Current Pharmaceutical Design, Volume 11, No. 6, 2005
Contents
Complications in Pregnancy – Recent Developments in Preventive Strategies and Treatment Modalities
Executive Editor: A.C. Bolte
Editorial
A.C. Bolte
A Five Century Evolution of Cervical
Incompetence as a Clinical Entity Pp.687-697
S.M.
Althuisius and G.A. Dekker
Preeclampsia: A Couple’s Disease with
Maternal and Fetal Manifestations Pp.699-710
G.A.
Dekker and P.Y. Robillard
Amino Thiols, Detoxification and Oxidative
Stress in Pre-Eclampsia and Other Disorders of Pregnancy Pp.711-734
M.T.M. Raijmakers, W.H.M. Peters, E.A.P. Steegers and L. Poston
Thrombophilia and Pregnancy Pp.735-748
M.J. Kupferminc
Treatment of Hypertensive Complications in
Pregnancy Pp.749-757
K.H.
Coppage and B.M. Sibai
Pharmacological and Surgical Therapy for
Primary Postpartum Hemorrhage
Pp.759-773
F.W. Bouwmeester, A.C. Bolte and H.P. van Geijn
General Articles
Drug Delivery Strategies for the Treatment of
Helicobacter pylori Infections Pp.775-790
B.R. Conway
Differential Contribution of Clinical Amounts
of Acetaldehyde to Skeletal and Cardiac Muscle Dysfunction in Alcoholic
Myopathy Pp.791-800
Toshiharu Oba, Yoshitaka Maeno and Kazuto Ishida
Mucosal Adjuvants Pp.801-811
L. Stevceva, and M.G. Ferrari
Abstracts
[Back to top] Editorial
A.C. Bolte
During normal pregnancy a series of physiologic changes occur that lead
to major maternal adaptations and that support fetal growth and development. In
uncomplicated pregnancies these impressive physiologic changes in the mother
and the fetus will take place as a rule. Inadequate adaptation to pregnancy
appears to play an important role in the development of complications in
pregnancy. Maladaptation to pregnancy has been associated with recurrent
miscarriage, placental abruption, inadequate fetal growth and fetal death,
preterm birth and a number of maternal gestational disorders. It is recognized
that the fetus, through its paternally derived genes, and the maternal
constitution both contribute to most complications in pregnancy.
Some complications in pregnancy are potentially serious and can be
life-threatening for the mother and her child. For instance, of the problems
that are addressed in this issue about complications in pregnancy, hypertensive
disorders can jeopardize the life of a mother and her child. Massive obstetric
hemorrhage poses chiefly a threat for the mother and preterm birth exposes the
neonate to a diversity of problems associated with prematurity.
Preterm birth is one of the leading causes of neonatal morbidity and
mortality. The incidence of preterm birth in developed countries is
approximately 5 -10%. The etiology of preterm birth is multifactorial. Preterm
birth is induced in about 25% and spontaneous in the remaining 75%. Neonatal
morbidity and mortality are closely related to gestational age. No significant
difference in neonatal morbidity is found between preterm and full term infants
after 32-34 weeks’ gestation. Lowering the incidence of preterm birth and
related neonatal morbidity and mortality remains a major goal in obstetrics.
With regard to spontaneous occurring preterm delivery cervical
incompetence is a specific problem. Intriguing is the fact that the apparent
inability of the uterus to carry the pregnancy to term in the same couple can
differ with subsequent pregnancies.
The results of the Dutch CIPRACT Trial (Cervical Incompetence
Prevention Randomized Cerclage Trial), a multicenter prospective study
comparing management with and without a therapeutic cerclage in women
considered to be at high risk of preterm delivery, provide the foundation for a
thorough review of cervical incompetence by Dr. Sietske Althuisius from the
Department of Obstetrics and Gynaecology at the Vrije Universiteit medical
center, Amsterdam, Netherlands, and by Professor Gus Dekker from Women’s and
Children’s Division Lyell McEwin Health Service, Northern Campus University of
Adelaide, Australia [1].
