It is well known that babies of low birth weight, defined as 2,500g or lower, born after exposure under harmful uterus environment of the mother who had any kind of stress, are susceptible to lifestyle related diseases in the course of their grown-up to adults. (well known as Barker hypothesis)(1) For example, 8.2 times higher for diabetes mellitus, 18 times higher for hyperlipidemia, 3.6 times higher for coronary-arterial disease (such as myocardial infarction), 3 times higher for depression, as compared to those who were born at normal ranges of their birth weight. (Hales CN et al)(2) Looking at one of the social problems in these days, increasing trend of suicide cannot be determined unrelated to preterm birth and its associated treatments.
Preeclampsia (or gestational hypertension) occurs in 7% to 8% of pregnant women. One of the most serious cause of maternal and neonatal deaths (perinatal deaths ; death between a few weeks before birth and one week after) can be attributed to the disorder. NPO March of Dimes in the United States published their survey revealed up to a million new born died each year globally, within a month after delivery due to preterm birth. The root cause of gestational hypertension and preterm birth, which are major obstetric complications, has yet fully elucidated, thereby symptomatic medications are a sole option for alleviation until present time.
When the mother was challenged by the stress, fetus reacts on the bad environment in the uterus (such as hypoxia; a status that the oxygen supply is not sufficient) then secretes peptide hormone called angiotensin. Angiotensin is a composition of several to ten amino-acids and possesses property to increase the blood pressure. This “act” of fetus is the protection against hypoxic stress challenge, trying to obtain higher blood pressure brought by angiotensin. However, contradiction to this protective effect, excess amount of angiotensin causes high blood pressure on the mother, which is because the hormone evade into the mother's blood circulation through placental barrier (the organ which connects fetus and mother) due to its small molecule size. Gestational hypertension is considered partly determined by excess flow-in of fetal angiotensin into the body of the mother. When treating maternal hypertension with antihypertension drugs, here again, small size compounds of the drug evade into the body of fetus through placenta and exert blood lowering effect on the fetus that is contradictive and worsen utero-environment. In such an undesirable condition of stressful environment, the fetus also secretes another hormone called vasopression, a peptide hormone having properties to contract uterine or suppress urination. Fetus when predicts risk of too early birth (preterm delivery), releases vasopressin, in order to protect itself against hypoxic stress, as seen in the similar mechanism with releasing angiotensin, Vasopressin likewise, flow into the mother’s body through placenta, because of its small molecules, and exert contractile effect on uterus. Preterm delivery is considered partly determined by flow-in of excess amount of fetal vasopressin into the body of the mother. In the course of development, fetus also secretes another different peptide hormone called oxytocin, which possesses property of uterine contraction. As the molecules of this hormone are also small enough to pass placental barrier, hence, produces labor (rhythmical strong contraction of uterus) and brings child birth.
Scientists focused in the past mostly on hormone and its hormonal effects on the human, such as vasocontractile effects of angiotensin, antiurinary effect of vasopression, and utero-contractile effect of oxytocin. These hormones are essential for the growth and thus secreted since after early phase of gestation, however, if over secreted under the stress, may cause placental invasion into maternal blood flow resulting in either physiological (labor) or pathological (gestational hypertension and preterm deliver) reactions of the mother,
Having looked at the mechanisms of feto-maternal relationship a fundamental treatment approach against gestational hypertension and preterm delivery should be the administration of a chemical compound which lyses excess hormones, angiotensin, vasopression, and oxytocin, flew into the mother. Technically, such compounds are called enzyme and such compounds must not pass the barrier of placenta hence not affecting fetus. Here is our proven point of ultimate importance to have this placental enzyme called aminopeptidase (APA or P-LAP) administered and let it lyse excess hormone, consequently lower maternal blood pressure and carry over gestation. (Mizutani S et al.,)(3) This means angiotensin proteinase (APA) has a potent blood pressure lowering effect, vasopressin and oxytocin proteinase (P-LAP) is effective to prolong gestation and can control labor as well as preterm delivery. (results of pre clinical studies) More importantly, APA and P-LAP do not pass the barrier of placenta.
