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Thatcher's Thoughts Age related increase in uterine dysfunction during labor

Index for entries posted 11/21/00:

Lower cholesterol -- lower dementia
Age related increase in uterine dysfunction during labor
Worrisome ovarian cysts

Lower cholesterol -- lower dementia
Title: Statins and the risk of dementia
Author: H. Jick, et al.
Address: Lexington, MA 
Source: The Lancet 356:1627-1631 (November) 2000 
Summary: It is estimated that dementia affects 10% of the population older than 65 years and vascular and lipid-related mechanisms are thought to have a role in the pathogenesis of Alzheimer's disease and vascular dementia. Thus, researchers conducted a study of the potential effect of HMG CoA (3 hydroxy-3menthylglutaryl-coenzyme A) reductase inhibitors (statins) and other lipid-lowering agents on dementia. The study population initially included 3 groups who were 50 years and older. Group 1 consisted of all individuals who had received lipid-lowering agents; group 2 included all individuals with a clinical diagnosis of untreated hyperlipidaemia; and group 3 was a randomly selected group of other individuals. From these three groups, all cases with a computer recorded clinical diagnosis of dementia were identified. Each case was matched with as many as four controls derived from the base population on age, sex, practice, and index date of case. Included in the study were 284 subjects with dementia and 1,080 controls. 13% of the controls had untreated hyperlipidaemia, 11% were prescribed statins, 7% other LLAs, and 69% had no hyperlipidaemia or LLA exposure. Researchers found that individuals 50 years and older who were prescribed statins had a substantially lower risk of developing dementia, independent of the presence or absence of untreated hyperlipidaemia or exposure to non-statin LLAs. However, the available data do not distinguish between Alzheimer's disease and other forms of dementia. 
Comment: This reminds me of a cartoon of a physician looking over his desk and telling a perimenopausal patient, "I'm going to take you off additives and put you on preservatives." An interesting comparison might be made with HRT. Both are needed because of our extended life expectancy and to help extend it. Both have benefits greater than the reason for which they are indicated. Both are associated with unwanted side-effects. It is too early to know the impact of lipid lowering agents on large populations over many years. The frontier of pharmaceutical research is drugs to acclimate our genetic predispositions into our 21st century lifestyle. 

Age related increase in uterine dysfunction during labor
Title: The relationship between maternal age and uterine dysfunction: A continuous effect throughout reproductive life 
Author: D. Main, et al. 
Address: San Francisco, CA
Source: American Journal of Obstetrics and Gynecology 183:1312-1320 (November) 2000 
Summary: This study was undertaken to determine whether there is a continuous effect of maternal age on uterine function. Using a comprehensive computerized database and medical record system, researchers identified 8496 low risk patients who were nulliparous and in spontaneous term labor with singleton fetuses in vertex presentation. Subjects were analyzed according to maternal age for measures of labor dysfunction and rates of operative delivery. The use of oxytocin, duration of second stage of labor, cesarean delivery, cesarean delivery for failure to progress and operative vaginal delivery rates were significantly increased with advancing maternal age. These increases appeared to be continuous functions beginning during the early 20s instead of a new phenomenon beginning after age 35. Researchers concluded that among nulliparous patients with uncomplicated labor there is a continuously increasing risk of uterine dysfunction related to maternal age. 
Comment: On analysis of a large number of studies on the adverse effects of aging on pregnancy and labor, there are three risks that seem to stand out as incontrovertible. There is an increased risk of spontaneous abortion / chromosomal abnormalities and there is an increased risk of C-section. Some have stated this is because of the increased incidence of fibroids and anatomic abnormalities. Others have proposed that there is a greater propensity for the obstetrician to intervene because of perceived risk. When both of these are excluded, C-section rates are still higher and seem to be related to uterine dysfunction. 

Worrisome ovarian cysts
Title: Worrisome ovarian cysts 
Author: W. Gotlieb, et al.
Address: Tel Hashomer, Israel 
Source: American Journal of Obstetrics and Gynecology 183:541-546 (September) 2000 
Summary: Researchers performed a retrospective analysis of ultrasonographic characteristics and CA 125 levels in 91 patients with ovarian tumors of borderline malignancy. In 75% of the patients, serous tumors of borderline malignancy were associated with elevated CA 125 levels, compared with 30% of mucinous tumors. In stage IA serous tumors, CA 125 was elevated in 35% of patients, compared with 89% of tumors that had spread beyond the ovary. Mucinous tumors were larger on ultrasonography than serous tumors. Mucinous tumors were also multilocular in half the patients and contained papillations in 40%. Serous tumors were multilocular in 30%, but presented with solid or papillary patterns in 78%. A resistance index of less than 0.4 was found in 36% of mucinous tumors and half the cases of serous tumors. In 13%, ultrasonographic traits were compatible with a simple cyst, including 1 patient with microinvasion and 1 patient with stage IIIB disease. Sensitivity of gray-scale ultrasonography was 87% that of CA 125 measurement was 62%, and that of flow was 55%. At least 1 diagnostic test result was abnormal in 93%, 2 were abnormal in 69%, and all 3 were abnormal in 21%. A high proportion of borderline tumors of the ovary, particularly of the serous type, were associated with elevated CA 125 levels and abnormal ultrasonographic characteristics, although some tumors presented as simple cysts. 
Comment: The great fear is that a cyst found on ultrasound is cancerous. While this is rare in the woman of reproductive age, it does occur. This study was particularly distressing because some of the borderline tumors and 2 cancers were associated with "simple cysts," i.e. those with a thin wall and none of the usual signs that raise suspicion. Persistent cysts should not be dismissed and a CA 125 seems to be a relatively good 2nd step. 

