Medical Hypotheses (2004) 63, 1057–1064
http://intl.elsevierhealth.com/journals/mehy
Hypothesis: selective phosphodiesterase-5
inhibition improves outcome in preeclampsia
J.W. Downinga,*, R. Ramasubramaniana, R.F. Johnsona, B.H. Minztera,
R.L. Paschalla, H.W. Sundellb, B. Engelhardtb, R. Lewisc
a
Department of Anesthesiology, Vanderbilt University School of Medicine, 1313 21st Ave. So. 504
Oxford House, Nashville, Tennessee, USA
b
Department of Pediatrics,Vanderbilt University, Nashville, Tennessee, USA
c
Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, Tennessee, USA
Received 22 April 2003; accepted 13 March 2004
Summary The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The
trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters.
Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an
excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment
focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby.
We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by
persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and
phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and
improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition
improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance
falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed.
Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental
phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 30 50 -cyclic
monophosphate is boosted due to slowed hydrolysis. Adenosine 30 50 -cyclic monphosphate levels increase in parallel.
Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves.
Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted.
Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall.
Preemption of oxidative stress initiated by “consumptive” oxidation of nitric oxide stabilizes the vascular endothelium
and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 30 50 -cyclic monphosphate offsets the
extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented.
*
Corresponding author. Tel.: +1-615-322-8476; fax: +1-615-3431732.
E-mail address: [email protected] (J.W. Downing).
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2004.03.042
1058
Downing et al.
One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically
should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ
functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician
of impending fetal compromise. Fetal growth and vital organ maturation can continue.
As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed.
The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by
midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be
less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency
virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic
has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will
help restore them fiscally.
c 2004 Elsevier Ltd. All rights reserved.
Background
Preeclampsia is a leading cause of maternal morbidity and death worldwide [1]. Intrauterine
growth restriction (IUGR) and hypoxemic fetal
distress associated with preeclampisa are indications for expedient delivery in almost 15% of preterm births [2]. Extremely low birth weight (ELBW)
babies delivered for both maternal and fetal indications are likely to die. Survivors are often both
mentally and physically handicapped [3].
Contemporary treatment of preeclampsia seeks
primarily to avoid life-threatening maternal complications. Control of hypertension and seizure
prevention is paramount. Careful observation of
the output of urine and invasive hemodynamic
monitoring as indicated guide the restoration of
the characteristic restricted plasma volume and
guard against circulatory overload. Treatment
failure compels premature delivery, the only
known cure for preeclampsia.
Evidence
In 1832 John Burns of Glasgow, Scotland wrote
that: “. . .there is nothing either more difficult, or
more mysterious, [than] the etiology of puerperal
convulsions” [4]. More than 170 years later the
pathogenesis and pathophysiology of preeclampsia/eclampsia remain conundrums that still provide
fertile areas for on-going research [5]. Abnormal
maternal vascular reactivity, coagulopathy, uteroplacental insufficiency and poor fetoplacental
perfusion are pathognomonic of this disorder. Especially remarkable is the random failure of endovascular trophoblastic invasion to replace the
endothelium and destroy the musculoelastic architecture of the spiral arteries. The widespread
conversion of these normally tonic vessels into
passive, low resistance uteroplacental conduits
during placentation is thwarted. Reported adverse
changes in placental Doppler flow velocity wave
form patterns associated with preeclampsia support the notion that its pathophysiology stems
largely from this well-described vascular anomaly
[6]. Unmodified spiral arteries remain intact and
retain their responsiveness to key endogenous vasoconstrictor and vasodilator compounds. These
vasoactive agents include endothelin, thromboxane, catecholamines, 5-hydroxytryptamine (5-HT),
angiotensin, prostacyclin and nitric oxide (NO)
donors. Other factors that inhibit normal placentation are intervillous thrombosis and placental
atherosis, infarction, and abruption [7].
In the lungs efficient gaseous exchange is contingent upon optimum matching of ventilation to
perfusion (V=Q matching) brought about by activation of the pulmonary hypoxic vasoconstrictor
(PHV) response. In 1987, Howard [8] suggested
that a similar biological response, hypoxic fetoplacental vasoconstriction (HFPV), might control
fetoplacental intravillous blood flow. Studies using
the dual perfused, single isolated, human placental cotyledon support this assertion [9–12]).
Healthy transplacental exchange probably hinges
around HFPV dependent regional adjustments of
previllous umbilical arteriolar tone that optimize
maternal/fetal (Qm =Qf ) blood flow distribution
and matching.