Presently, commonly used drugs to treat gestational hypertension and preterm birth are beta2 receptor agonist which was originally developed for anti-asthma. Another drug is magnesium sulfate originally anti-convulsion. Magnesium sulfate should be used one shot intravenous to the patient when severe hypertension and subsequent eclampsia were observed. Administration is justified when its benefits override side effect, but longer continuous use is getting common recently. High dose of magnesium sulfate may cause side effects such as cardiac arrest. There are some reports the compound is responsible in the increasing events of inter cranial hemorrhage and perinatal deaths. (Mittendorf R, Pryde PG)(4) BfArM(German Drug Agency) published a statement in may 2009 regarding questionable efficacy of magnesium sulfate for the treatment of threatened premature labor.(5) We have found significant hypoplasia in myocardium vessels in rodent pups after long term exposure (later of gestation) of clinical dose of magnesium sulfate to pregnant hypertension rats (SHR) (Ishii et al.,)(6) Beta2 receptor agonists (beta2 stimulants) have numbers of side effects such as tachycardia, hyperglycemia, thrombocytopenia besides a serious adverse side effect of pulmonary edema. Long term administration of beta2 stimulants may cause arrhythmia in the mother, as well as extrasystole, (extra heart beats) and myocardial ischemia. A recent case in the United States FDA is terbutalin, a beta stimulant, received withdrawal mandate both for oral and intravenous (more than 72 hours drip) due to observation of maternal cardiac side effect.(7) Magnesium sulfate and beta2 stimulants are small compounds which easily pass placental barrier and exert stress on the heart of fetus. There is a report on myocardial necrosis in neonate after long term administration of a beta2 stimulant. (Fletcher SE et al.)(8)
It is noteworthy to know the link between start of use of beta2 stimulants in 1970s and increased suicides of young man under the age of 30, was it a coincidence? (9)(10)(11) The use of magnesium sulfate for pregnant women starts from 1990s. Newspapers report families of child cardiomyosis spent a lot of money to receive heart transplantation in the US. Were the abnormality not caused by one of the risk factors responsible in drug exposure in the uterus while a child was in a fetal age. Nevertheless, the reality is physicians had to take few options available at present facing under the life threatening situation of avoiding premature birth of the baby and saving the life of the mother.
In the treatment of severe gestational hypertension, common antihypertension drugs offer limited effects on lowering blood pressure. Together with side effects of these drugs, caesarean operation is often chosen as the only option because removal of the fetus from the mother recovers from high risk hypertension at the expense of ultra low weighted neonates. Consequently, the number of low weighted babies increase.(12)
Can gestational hypertension be treated without using beta2 stimulants or magnesium sulfate?
In the severe gestational hypertension, the level of urinary estrogen and progestin were decreased. From this insight, an old medical literature taught a combined estrogen-progestin medication was effective. (Smith GVS, Smith OW)(13) Based upon this fact, we tried estrogen-progestin therapy, without using antihypertensive drugs, on the patient of severe gestational hypertension, and we witnessed alleviation of hypertensive and edematous symptoms, extension of three weeks of gestation, and delivered a boy weighted 1,750g after caesarean operation. The estrogen-progestin therapy was effective and safe. It was a big challenge for us executing a treatment not approved in the world obstetric medicine. In 1975, we had another opportunity to treat with this therapy on the same severe gestational hypertension mother, the results were similar that blood pressure and edema were improved and a newborn girl weighted 1,850g after three weeks carried over gestation at 38 weeks, was in a very good health condition.(14) (Mizutani S et al.) Despite these convincing results, the limitation of estrogen-progestin therapy is up to three weeks of prolongation of gestation. The mother and her child of this case will join our NPO as a member. The safety of this therapy is thus proven over three generations. Recently, (February 2011) United States FDA published their statement on progestin regimen as one of the recommended medical option in the treatment of preterm birth.(15)
Based upon fore mentioned facts, we have dispatched our slogan that aims to protect fetus against gestational hypertension and preterm delivery and appeal for the development of better drugs early for the clinical use.
Firstly, we will actively educate patients and their families about the disorders of gestational hypertension and preterm birth.
Secondly, we will demonstrate the needs of a new drug aminopeptidase for the optimal treatment of gestational hypertension and preterm birth, and claim for early development and approval of the drug in Japan, which might become an innovative biological product developed in Japan.
Thirdly, we will propagandize usefulness and limitation of estrogen-progestin therapy as an alternative for beta2 stimulants and magnesium sulfate and promote clinical applications.
It is our NPO’s aim to support collapsing situation of the obstetric medicine and a shortage of NICUs in Japan. Since after 1970, we concentrated our research activities on the two important unsolved problems in the obstetric medicine, namely gestational hypertension and preterm threatened birth. Our ultimate goal of this NPO is to contribute for solving medico-social issues in the obstetric medicine, and provide people nationwide with the education for correct knowledge based on our long history of perinatal obstetric research.
The Chairman of a board of NPO Society For Caring Fetus and Mother In Pregnancy Induced Hypertension And Preterm Labor (P-LAP Society)
Professor Emeritus, Nagoya University Director, Daiyabilding Lady's Clinic
Pregnancy induced hypertension occurs in about 7 to 8% of pregnant mothers, and it is one of the most serious causes of obstetric death affecting both mothers and babies. NPO March of Dimes reported as many as one million babies die every year at the time around birth. Yet, with many cases, no fundamental cure is available worldwide.
A serious complication called eclampsia, a sudden-onset life-threatening spasm may follow after severe high blood pressure. Hence, pregnancy induced hypertension was given another term, preeclampsia.