Thatcher's Thoughts Diabetes & Maternal Age

Index for entries posted 09/15/00:

1. Birth weight and risk of type 2 diabetes 
2. Obesity gene
3. Maternal age and risk of type 1 diabetes

Birth weight and risk of type 2 diabetes
Title:The fetal and childhood growth of persons who develop type 2 diabetes
Author: T. Forsen, et al.
Address: Helsinki, Finland
Source: Annals of Internal Medicine 133: 176-182 (August) 2000
Summary:Because type 2 diabetes is linked to low birthweight followed by obesity in adulthood, researchers speculated that those who develop the disease might have a particular pattern of growth from birth through childhood. Thus, they examined the relation of type 2 diabetes to size at birth and childhood growth. Researchers identified 471 men and women born in Helsinki between 1924 and 1933, and still lived in Finland in 1971, who developed type 2 diabetes. The cumulative incidence of type 2 diabetes was 7.9% in men and 5.4% in women. The incidence increased with decreasing birthweight, birth length, ponderal index, and placental weight. The odds ratio for type 2 diabetes was 1.38 for each 1 kg decrease in birthweight. The mean weights and heights of the children at 7 years of age who later developed type 2 diabetes were about average. Thereafter, their growth in weight and height was accelerated until 15 years of age. Children of both sexes whose mothers had a high body mass index in pregnancy had more rapid growth during childhood and an increased incidence of type 2 diabetes. Researchers concluded that their findings are consistent with the hypothesis that type 2 diabetes is programmed in utero in association with low rates of fetal growth. 
Comment: The relationship between low birthweight and insulin resistance is clearly established. There has been less information on birthweight and diabetes. There also seems to be an association between low birthweight and premature adrenarche (pubic hair development). One hypothesis is that stress related to growth restriction results in a premature activation of the adrenal axis. This same effect could contribute to the development of PCOS. A potential outcome of the additional possible effect is the development of PCOS, possibly a non-genetic cause of PCOS. To the contrary, large babies are sometimes associated with gestational diabetes, also a known risk factor for later development of type 2 diabetes. 

Obesity gene
Title:Independent confirmation of a major focus for obesity on chromosome 10
Author: A. Hinney, et al.
Address:Marburg, France
Source:The Journal of Clinical Endocrinology & Metabolism 85:2962-2965 (August) 2000
Summary: Linkage of obesity to chromosome 10p12 with a maximal multipoint LOD score of 4.85 was reported upon use of an affected sib-pair approach including nuclear families in which the adult index case had a BMI greater than or equal to 40kg/m2 and at least one further sibling had a BMI greater than or equal to 27 kg/m2. In an effort to reproduce this linkage finding, researchers genotyped 11 markers spanning approximately 23 cm from 10p13 to 10q11 in a total of 386 individuals stemming from 93 nuclear families with two or more young obese offspring with a BMI greater than or equal to the 90th age percentile. The highest multipoint maximum likelihood binomial LOD score using the extreme concordant sib-pair approach in which one sib had a BMI greater than or equal to the 95th percentile, and other sibs a BMI less than or equal to the 90th percentile was 2.32. Six markers yielded nominal p-values less than 0.05, the highest two point MLB-LOD score of 2.45 was obtained for the marker TCF8. Transmission disequilibrium tests for the most frequent parental allele yielded no nominal p-value less than 0.05. The linkage results confirm the presence of a major susceptibility locus for obesity in a region near the centromere on chromosome 10. 
Comment: Once the (a) gene is found, can it be fixed? 

Maternal age and risk of type 1 diabetes
Title:Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study
Author: P. Bingley, et al. 
Address: Bristol, England
Source:British Medical Journal 321: 420-424 (August) 2000
Summary: In a prospective population based family study, researchers studied the impact of parental age at delivery and birth order on subsequent risk of childhood diabetes. Subjects were 1375 families in which one child or more had diabetes. Of 3221 offspring, 1431 had diabetes and 1790 remained non-diabetic at a median age of 16.1 years. It was discovered that maternal age at delivery was strongly related to the risk of type 1 diabetes in the offspring. The risk increased by 25% for each five year increase of maternal age, so that maternal age at delivery of greater than or equal to 45 years was associated with a relative risk of 3.11 when compared with a maternal age of less than 20 years. Paternal age was also associated with a 9% increase for each five year increase in paternal age. However, the relative risk of diabetes, adjusted for parental age at delivery and sex of offspring, decreased with increasing birth order. The overall effect was a 15% risk reduction per child born. Researchers speculated that the increase in maternal age at delivery in the United Kingdom over the past two decades could partly account for the rise in incidence of childhood diabetes over this period.
Comment: A curious association, but a mechanism is still lacking. 

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