Induced (iatrogenic) preterm birth for maternal or fetal indications is
frequently associated with the clinical syndrome of preeclampsia. Preeclampsia
is a complex multisystemic disorder of which the cause remains elusive and is
likely multifactorial. There is a relation with defective placentation early in
pregnancy. This defective placentation is most extensively investigated in
preeclampsia but the same pathological changes are observed in placentas from
small for date neonates. This association leads to the suggestion that some
cases of fetal growth restriction differ from preeclampsia only in the maternal
response to a shared placental pathology. In other words the placental problem
causes both maternal and fetal syndromes. The balance of the two syndromes
varies: in some cases there is a major fetal problem and in other cases
maternal problems dominate the clinical picture. The link between abnormal
placentation and the maternal and fetal syndromes is incompletely disclosed.
Inappropriate maternal endothelial cell activation and more recently
generalized intravascular inflammation have been implicated in the mechanisms
of disease responsible for the clinical syndrome of preeclampsia. From the
Women’s and Children’s Division of Lyell McEwin Health Service, Northern Campus
University of Adelaide, Australia and from the department of Neonatology of the
Center Hospitalier Sud-Reunion, France, Professor Gus Dekker and Dr.
Pierre-Yves Robillard in their review discuss the possible role of the maternal
immune system and the feto-placental hemi-allograft in the etiology of
preeclampsia [2].
The role of placental and maternal oxidative stress in preeclampsia and
other disorders of pregnancy is excellently reviewed by Dr. Maarten Raijmakers
and colleagues from the Maternal & Fetal Research Unit, St Thomas'
Hospital, London, United Kingdom. In the paper by Dekker and Robillard as well
as in the paper by Raijmakers and colleagues it is observed that the etiology
and pathogenesis of the preeclamptic syndrome remain elusive and that the
current hypotheses are not mutually exclusive, but most likely interact to some
extend. Thus far results of prevention-studies in either low-risk or high-risk
populations has been disappointing and the increasing knowledge of the
pathology of preeclampsia and other pregnancy-related disorders should help in
designing more successful strategies for prevention [3].
A number of risk factors for preeclampsia and other complications of
pregnancy have been identified. Risk factors are not the cause of the adverse
pregnancy outcome, but their presence increases the susceptibility of for instance
preeclampsia and recurrent miscarriage. Knowledge of the risk factors can help
identifying groups of women at high risk for pregnancy complications and also
has a place in designing preventive strategies. Thrombophilia is one of the
recognized risk factors for adverse pregnancy outcome. Professor Michael
Kupferminc from the Department of Obstetrics and Gynecology, Lis Maternity
Hospital, Tel Aviv Sourasky Medical Center, Israel, discusses the relation
between thrombophilias and adverse pregnancy outcomes and concludes that before
recommendations about treatment can be made definitely more studies are needed
[4].
Hypertensive disorders constitute the most common medical complications
of pregnancy. Chronic hypertension accounts for approximately 30% of
hypertension during pregnancy. In the remaining 70% the hypertension resolves
after delivery and is presumed to be pregnancy-induced and as such a form of
secondary hypertension. Problems encountered when treating hypertension in
pregnancy are the direct and/or indirect fetal effects which sometimes are
intended but often are unwanted. However, evidence exists that the use of
antihypertensive drugs in severe hypertension in pregnancy is beneficial for
the mother. Dr. Kristin Coppage and Professor Baha Sibai from the Department of
Obstetrics and Gynecology at the University of Cincinnati, Ohio, USA, provide
an overview of antihypertensive agents available for the treatment of
hypertensive disorders in pregnancy thereby taken into account the often conflicting
interests of the mother and her baby [5].
Another serious complication of pregnancy is massive primary postpartum
hemorrhage. Uterine atony is still is the leading cause of this obstetric
emergency but with increasing cesarean section rates a steady rise in the
incidence of placenta previa and placenta accreta/percreta is noted as cause of
obstetrical hemorrhage. Management options are reviewed by Drs. Frank
Bouwmeester and colleagues from the Department of Obstetrics and Gynecology,
Vrije Universiteit medical center, Amsterdam, Netherlands [6].