Without precisely known underlying pathology, complete cure or prevention of these abnormalities has not been met even under contemporary medicine. What could be done is giving symptomatic treatments using odd drugs associated with serious side-effects, or otherwise, remove a fetus, or fetuses, from the mother at premature gestational stages. Inevitably newborns became so called low-birth-weight infants who thereafter suffer from handicaps probably in their life-time. So choicelessly, substitute chemicals such as magnesium and beta2 receptor stimulants essentially for treating spasm and asthma respectively, will be excessively used in the hope to prolong gestation. However, this again poses drug-induced adverse effects on the fetus.
Despite the fact that hardly any safer medications available for solving this dilemma, scanty amount of new drug research is undertaken in the area of obstetric treatment.
The biology of mother and baby is a delicate endocrine balance augmented and mediated by a mystique organ called the placenta. Hormones secreted from fetus and enzymes secreted from placenta plays a key role in maintaining the balance all the way through gestational period until the delivery of a baby.
External stimulants such as stress from the mother, environmental chemicals, and adverse drug effects are all dangerous to the fetus.
Because the development of fetus is said replicate 4 billion years of mankind evolution in as short as 280 days, stimulants can affect fetus in various - still comprehensively unknown - ways which may induce lifelong physiological and neuro-psychological dysfunctions. There has been and now increasingly more number of epidemiological and lab based reports address these risks.
Then what can we do now to solve this problem?
Doctor Shigehiko Mizutani, MD Professor emeritus of Nagoya University who is a leading scientist in this field discovered innovative medical strategy tackling these sophisticated problems.
As described earlier, balancing feto-maternal endocrine milieu is in essence, how the placental enzyme react against fetal hormone secretion which is a vital action against environmental stress protecting fetus itself. Simultaneously, placental enzyme neutralizes excess fetal hormone to penetrate into maternal circulation, thus prevent from fetal-hormone-induced high blood pressure. Professor Mizutani identified DNA sequence of this enzyme, led to synthesized, genetic engineered placental leucine aminopeptidase (P-LAP) which is believed to offer the ultimate treatment for pregnancy induced hypertension and prevent preterm birth.
Along his long and massive research path, Professor Mizutani came across to one of the fundamental female hormones, progesterone, having a natural property to maintain gestation and stimulates secretion of placental enzymes. Professor Mizutani, immediately attempted this line of strategy on a pregnant woman with severe hypertension, but with his own inventive application. This unique trial, criticized eccentric against academic common sense that time, was rewarding. Now he witnessed more than 20 babies successfully delivered by their mothers suffering from the disease, noteworthy, without any drug induced adverse consequences.
This year, Professor Mizutani established NPO in Aichi Japan, in the expectation that his natural hormone regimen will become a standard therapy for pregnancy induced hypertension and prevention of preterm birth.
There is no doubt that the base of the drug development must be dictated by medical and social needs and never entirely by economic interests. Our NPO will continue envisaging development of pharmaceutical bio P-LAP, therefore, support from the community, the academy and policy makers as well as drug manufacturers is indispensable.
B.A.1965Nagoya University School of Medicine
M.D.1970Post Graduate course of Nagoya University School of Medicine
(Obstetrics and Gynecology)
|1970-1974||Staff, Nagoya National Hospital,Aichi|
|1974-1977||Chief, Department of Obstetrics and Gynecology, Shizuoka Saiseikai Genaral Hospital, Shizuoka|
|1977-1980||Lecturer, Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Shizuoka|
|1980-1981||Director, Department of Obstetrics and Gynecology, Hamamatsu Medical Center, Shizuoka|
|1981-1982||Director, Department of Obstetrics and Gynecology Nagoya Rinkou Hospital,Aichi|
|1982-1985||Assistant Professor, Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Aichi|
|1985-1987||Lecturer, Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Aichi|
|1987-1997||Assosiate Professor, Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Aichi|
|1997-2000||Professor and Chairman, Department of Obstetrics and Gynecology Nagoya University School ofMedicine, Aichi|
|2000-2004||Professor and Chairman, Department of Obstetrics and Gynecology Nagoya University, Graduate School of Medicine, Aichi|
|2004-||present Professor Emeritus, Nagoya University, Aichi
Adviser, Department of Medical Science of Proteases,
Nagoya University School of Medicine, Aichi
|2004-||present Director, Daiyabilding Lady's Clinic|
Japan Society of Obstetrics and Gynecology (honorary member)
Japan Society Proteases in Pathophysiology (chairman)
The Endocrine Society (honorary member)
|Chairman||Professor Emeritus Nagoya University, Director Daiyabilding Lady's Clinic, Shigehiko Mizutani M.D.|
|Vice-chair||Member of the House of Representatives, Yuko Sato|
|Vice-chair||Director of Office Ob-Gyn Ltd., Hiroyuki Okano|
|Inspector||Professor Emeritus Fujita Health University, Director Nagoya Comprehensive Medical Center, Hitoshi Hishida M.D.|
Robert Mittendorf, MD, DrPH, FACOG