A favorable Qm =Qf ratio promotes umbilical venous uptake of oxygen and nutrients from the intervillous space and facilitates their carriage and
delivery to the fetus. Regional uteroplacental insufficiency and consequent reduced fetal oxygen
availability trigger compensatory HFPV. This physiologically protective response steers umbilical
arteriolar blood flow away from hypoxemic villi
towards better-oxygenated areas of the placenta.
HFPV thus guards against fetal biochemical imbalance and starvation.
Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia
Myatt et al. [13] studied the influence of NO on
thromboxane and endothelin induced fetoplacental
vasoconstriction in the dual perfused, single isolated human placental cotyledon. They concluded
that: “Nitric oxide appears to contribute to maintenance of basal vascular tone and to attenuate
the actions of vasoconstrictors on this circulation.”
Using the same laboratory model NO donation and
PDE5 inhibition have been shown to counteract
HFPV provoked by both 5-HT and hypoxia [14–17].
The signal transduction pathway believed to be
responsible for the characteristic maternal vasodilatation and low placental vascular resistance of
a healthy pregnancy begins with NO synthesis under
the control of NO synthetase (Fig. 1). NO release
activates guanylate cyclase (sGC) to convert
guanine triphosphate (GTP) to guanosine 30 50 -cyclic
monophosphate (cGMP) [18]. Cyclic GMP receptor
stimulation causes smooth muscle cell cGMP-dependent protein kinases to initiate myosin light
chain dephosphorylation, relaxing smooth muscle.
Adenosine 30 50 -cyclic monophosphate (cAMP) concentrations in vascular smooth muscle and platelets increase in parallel with the accumulating
levels of cGMP.
Substrate specific phosphodiesterases (PDE5 and
PDE4, respectively), hydrolyze cGMP and cAMP.
Cyclic GMP-binding phosphodiesterases (PDE3 and
PDE5), cGMP (PKA1) dependent protein kinase and
cAMP (type 1PKA) dependent protein kinase have
been identified in the human placenta [19,20].
Cyclic GMP and cAMP inhibit platelet aggregation
and preserve microvascular integrity by preventing
capillary hyperpermeability and vascular leakage.
Figure 1 Failure of the normal nitric oxide (NO)–cyclic
guanosine monophosphate (cGMP) first and second messenger transduction pathway together with aberrant NO
production and almost simultaneous “consumptive” superoxide and lipid oxidation underlie the pathogenesis of
severe preeclampsia. NO, nitric oxide: NOS + nitric oxide
synthetase: GTP, guanosine triphosphate; cGMP, cyclic
guanosine monophasphate; cAMP, cyclic adenosine
monophosphate; 5GMP, 5-guanosine monophosphate;
[O2 ], superoxide; OONO, peroxynitrite; PDE5, phosphodiesterase-5; SOD, superoxide dismutase.
1059
In addition, cAMP exhibits immunosuppressant and
antiinflammatory properties.
The NO–sGC–cGMP first and second messenger
pathways in the lungs probably regulate PHV to
optimally adjust pulmonary V=Q distribution and
matching. At lower altitudes PHV maintains V=Q
equilibrium to secure normal arterial oxygen and
carbon dioxide tensions. But at high altitude a low
ambient O2 pressure and therefore reduced alveolar
O2 tension provokes a vigorous PHV response that
increases pulmonary artery pressure without improving gas exchange [21]. Persistent PHV increases
pulmonary arteriolar resistance and causes pulmonary arterial hypertension, ultimately leading to
cor pulmonale. Hypoxemic chronic obstructive
pulmonary disease (COPD) predicates a similarly
protracted pathological course and outcome.
Analogous biochemical strategies probably influence HFPV in order to adjust placental perfusion and
Qm =Qf distribution and matching [8–12].The low
resistance, high flow fetoplacental circulation lacks
innervation but does possess tonic previllous umbilical arterioles responsive to humoral and reagent
Figure 2 The hypothetical pathophysiological cascade
induced by vasoconstriction of the uteroplacental and
fetoplacental circulations in preeclampsia. Cor placentale is potentially lethal to the fetus. IUGR and in particular hypoxemic fetal stress demand emergent preterm
delivery often before 26 weeks gestational age. Neonatal
death or a poor long-term outcome, for example,
cerebral palsy may result. cGMP, cyclic guanosine
monophosphate; HFPV, hypoxemic fetoplacental vasoconstriction; Ua, umbilical artery; UV, umbilical vein;
RV, right venticular; Qm/Qf, uteroplacental/fetoplacental-blood flow match; IUGR, intrauterine growth
restriction; VO2 , oxygen availability/uptake.
