Outcome of pregnancy in users of natural family planning.
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Animals↗
Biomedical subjects
J L Simpson
Publications and source records attributed to J L Simpson.
Disorders of gonadal development in humans.
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Disorders of Sex Development↗
Translocations are infrequent among couples having repeated spontaneous abortions but no other abnormal pregnancies.
During the years 1977 to 1986, cytogenetic studies were performed on 342 women and 297 men whose reproductive history included one or more first trimester spontaneous abortions. Thirty-nine women and 35 men experienced not only early fetal losses but also one or more stillborn infants, liveborn anomalous infants, or early neonatal deaths. Among the 303 women and 262 men evaluated solely because of repetitive abortions, only 1 woman and 1 man showed a translocation. Two translocations were detected among the 39 women and 35 men having not only repetitive abortions but also a stillborn infant, anomalous liveborn, or unexplained neonatal death. Only among the 25 women having abortions and other abnormal perinatal events was the frequency of translocations high (2/25 or 8%). Our data continue to indicate that balanced chromosomal translocations are relatively infrequent in individuals having repeated abortions but no other adverse perinatal outcome.
Abortion, Habitual↗
Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception.
Whether pregnant women with insulin-dependent diabetes mellitus have an increased risk of spontaneous abortion is controversial. To address this question, we enrolled 386 women with insulin-dependent diabetes and 432 women without diabetes before or within 21 days after conception and followed both groups prospectively. Sixty-two diabetic women (16.1 percent) and 70 control women (16.2 percent) had pregnancy losses (odds ratio, 0.99; 95 percent confidence interval, 0.67 to 1.46). After adjustment for known risk factors for spontaneous abortion, the rate was still not significantly higher in the diabetic group (odds ratio, 0.91; 95 percent confidence interval, 0.59 to 1.40). Nonetheless, among the diabetic women, most of whom had good metabolic control, those who had spontaneous abortions had higher fasting and postprandial glucose levels in the first trimester than those whose pregnancies continued to delivery (P = 0.01 for fasting glucose levels and P = 0.005 for postprandial levels). In the small subgroup of diabetic women with poor control, who had elevated values for glycosylated hemoglobin in the first trimester, each increase of 1 SD above the normal range was associated with an increase of 3.1 percent in the rate of pregnancy loss (95 percent confidence interval, 0.6 to 5.6). We conclude that diabetic women with good metabolic control are no more likely than nondiabetic women to lose a pregnancy, but that diabetic women with elevated blood glucose and glycosylated hemoglobin levels in the first trimester have a significantly increased risk of having a spontaneous abortion.
Abortion, Spontaneous↗
Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis.
To determine how much insulin-dependent diabetes increases a woman's risk of giving birth to a malformed infant and how that risk is influenced by metabolic control, we followed 347 diabetic and 389 control women who enrolled in the study within 21 days of conception (the early-entry group) and 279 diabetic women who entered later (the late-entry group). We detected major malformations in the infants of 4.9 percent of the early-entry diabetic women, 2.1 percent of the controls, and 9.0 percent of the late-entry diabetic women. Malformation rates were significantly higher among offspring of early-entry diabetic women than among those of controls (odds ratio, 2.45; lower one-sided 95 percent confidence limit, 1.12; P = 0.027), and higher among late-entry than among early-entry diabetic women (odds ratio, 1.91; lower one-sided 95 percent confidence limit, 1.07; P = 0.032). Mean blood glucose and glycosylated hemoglobin levels during organogenesis were not significantly higher in women whose infants were malformed. Hypoglycemia (glucose, less than or equal to 50 mg per deciliter [2.8 mmol per liter]) was not significantly more common in the same group. Hyperglycemia and glycosylated hemoglobin were not correlated with malformation. The data suggest that more sensitive measures are needed to identify the teratogenic mechanisms, or that not all malformation can be prevented by good glycemic control. Despite the increased malformation rate among infants of the early-entry diabetic women, as compared with the controls, the more favorable outcome seen in the former group as compared with the late-entry group justifies the attempt to achieve good metabolic control around the time of conception.