I would like to thank the authors who contributed to this issue about
complications in pregnancy. Although the understanding of pathological
mechanisms that occur in pregnancy has increased steadily over decades
prevention and treatment of many pregnancy complications remain problematic.
Recent advances in the understanding of several pregnancy-related complications
are addressed and new concepts are put forward. Cervical incompetence appears
to be a continuous variable rather than a categoric variable and cervical
incompetence and preterm labor are not distinct entities but rather part of a
spectrum leading to preterm delivery. The results of studies into etiology and
pathogenesis of preeclampsia show that preeclampsia probably is not a distinct
entity but that it is one possible manifestation of maladaptation to pregnancy
that can manifest itself in other ways as well. Increasing knowledge raises new
questions. Tests or early markers for the prediction adverse maternal or fetal
pregnancy outcome are required. This should then stimulate the development and
testing of innovative preventive and treatment strategies.
[Back to top] A Five Century Evolution of Cervical
Incompetence as a Clinical Entity
S.M.
Althuisius and G.A. Dekker
Since cervical incompetence was introduced in the English literature in
1678, our understanding and obstetric management of this clinical entity, have
changed tremendously over the years. This review shows the historical
perspective of the development of cervical incompetence as a distinct clinical
entity and an all or nothing phenomenon to cervical incompetence as part of a
spectrum leading to preterm delivery, which can express differently in
subsequent pregnancies. These changes in our understanding imply consequences
for the obstetric management of cervical incompetence.
This review focuses on the obstetric management of women considered to
be at high risk of preterm delivery due to cervical incompetence, by
transvaginal ultrasonographic follow-up of cervical length and transvaginal
cervical cerclage.
[Back to top] Preeclampsia: A Couple’s Disease with
Maternal and Fetal Manifestations
G.A.
Dekker and P.Y. Robillard
Preeclampsia still ranks as one of obstetrics major problems.
Clinicians typically encounter preeclampsia as maternal disease with variable
degrees of fetal involvement. More and more the unique immunogenetic
maternal-paternal relationship is appreciated, and as such also the specific
‘genetic conflict’ that is characteristic of haemochorial placentation. From
that perspective preeclampsia can also been seen as a disease of an individual
couple with primarily maternal and fetal manifestations. Factors that are
unique to a specific couple would include the length and type of sexual
relationship, the maternal (decidual natural killer cells) acceptation of the
invading cytotrophoblast (paternal HLA-C), and seminal levels of transforming
growth factor-b and probably other cytokines. The magnitude
of the maternal response would be determined by factors including a maternal
set of genes determining her characteristic inflammatory responsiveness, age,
quality of her endothelium, obesity/insulin resistance and probably a whole
series of susceptibility genes amongst which the thrombophilias received a lot
of attention in recent years.
[Back to top] Amino Thiols, Detoxification and Oxidative
Stress in Pre-Eclampsia and Other Disorders of Pregnancy
M.T.M. Raijmakers, W.H.M. Peters, E.A.P. Steegers and L.
Poston
New knowledge of placental development and function suggests that
several common complications of pregnancy could share a similar origin. It is
suggested that impaired placental development in early pregnancy may lead to
placental oxidative stress and subsequently to the maternal syndromes such as
recurrent early pregnancy loss and pre-eclampsia. Oxidative stress has been
most extensively investigated in pre-eclampsia, resulting in hundreds of
publications and many reviews. In general the literature points to the presence
of placental and maternal oxidative stress. However, conformity amongst the
relevant data is not absolute, most probably the result of the diversity of
biomarkers investigated and the methods employed to assess oxidative stress,
which generally depend on the assessment of end products of oxidative stress.
Recently, new techniques have been developed that use different approaches
based on the “real-time” measurement of oxidative stress by the redox status of
thiols or the assessment of superoxide generation, whereas the role of Phase
I/Phase II biotransformation pathways in oxidative stress was recognised.
This review focuses on this biotransformation system, the thiol redox
status and the involvement of these systems in oxidative stress associated with
reproduction and pregnancy disorders, with the emphasis being laid on the
syndrome of pre-eclampsia.