1060
stimuli. In preeclampsia chronic fetoplacental
hypoxemia induces persistent HFPV and Qm =Qf inequalities (Fig. 2). Unrelenting previllous arteriolar
spasm increases upstream umbilical arterial resistance manifesting as absent or reversed umbilical
arterial end diastolic Doppler flow waveforms that
correlate well with adverse perinatal outcome [22].
Fetal right ventricular impedance, workload and
myocardial oxygen demand increase leading to
hypoxemic fetal right heart failure and circulatory
decompensation.
The above scenario mirrors the inexorable but
more drawn out course of events seen in adults at
high altitude or with COPD that induce and perpetuate pulmonary hypertension leading to cor
pulmonale and death. Consequently Sebire and
Talbert [23] have aptly labeled this potentially lethal fetal condition “cor placentale”. Clinically
these changes manifest initially as a non-reassuring
fetal heart rate patterns. Unchecked they lead to
agonal fetal bradycardia, a clinical sign that mandates immediate delivery to save the baby’s life.
Placental NO synthetase (NOS) activity reportedly may decrease, increase or not change in preeclampsia [24,25]. Oxygen dependent NOS activity
decreases with hemoglobin desaturation [21].
Reduced production or increased “consumption”
(see below) of NO in preeclampsia limit its
bioavailability and hence decreases cGMP and
Figure 3 “Consumptive” NO superoxide and lipid oxidation causes a build up of reactive oxygen species (ROS)
and hampers the NO–cGMP first and second messenger
pathway in preeclampsia. Maternal oxidative stress leads
to multiple organ damage and death. Uteroplacental
circulatory perturbations critically compromise fetal
oxygenation and nutrition. NO, nitric oxide; [O2 ], superoxide; OONO , peroxynitrite; *ROS, reactive oxygen
species; H2 O2 , hydrogen peroxide; NO2 , nitrogen dioxide;
NO3 , nitrogen trioxide; MBP, maternal blood pressure;
HELLP, Hemolysis, elevated liver enzymes and low
platelet count.
Downing et al.
cAMP expression. A dearth of vasodilatory cyclic
nucleotides favors maternal vasoconstriction
leading to uncontrolled maternal hypertension
(Fig. 3). Further consequences of severe maternal
vasospasm are plasma volume restriction, hemoconcentration and hyperviscosity. Other anomalies
that threaten the mother include platelet aggregation, coagulopathy and an unbridled inflammatory response to pregnancy.
Concurrently, spiral artery vasospasm, placental
atherosis, placental infarction and placental
abruption induced by the mother’s excessively high
blood pressures cause uteroplacental hypoxemia.
Widespread reflex HFPV is invoked in a compensatory effort to reestablish an overall placental
Qm =Qf match compatible with fetal survival
(Fig. 2). Fetal nutrient supplies are jeopardized and
oxygen availability to the fetus is seriously
curtailed.
Referring once again to Fig. 1, hypoxemia promotes an interaction between NO and superoxide
(O2 ) that produces peroxynitrite (ONOO ), a potent pro-oxidant that nitrosylates cellular proteins
and lipoproteins [26]. Increased ONOO production
from the placenta induced by fetoplacental hypoxemia in concert with the generation of other NO
based reactive oxygen species or ROS [nitrogen
dioxide (NO2 ) and nitrogen trioxide (NO3 )] trigger
maternal oxidative stress (Fig. 4). NO “consumption” by superoxide further erodes its bioavailability and limits it vasodilatory potential. In
addition, the antioxidant reaction normally facilitated by NO that converts pro-oxidant hydrogen
peroxide (H2 O2 ) to water and oxygen is slowed
Figure 4 Profound vasoconstriction and maternal oxidative stress triggered by failure of the normal NO–cGMP
biological cascade likely instigate the well-known and
serious maternal complications associated with preeclampsia. NO, nitric oxide cGMP, cyclic guanosine
monophosphate cAMP, cyclic adenosine monophosphate
ARDS, adult respiratory distress syndrome.
Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia
leading to a build up of H2 O2 further fueling maternal oxidative stress.
Collectively, these events in the mother lead to
an explosive pro-oxidant cascade as depicted in
Fig. 4. Maternal oxidative stress coupled with an
exaggerated inflammatory response to pregnancy
causes endothelial swelling and dysfunction, capillary hyperpermeability, vascular leakage, platelet
aggregation, thrombosis and atherosis. The end
results, irreversible cellular damage and multi-organ failure are lethal [27].
