfa because it is the limiting factor of oxygen availability to
the fetus. Our global parameters are Pstarm, Pstarf, Vp and Vf. We initialize with all of
our researched values for the global parameters along with those for Qm, Qf, [Hb]m,
[Hb]f. This displays steady state results. For each graph, the y-axis, displaying values
of Pfa, ranges from 10 to 20 mmHg, as a means for comparison. The standard values
are highlighted.

For our first graph, we vary Qm, from 0.5 to 1.0 L/min, in increments of 0.01.

Next we vary Qf, from 0.2 to 0.7 L/min, in increments of 0.01.
9

Next we vary [Hb]m, from 0.001 to 0.002 mol/L, in increments of 0.00002.

Next we vary [Hb]f, from 0.001 to 0.002 mol/L, in increments of 0.00002.

We can see that a decrease in fetal blood flow and hemoglobin concentration
much more significantly affects Pfa than maternal blood flow and hemoglobin
10

concentration. This is consistent with clinical research, since smoking during pregnancy
has been shown to reduce the production of a chemical substance that relaxes blood
vessels in the umbilical cord which leads to lowered blood flow to the fetus and limiting
the amount of oxygen delivered.
A decrease in all four values will decrease the partial pressure in the fetal artery,
meaning less oxygen is available for the fetus.

3.1 The General Model

Now we aim to create a model to simulate smoking and in doing so, analyze its
effects on Qm, Qf, [Hb]m, and [Hb]f. This model demonstrates a hypothetic situation
when a person is smoking or not smoking over a period of time. First we need to
initialize the program. In this, we name the parameters for Qm_normal, Qf_normal,
[Hb]m_normal, [Hb]f_normal, Qm_smoke and Qf_smoke. Qm_smoke and Qf_smoke are
the maternal and fetal flow, respectively, to the placenta while smoking. These values
were found through research:

Qm_smoke = 0.350 L/min
Qf_smoke = 0.175 L/min

We need to devise a system to account for the duration of time and size of the
time steps. The variable "klokmax" is something that needs to be defined. It is the total
number of time steps that the program will take, so it is related to the total time tmax by
the relationship:
tmax = klokmax * dt
We proceed by first defining tmax, and then divide by dt, the duration of one time step,
to get klokmax. We make sure that klokmax is an integer by rounding up the result.
tmax = (duration of the computer experiment)
dt = (duration of one time step)
klokmax = ceil(tmax/dt) (number of time steps in the computer experiment)

The actual values of "tmax" and "dt" depend on what units you have chosen to
use for measuring time. For example, suppose you wanted the experiment to cover the
full time of gestation, i.e., 9 months, and suppose you wanted the time step to be 10
minutes, and you have chosen the unit of time to be one hour. Then you could say:
tmax = 9*30*24 = 64800 duration of the computer experiment (in hours)
dt = 10/60 = 0.16667 duration of one time step (in hours)

We then define the various "tau" values as inputs to the program. Estimates of
these values were found in the literature about smoking and CO poisoning. In these
"tau" values, "f" or "m" mean "fetal" or "maternal," respectively.
We are assuming that during smoking the concentration of hemoglobin that is not
poisoned by CO decays exponentially with a time constant that we call "tauSm" or
"tauSf" The time constant is the time it takes for the amount to decay to 1/e of its original
value.

11

tauSm = 2 minutes
tauSf = 6 minutes
Likewise, we are assuming that during a non-smoking period of time the
concentration of hemoglobin that is not poisoned by CO recovers exponentially with
time constant that we call "tauRm" or "tauRf." Here, what is exponentially decaying is
the difference between the normal value and the value at any particular time.
tauRm = 5 minutes
tauRf = 9 minutes
Since CO binds very strongly to hemoglobin and holds on tightly, it follows that tauSm is
smaller than tauRm and tauSf is smaller than tauRf.

We also have to create an array for times in which our program will be evaluated. In
this particular model, time is measured in minutes.

With this, we create S.m. S refers to a dimensionless measure of either smoking or not
smoking. It is called from the main loop of the program, smoking_while_pregnant.m.
The current value of t is sent to S.m and the result, either 0, which indicates not
smoking, or 1, that indicates smoking, is made use of in the main program.