[Back to top] Thrombophilia and Pregnancy
M.J. Kupferminc
Preeclampsia, intrauterine growth restriction and placental abruption
greatly contribute to maternal and fetal morbidity and mortality. Thrombophilia
is an inherited or acquired condition that predisposes individuals to venous
and/or arterial thrombosis. Recently, three important inherited thrombophilias
have been discovered. An inherited mutation in the gene coding for coagulation
factor V (factor V Leiden), and a mutation in prothrombin that is associated with
higher plasma levels of prothrombin. Both mutations result in an increased
susceptibility to develop venous thrombosis. Hyperhomocysteinemia, which is
associated with mutations in the gene for methylenetetrahydrofolate reductase,
is a risk factor for venous and arterial thrombosis. The presence of
antiphospholipid antibodies, an acquired thrombophilic condition, is associated
with venous and arterial thrombosis.
The term placental vasculopathy, is used to describe pathological
placental changes that have been associated with preeclampsia, intrauterine
growth restriction, placental abruption and fetal loss. The known thrombotic
nature of the placental vasculopathy and the increased thrombotic risk with the
presence of thrombophilias suggest, a cause-and-effect relationship between
inherited and acquired thrombophilias and a number of severe obstetric
complications. Testing patients with these complications for thrombophilias may
have therapeutic implications for future pregnancies.
[Back to top] Treatment of Hypertensive Complications in
Pregnancy
K.H. Coppage and B.M. Sibai
Hypertension is the most common medical disorder during pregnancy [1].
Approximately 70 percent of women diagnosed with hypertension during pregnancy
will have gestational hypertension-preeclampsia. The term gestational
hypertension-preeclampsia is used to describe a wide spectrum of patients who
may have only mild elevation in blood pressure to those with severe
hypertension with various organ dysfunctions (acute gestational hypertension,
preeclampsia, eclampsia, and the syndrome of hemolysis, elevated liver enzymes,
and low platelets (HELLP syndrome). The exact incidence of gestational
hypertension-preeclampsia in the United States is unknown. Estimates range from
6% to 8% of all pregnancies [1].
The treatment of hypertensive disorders in pregnancy requires careful
assessment of the maternal and fetal conditions. Therapeutic decisions must
take into account fetal age, maternal symptoms, tests of fetal well-being, as
well as maternal status, in order to ensure the best overall outcome. Treatment
of mild gestational hypertension with antihypertensive medications has not been
shown to improve outcome, however, in cases of severe disease treatment has
been shown to be beneficial.
The purpose of
this review is to discuss the different treatment modalities used in the
hypertensive disorders of pregnancy. Management strategies will not be
discussed.
[Back to top] Pharmacological and Surgical Therapy for
Primary Postpartum Hemorrhage
Early postpartum hemorrhage remains a significant cause of maternal
morbidity and mortality. Postpartum hemorrhage is most commonly due to uterine
atony and often responds to medical treatments such as administration of
uterotonic drugs, alone or in combination with uterine massage or bimanual
compression. As the incidence of cesarean section continues to rise, the
problem of placenta previa and accreta is likely to become more common. For
first-line management of postpartum hemorrhage adequate blood and fluid
replacement is mandatory. In recent years new therapeutic measures to control
the bleeding have gained attention. Although, these newer therapies focus on
avoiding the need for emergency hysterectomy and preservation of reproductive
function, reports of subsequent pregnancies are still scarce. Established
management options are shortly reviewed and novel medical and surgical
treatments are more extensively discussed.
[Back to top] Drug Delivery Strategies for the Treatment of
Helicobacter pylori Infections
B.R. Conway
Helicobacter pylori
is one of the most common pathogenic bacterial infections, colonising an
estimated half of all humans. It is associated with the development of serious
gastroduodenal disease - including peptic ulcers, gastric lymphoma and acute
chronic gastritis. Current recommended regimes are not wholly effective and
patient compliance, side-effects and bacterial resistance can be problematic.