The NO–sGC–cGMP signaling system and lipid
peroxidation reactions not only preserve vascular
homeostasis in health but also paradoxically may
instigate arterial disorders [28]. Additionally, NO
possesses both proinflammatory and anti-inflammatory properties [29]. Perturbations in NO production and biological inactivation are therefore
often blamed for organ dysfunction and disease.
We surmise that in preeclampsia reduced NO bioavailability translates into a decrease in cGMP expression and cAMP co-production. Maternal
endothelium dependent vasodilatation is impaired.
Biological constraints that normally offset vasoconstriction and the inflammatory response to
pregnancy are blunted.
Uncontrolled maternal hypertension can precipitate hemorrhagic stroke and in concert with the
pro-oxidant related increase in capillary permeability provoke cerebral edema. Furthermore, a
major increase in left ventricular impedance and
afterload may precipitate left heart failure. Left
ventricular overload coupled with increased vascular leakage leads to pulmonary edema. Increased
NO “consumption” by superoxide triggered by
fetoplacental hypoxemia further depletes NO bioactivity and leads to a dangerous build up of ROS
(ONOO , NO2 , NO3 and H2 O2 ). The delicate balance between organic pro-oxidant and antioxidant
activity is upset initiating and then fueling maternal oxidative stress [2,27,30,31]. Cyclic AMP’s immunosuppressive and anti-inflammatory influences
diminish [32]. These potentially lethal pathophysiological events are summarized in Figs. 3 and 4.
Hypothesis
Based on the assumptions outlined previously, we
postulate that selective placental PDE5 inhibition
will forestall the cataclysmic pathophysiological
changes that provoke the clinical onset and progression of preeclampsia. With two exceptions, low
dose aspirin ingestion and antioxidant vitamin C
and E administration [33,34], no other previously
suggested remedies for preeclampsia cite preven-
1061
tion as their chief objective. Targeting PDE5 enzyme activity with a specific phosphodiesterase
inhibitor to impede cGMP hydrolysis (Fig. 1)
increases intracellular cGMP and cAMP concentrations to vasodilate uteroplacental and fetoplacental vasculature. Intervillous and intravillous
perfusion improve and Qm =Qf matching stabilizes.
Fetoplacental hypoxemia is alleviated. Appropriate
fetal nutrition resumes.
Maternal hypertension subsides as cGMP and
cAMP induced vasodilation counteracts the profound vasoconstriction pathognomonic of severe
preeclampsia. The risks of a catastrophic cerebral
bleed and swelling of the brain recede. The onset
of the pro-oxidant cascade that generates maternal oxidative stress is forestalled. The likelihood of
left heart failure and pulmonary edema diminishes.
Proinflammatory cellular and mediator activities
subside. Maternal endothelial and platelet functions recover. Irreversible cellular damage, multiple organ failure and maternal death are averted.
Delivery can thus be delayed with relative safety
for the mother. Fetal organ maturation and physical development proceed unabated.
Rationale
Uteroplacental insufficiency targets the fetoplacental unit, the alleged pathogenic epicenter of
preeclampsia [7]. Impaired intervillous perfusion
predicates IUGR and fetoplacental hypoxemia.
Fetoplacental hypoxemia triggers maternal vasospasm that is the foundation for the development
of severe hypertension, a plasma volume deficit,
hemoconcentration, hyperviscosity, and renal
failure. Loss of capillary endothelial integrity leads
to a further depletion in maternal plasma volume
and the development of flagrant tissue and organ
edema. For example, gross laryngeal edema may
hamper attempts to intubate the trachea during
rapid sequence induction (RSI) of general anesthesia for cesarean section [35]. Worsening of
preexisting cerebral edema and the sudden onset
of left ventricular failure and pulmonary edema are
other dangerous consequences of a poorly conducted RSI that fails to control the reflex hypertension induced by laryngeal stimulation.
Uncontrolled hypertension coupled with oxidative stress and an excessive gestational inflammatory response in the mother increase the chances
of serious clinical complications appearing. For the
mother these include hemorrhagic stroke, cerebral
thromboses, thrombocytopenia, the HELLP syndrome [hemolysis (H) with elevated liver enzymes
1062
(EL) and a low platelet count (LP)], liver hematomata, cardiomyopathy and the adult respiratory
distress syndrome (ARDS) (Fig. 4).