In this p gram ro , if S(t)=1, the mother is smoking, and:

m
=
m smokc

]
=
] smokc

|Eb]
m
= |Eb]
m
-Jt - (|Eb]
m
touS
m
)
|Eb]
]
= |Eb]
]
- Jt - (|Eb]
]
touS
]
)

Or else, S(t)=0, the mother is not smoking, and:

I

m
=
m nomu

]
=
] nomuI

|Eb]
m
= |Eb]
m
+ Jt - (|Eb]
m nomuI
- |Eb]
m
)touR
m

|Eb]
]
= |Eb]
]
+ Jt - (|Eb]
] nomuI
- |Eb]
]
)touR
]


With these equations, we can run the main program.

Given tmax = 200 minutes, dt = 1 minute, and
times = [10,20,30,40,50,60,70,80,90,100,110,120,130,140,150,160,170,180,190,200]

Then we can plot:








12

S vs. t
0 20 40 60 80 100 120 140 160 180
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
t
S

In this model, it can be seen that the woman is smoking from 10 to 20, 30 to 40,
50 to 60, 70 to 80, and 90 to 100 minutes. This shows that the mother is smoking
every other ten minutes for the first 100 minutes, then does not smoke for the next 100
minutes.

Qm vs. t
0 20 40 60 80 100 120 140 160 180 200
0.35
0.4
0.45
0.5
0.55
0.6
0.65
0.7
t
Q
m

13

In the intervals when the mother is smoking, the Qm drops drastically and almost
immediately to .350 L/min, half of its normal value, and fully recovers when the mother
is not smoking. We assume that the effect on blood flow happen instantaneously. The
decrease in blood flow corresponds to smaller placentas seen in smoking mothers.

Qf vs. t
0 20 40 60 80 100 120 140 160 180 200
0.16
0.18
0.2
0.22
0.24
0.26
0.28
0.3
0.32
0.34
0.36
t
Q
f

In the intervals when the mother is smoking, the Qf drops drastically and almost
immediately to .175 L/min, half of its normal value, and fully recovers when the mother
is not smoking.

[Hb]m vs. t
0 20 40 60 80 100 120 140 160 180 200
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
x 10
-3
t
[
H
b
]
m

The decrease in the effective amount of hemoglobin available is due to some of
its binding sites being occupied by CO instead of oxygen. It is not instantaneous,
14

because we assume it takes time for the CO to bind to and detach from hemoglobin.
We create this graph by solving differential equations. During smoking the
concentration of hemoglobin that is not poisoned by CO decays and recovers
exponentially with the time constants. We can see that the concentration of hemoglobin
decays more quickly than it recovers, so while the mother continues to smoke on
regular intervals, there is a periodic steady state and the concentration does not reach
its normal value. Once the mother stops smoking it can fully recover. The decrease in
oxygen delivery due to decreased available hemoglobin correlates to fewer fetal
capillaries seen in smoking mothers.
When the mother is smoking in this particular graph, [Hb]m decreases until it hits
zero, which is not realistic, then recovers while the mother does not smoke. The
concentration of maternal hemoglobin decreases faster than it recovers, which is
externally valid as it is observed in real-life research studies. Thus, it never reaches its
original value while the mother continues to smoke in regular intervals. It reaches
approximately 0.0017 mol/L, which is 90% of the normal value. Only after the mother
does not smoke for t = 20 minutes will the [Hb]m return to its original value of 0.00189.

[Hb]f vs. t
0 20 40 60 80 100 120 140 160 180 200
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
x 10
-3
t
[
H
b
]
f

When the mother is smoking, [Hb]f decreases, first to approximately 0.00035
mol/L, and after the second consecutive interval of smoking to approximately 0.00025
mol/L. The concentration of fetal hemoglobin decreases faster than it recovers, which is
externally valid as it is observed in real-life research studies. It recovers to about
0.00135 mol/L while the mother continues to smoke in regular intervals, which is 76% of
the normal value. Only after the mother does not smoke for t = 60 minutes will the [Hb]f
return to its original value of 0.00178.