Drug delivery to the site of residence in the gastric mucosa may improve
efficacy of the current and emerging treatments. Gastric retentive delivery
systems potentially allow increased penetration of the mucus layer and
therefore increased drug concentration at the site of action. Proposed gastric
retentive systems for the enhancement of local drug delivery include floating
systems, expandable or swellable systems and bioadhesive systems. Generally,
problems with these formulations are lack of specificity, limited to mucus
turnover or failure to persist in the stomach. Gastric mucoadhesive systems are
hailed as a promising technology to address this issue, penetrating the mucus
layer and prolonging activity at the mucus-epithelial interface. This review
appraises gastroretentive delivery strategies specifically with regard to their
application as a delivery system to target Helicobacter.
As drug-resistant strains emerge, the development of a vaccine to eradicate
and prevent reinfection is an attractive proposition. Proposed prophylactic and
therapeutic vaccines have been delivered using a number of mucosal routes using
viral and non-viral vectors. The delivery form, inclusion of adjuvants, and
delivery regime will influence the immune response generated.
[Back to top] Differential Contribution of Clinical Amounts
of Acetaldehyde to Skeletal and Cardiac Muscle Dysfunction in Alcoholic
Myopathy
Toshiharu Oba, Yoshitaka Maeno and Kazuto Ishida
Acute intoxication due to alcohol consumption has been known to elicit
reversible skeletal and cardiac muscle dysfunction, or “alcoholic myopathy and
cardiomyopathy”. Sometimes, irreversible muscle damage can be induced after
heavy alcohol drinking. Many researchers have proposed that acetaldehyde, the
major oxidised product of alcohol, may be a primary factor underlying
alcohol-induced muscle dysfunction. Because acetaldehyde is rapidly metabolised
to acetate by aldehyde dehydrogenase (ALDH) mainly in the liver, blood
concentration of acetaldehyde is maintained at a low level even after heavy
alcohol intoxication. In alcoholics, blood acetaldehyde level is relatively
high, probably due to hepatic inhibition of ALDH activity. Several mM of
acetaldehyde have been used for studies of cardiac muscle contraction, the
intracellular calcium transient, and the L-type calcium channel. In skeletal
muscle, the calcium release channel/ryanodine receptor activity has been
reported to be inhibited by exposure to 1 mM acetaldehyde. However, these
observations were made using potentially lethal concentrations of acetaldehyde,
so the hypothesis that acetaldehyde plays a crucial role on alcoholic myopathy
is questionable. In this review, we will summarise the effect of alcohol and
its major oxidised product, acetaldehyde, on skeletal and heart muscles and
propose a toxic contribution of clinical concentrations of acetaldehyde to
alcoholic myopathy. In addition, this review will include briefly the effect of
acetaldehyde on diabetic cardiomyopathy.
[Back to top] Mucosal Adjuvants
L. Stevceva, and M.G. Ferrari
Vaccines delivered through mucosal surfaces are increasingly studied
because of their properties to effectively induce mucosal immune responses, are
cheap, easily administrable and suitable for mass vaccinations. The prospects
of development of edible and intranasally administered (perhaps through nose
drops or spray) vaccines are inciting a lot of interest and generating many
studies. One major obstacle is to be able to induce systemic as well as mucosal
responses to mucosal vaccines. Apart from immunizing with live viruses, this
has proven to be a challenge and one way to overcome it is by using adjuvants.
It is well established that toxins with little or no capacity to activate
adenylate cyclase and thus lacking toxicity (CT or mutant Echerichia Coli
labile toxin) improve performance of mucosal vaccines. Synthetic
oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG) have
synergistic action with other adjuvants, such as alum and CT when delivered
mucosally. There are several other important candidates for use as mucosal
adjuvants. The proinflammatory cytokines IL-1a,
IL-12, and IL-18 can replace CT as a mucosal adjuvant for antibody induction
and induce an increase of mucosal CTL’s. IL-15 also has the potential to
increase antigen-specific CTL activity when used as an adjuvant while IL-5 and
IL-6 were shown to be able to markedly increase IgA reactivity to co-expressed
heterologous antigen. Chemokines such as MCP-1 could also be used as potential
adjuvant for mucosally administered DNA vaccines as it significantly increases
mucosal IgA secretion and CTL responses.