From the fetal point of view IUGR is a hallmark
of severe preeclampsia. Other hazardous conditions that threaten the fetus include hypoxemic
stress, metabolic and respiratory acidemia, cor
placentale and, in association with uncontrolled
maternal hypertension, placental abruption. Since
delivery is currently the only known cure for preeclampsia, the presence of any of these lifethreatening pathological entities in the mother or
her baby necessitates urgent premature delivery by
cesarean section in order to avoid permanent injury or death.
Inhaled NO and PDE5 inhibitors are used to treat
adult and neonatal pulmonary arterial hypertension [21,36]. PHV is abolished and pulmonary arterioles dilate. Intrapulmonary V=Q matching and
oxygenation improve. Metabolic and respiratory
acidemia is relieved. Pulmonary artery pressures
fall, right ventricular impedence and afterload
decrease and cor pulmonale is avoided. Notably
sildenafil, a well-established PDE5 inhibitor, has
been shown to modulate the harmful rebound
pulmonary hypertension that follows inhaled NO
withdrawal in newborns and infants [37].
In severe preeclampsia nitrovasodilators modulate maternal hypertension and improve Doppler
uterine artery pulsatility indices [38]. In theory NO
donors increase cGMP expression and the parallel
increase in cAMP production. Tonic spiral arteries
serving the uteroplacental circulation dilate. Umbilical previllous arteriolar spasm (HFPV) within the
fetoplacental circuit relaxes. Uteroplacental insufficiency and fetoplacental hypoxemia are alleviated. Placental Qm =Qf matching improves. Better
fetal oxygenation assuages fetal metabolic and
respiratory acidemia. Fetal nutrition is enhanced.
Upstream resistance to umbilical artery blood flow
returning to the placenta falls. Fetal right ventricular impedance and afterload are reduced.
Myocardial workload and oxygen demand diminish.
Right heart function improves and cor placentale is
averted. The signs and symptoms of fetal stress
abate.
We submit that selective placental PDE5 inhibition, by slowing placental cGMP breakdown and
increasing cyclic nucleotide availability will provide the same benefits as NO donation but without
the risk of precipitating relative maternal systemic
hypotension and for a longer time. Excess NO expression brought on by the vicious cycle of oxidative “consumption” as depicted in Fig. 1 will be
suppressed by the accumulation of cGMP and cAMP,
a well-established negative feed-back biomecha-
Downing et al.
nism. Hazardous complications related to uncontrolled maternal hypertension, rampant maternal
oxidative stress and an extreme inflammatory reaction to pregnancy are less likely to arise.
Verification of hypothesis
Our central tenet is that placental PDE5 inhibition
in preeclampsia dilates spiral arteries and umbilical
previllous arterioles. Uteroplacental insufficiency
and fetoplacental hypoxemia are alleviated to
protect both mother and child. We propose that
the therapeutic merits of PDE5 inhibition might
conveniently be tested in rats [39–41]. If increasing placental cGMP and cAMP availability alleviates
rodent hypertension, proteinurea and IUGR caused
by NO synthetase inhibition, an argument could be
made for conducting preliminary clinical studies in
humans with severe refractory preeclampsia.
However, in the light of sildenafil’s reported effects on the pulmonary circulation in neonates and
infants [37], the influence of PDE5 inhibition on the
fetal circulation should be taken into account before clinical trials are started.
If animal studies support the efficacy and safety
of PDE5 inhibitors and subsequent clinical trials
prove successful, how could mankind benefit in the
future? The recent introduction of tadalafil, a new
longer acting PDE5 inhibitor with a half life of 17.5
h, may make it possible for a mother with preeclampsia to continue her pregnancy safely beyond
25 weeks based on a one tablet a day regime [42].
Selective monitoring of vital organ functions
backed by conventional management will help
prevent the occurrence of life-threatening maternal complications. Time bought by PDE5 inhibitor
therapy will allow further fetal brain, lung and
kidney development. The fetus will continue to
mature physically. Regular biophysical profiles will
be used to monitor fetal progress. A better neonatal outcome will result. Consequently, maternal
and fetal mortality and morbidity will decrease.
Many women and their babies worldwide will benefit [1]. Parental anxiety and concern will diminish.
The costs incurred in treating these very sick
mothers and their ELBW babies will be substantially
reduced. The burden borne by doctors and nurses
staffing neonatal intensive care units will be lightened. Potentially productive lives will be saved, an
important consideration in the light of the current
worldwide AIDS pandemic and its continuing devastating effect on the work force and peoples’
living conditions in Africa and other parts of the
developing world. Much needed fiscal relief will be
Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia
provided for the financially strapped governments
that fund midwifery services in the poorer nations
of the globe.
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