From this, it is observed that the [Hb]f is more affected than the [Hb]m when the
mother is smoking. Therefore, the fetus has less availability to oxygen, which can
cause low birth weight, abnormalities, poor development, among many complications. It
is interesting to observe the inability of the concentration of hemoglobin and the blood
15

flow to return to normal values as smoking continues in regular intervals. This

correlates to smaller placentas and fewer fetal capillaries seen in smoking mothers.
In this project, we were able to observe that smoking changes hemodynamic
resistance of certain vessels in the mother and in the fetus. Through this, we were able
to calculate the effect on blood flow and on oxygen delivery.

4 Concluding Remarks and Further Works

Smoking is a behavior that has distinct consequences upon the smoker,
including effects on blood flow and on the concentration of hemoglobin in the blood.
Because of the connection between the fetus and its mother through the placenta and
umbilical cord, I expected that there would be effects upon these variables in the fetus
as well. In this study, we investigated the acute, immediate effects of smoking on the
circulation between fetus and mother. Results of this study revealed that the blood flow
and oxygen delivery to the fetus were compromised during smoking, and can be
illustrated through the use of a mathematical model.
Varied amounts and patterns of smoking can produce different affects on these
values, and our model can be used with different parameters to observe the
consequences of such. The model can also be used for different periods of gestation,
as it displays smoking over a period of time. Thus, a more intricate examination of the
different stages of pregnancy, focusing on bigger time spans and incorporating changes
and varying effects depending on the particular period of gestation, could allow for a
deeper investigation.
Another observation from this study is that there is a greater effect on the fetal
blood flow and fetal hemoglobin concentration. This is consistent with clinical research.
Smoking during pregnancy has been shown to reduce the production of a chemical
substance that relaxes blood vessels which leads to lowered blood flow to the fetus.
Specifically, nitric oxide in the fetal vessels causes restriction in the vessels, lowering
the blood flow in the umbilical cord which exclusively supplies the fetus with oxygen and
nutrients prior to birth.
Although the model is preliminary and not tuned yet to be realistic, it offers a
foundation for future investigation. Further research would be needed to determine
exact effects of smoking on maternal and fetal blood flow, as well as the accurate
values for decay and recovery time constants for the levels of effective hemoglobin
concentration during smoking.
The present investigation has significant implications for increased awareness of
the adverse effects of smoking during pregnancy. The reduction in blood flow may
result in retarded fetal growth and low birth weight when the infant is born. It can also
lead to poor development among other complications. Increased understanding of this
has the potential to affect the level of smoking during pregnancies and thus the
possibility of delivering healthier babies.



16

5 Acknowledgements

First, I would like to thank my advisor, Professor Charles S. Peskin, for his
supervision and guidance throughout the SURE 2009 program. I am extremely
fortunate to have had the opportunity to work with him. His help was invaluable to me
throughout the summer, showing me the ropes in MATLAB, pushing me through tough
formulations, and helping me withstand the numerous challenges and problems faced
throughout this project. His support allowed me to grow and learn substantially this
summer.
I would also like to thank the Courant Institute. With their financial support, I was
able to devote my time to pursuing this research. It was an amazing opportunity to
pursue a project that ties the two fields of tremendous interest to me and my studies,
mathematics and biology. I was able to gain a different perspective on the subject
matter, and to further understand the innate intricacies and complexities of the organs
explored and their function.
17

18

6 References

[1] Hoppensteadt, Frank C., and Charles S. Peskin. Modeling and
Simulation in Medicine and the Life Sciences. 2nd ed. New York, NY:
Springer, 2004.

[2] Koren G. Fetal toxicology of environmental tobacco smoke. Curr Opin
Pediatr. 1995;7:128-131.

[3] Lambers DS, Clark KE. The maternal and fetal physiologic effects of
nicotine. Semin Perinatol. 1996; 20: 115-26.

[4] Luck W, Nau H, Hansen R, et al. Extend of nicotine and cotinine transfer
to the human fetus, placenta and amniotic fluid of smoking mothers.
Dev Pharmacol Ther. 1985; 8: 384-95.

[5] Mller, Janine Santos et al. Acute Effects of Maternal Smoking on Fetal
Placental-Maternal System Hemodynamics Arq. Bras. Cardiol. 2002
Vol.78 No.2.

[6] Murray, Michelle. Antepartal and Intrapartal Fetal Monitoring. 3rd ed.
New York: Springer Company, 2006.