Surgery – Diagnostic testing – Respiratory
Reexamination Certificate
2000-07-14
2002-07-09
Shaver, Kevin (Department: 3736)
Surgery
Diagnostic testing
Respiratory
C600S529000, C600S543000
Reexamination Certificate
active
06416479
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods for using breath carbon monoxide (“CO”), more particularly end-tidal carbon monoxide (“ETCOc”) concentration measurements, to predict the occurrence of various pathological conditions during pregnancy as well as methods for using such measurements to determine the actual onset of such conditions.
BACKGROUND OF THE INVENTION
A. Pregnancy Induced Hypertension, Preeclampsia and the HELLP Syndrome
Pregnancy-induced hypertension (“PIH”) is a common medical complication of pregnancy which encompasses a group of disorders including preeclampsia (“PET”). PET is primarily a disease of the last trimester of pregnancy and is the most common medical complication of pregnancy. It has a reported incidence ranging between 5% and 10% depending on the population demographics.
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As the pathogenesis of these disorders is unclear, prediction and prevention remain an elusive goal.
PET is more common in a woman's first pregnancy and in women whose mothers or sisters had PET. The risk is also higher in women carrying multiple babies, in teenagers, and in women older than 40. Other women at risk include those with high blood pressure or kidney disease before becoming pregnant. The exact cause of PET is unknown. Symptoms of PET often include high blood pressure and proteinuria, and, in severe cases, headaches, blurring of vision and seizures. PET is often referred to by care providers as the “great masquerader” given its ability to mimic many other conditions such as the flu, a kidney infection or gallbladder disease.
End-organ damage, especially to the kidneys and liver, may result if the condition is not recognized early enough, and the condition can be life-threatening. Consequences for the late-term fetus include diminished placental blood flow, and subsequent wasting and asymmetrical growth of the fetus. At present, the best cure for the disease is delivery of the preterm baby followed by intensive neonatal care for the baby and intensive surgical care for the mother.
No single test is currently known which can diagnose PET. A pregnant woman's blood pressure is generally checked at each doctor's visit and a surge in blood pressure can be an early sign of PET. A urine test can determine if protein has been excreted in the urine. Certain blood tests may also indicate PET. When signs of PET appear, a doctor should watch the pregnant woman closely, possibly even daily, for rises in blood pressure, swelling, or urine excretion.
PET, and especially its severe variant, the HELLP (Hemolysis, Elevated Liver Enzymes and Low Platelets) Syndrome, a syndrome with a reported incidence in PET of between 2% and 12%, are frequently misdiagnosed at initial presentation.
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The pathogenesis of the HELLP Syndrome remains unclear. Hemolysis, defined as the presence of microangiopathic hemolytic anemia, is the hallmark of the HELLP Syndrome.
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The diagnosis of hemolysis in pregnant women is currently based on an abnormal peripheral blood smear, increased bilirubin >1.2 mg/dl and an increased lactic dehydrogenase >600 IU/L.
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However, it is difficult to identify women at risk for HELLP Syndrome as severe hypertension is not a constant or even a frequent finding in the HELLP Syndrome.
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Early diagnosis is critical because the morbidity and mortality rates associated with the severe forms of this disease have been reported to be as high as 25 percent.
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Neonatal morbidity and mortality are also high in these pregnancies.
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Since a delay in diagnosing PET can be fatal
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, a better means of identifying women destined to develop PET is desirable. An accurate predictive test may allow timely transfer of patients to centers where adequate intervention and treatment could be promptly provided. Thus far, no test exists that satisfies the criteria for a suitable screening.
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B. Premature Labor
Premature labor remains an important problem facing modem care-givers of pregnant women, demanding tremendous costs for the care of prematurely born infants. Preterm birth is the major cause of perinatal morbidity and mortality in the world. Prematurity is responsible for 75% of infant deaths and 50% of the long-term neurological handicaps, including cerebral palsy, blindness, deafness, and slow development. The survival rate of neonates is improved by 2% per day from the 23rd to the 26th week of pregnancy (i.e., from 16% at 23 weeks to 57% at 26 weeks), reaching an 80% survival rate at 28 weeks, and greater than 90% by 30 weeks of gestation. Therefore, any treatment that prevents or delays premature birth will profoundly reduce neonatal mortality and morbidity rates. However, the use of premature delivery depends on accurate early identification of premature uterine contractions (“PMC”).
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Recent attention has focused on the part that NO might play in maintaining myometrial (uterine smooth muscle) quiescence during pregnancy. CO, like NO, stimulates soluble guanylyl cyclase, thereby raising intracellular levels of cGMP in smooth muscle to produce relaxation. It has been suggested that the L-arginine-NO system may contribute to uterine quiescence during gestation and the initiation of labor at term.
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CO may similarly suppress myometrial contractility. The expression of large increases during pregnancy of heme oxygenase (“HO”), which catalyzes the degradation of heme to biliverdin and CO, has recently been demonstrated in the human myometrium.
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Furthermore, Acevedo and Ahmed have recently shown that induction of HO produces CO that limits uterine contractility in pregnant myometrium indicating a role for the HO—CO-cGMP pathway in the maintenance of the quiescent state of the uterus during pregnancy.
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A subsequent study did not support an up-regulation of HO during pregnancy and the data was inconsistent with a major role for CO in human myometrial quiescence.
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It has recently been found in an analysis of heme oxygenase-1 (“HO-1”) immunoreactive protein of rat uterus and placenta that, during pregnancy, the expression of HO increases, up to day 16, then decreases toward delivery.
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Similarly, in rat tissues during pregnancy it has been found that in the myometrium and placenta, HO-1 mRNA levels increase during pregnancy, up to day 16, then decrease towards delivery.
C. Intrauterine Growth Retardation
Intrauterine growth retardation (“IUGR”) is an important cause of perinatal morbidity and mortality. The pathophysiology that precedes the development of IUGR remains incompletely understood. The importance of the placental blood flow to the growing fetus is obvious. The possible role of HO and its by-product CO in the regulation of blood pressure and blood flow have only been realized over the last few years.
Recently, a case of heme oxygenase-1 (“HO-1”) deficiency was presented.
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The patient had a complete loss of exon-2 of the maternal allele and a two-nucleotide deletion within exon-3 of the paternal allele. This child had severe growth retardation, hemolytic anemia, low bilirubin levels, elevated thromomodulin and Von Wilebrand factor as well as iron deposition in the liver and kidney. This presentation was very similar to that observed in the HO-1 null mutant mice. In normal gestation the HO-1 enzyme is seen at high levels in the neonatal and fetal rat lung and liver, compared to adults.
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A current study found that HO expression in human placenta and placental bed implies a role in regulation of trophoblast invasion and placental function.
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Furthermore, the results suggested a role for CO in placental function, trophoblast invasion, and spiral artery transformation.
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D. The Effect of carbon monoxide in pregnancy
Cigarette smoking during pregnancy has been recognized for over three decades to be associated with reduced risks of PET.
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This paradoxical effect of exposure to tobacco during pregnancy, where smoking reduces the incidence of PET, but increases the perinatal morbidity and mortality and results in a well recognized health hazard to both the mother and her newborn, has long puzzled investigators.
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Natnithithadha Navin
Natus Medical Inc.
Orrick Herrington & Sutcliffe LLP
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