Blood Glucose↗
Parental decision following prenatal diagnosis of fetal chromosome abnormality.
In the event of prenatal diagnosis of fetal chromosome abnormality, parents must choose between continuation and termination of the pregnancy. To determine whether parents are capable of understanding differences in severity among aneuploidy syndromes, we examined the outcome chosen for all pregnancies in which a fetal chromosome disorder was diagnosed at Northwestern Memorial Hospital between January, 1977 and June, 1986. Among amniocentesis cases, 88% with autosomal aneuploidy were terminated, but only 41% with sex chromosome abnormalities and none with de novo structural rearrangements were terminated. Among a smaller group of chorionic villus sampling cases, all with abnormal results were terminated. Similar patterns of parental behavior were noted in other prenatal diagnosis units. We conclude that parents do distinguish among, and respond specifically to, fetal chromosome disorders of differing severity, at least in the second trimester of pregnancy. However, parents appear more inclined to terminate all pregnancies with chromosome abnormalities when the diagnosis has been made in the first trimester.
Abortion, Spontaneous↗
Pregnancy outcome associated with natural family planning (NFP): scientific basis and experimental design for an international cohort study.
Although natural family planning (NFP) is a form of contraception without ostensible maternal risks (other than pregnancy), potential fetal risks could exist if aging gametes are involved in inadvertent fertilization. In the following report, we first review animal studies firmly establishing that aging sperm and aging oocytes (delayed fertilization) cause chromosomal abnormalities in mammals and other species. We next review human studies associating decreased coital frequency with trisomy and studies of NFP populations that generally show no increased frequency of anomalous offspring or spontaneous abortions. Our rationale for initiating an international cohort study is presented, along with the experimental design selected. Preliminary findings indicate that the experimental design chosen will indeed provide information allowing NFP safety to be assessed definitively.
Aging↗
Growth disadvantage of 45,X and 46,X,del(X)(p11) fibroblasts.
We have previously shown that cell generation time (CGT) is prolonged in 45,X and certain X-deletion fibroblast lines (Simpson & Le Beau 1981). A consequence of that finding should be that cells with 45,X or an X-structural abnormality are at a competitive disadvantage when cocultivated with 46,XX cells. To test this hypothesis we prepared 15 minutes of cells from combinations of 9 different cell lines: four 45,X; one 46,Xdel(X)(p11); and four 46,XX. Each culture was monitored cytogenetically at frequent passage intervals for the percentage of the two cell lines. Significant differences were found between normal and abnormal lines in culture predominance, in the order predicted by our hypothesis (p less than 0.01). The specific mechanism by which absence of an X chromosome confers growth disadvantage is unknown, but is consistent with prolongation of CGT. Prolongation of CGT could also be responsible for the embryonic lethality, intrauterine growth retardation, short stature, and somatic anomalies commonly observed in individuals with absent or aberrant X chromosomes.
Cell Division↗
Low fetal loss rates after ultrasound-proved viability in early pregnancy.
Once pregnancy is recognized clinically, it is accepted that 12% to 15% undergo spontaneous abortion. However, the actual time of fetal demise has not yet been determined. To address this question, the outcomes of pregnancies identified before 21 days of conception by serum beta-human chorionic gonadotropin assays were studied. All subjects underwent ultrasound examinations at eight and 12 weeks' gestation. Among 220 women who had a viable pregnancy at eight weeks, only seven (3.2%) experienced a fetal loss thereafter. The results of this study suggest that most clinically recognized spontaneous abortions manifested after eight weeks actually represent pregnancies in which fetal demise occurred before eight weeks. These findings have important implications with respect to the safety of chorionic villi sampling and to the identification of exogenous agents that cause fetal wastage.
Abortion, Spontaneous↗
Metabolic basis for the protective effect of the antioxidant ethoxyquin on aflatoxin B1 hepatocarcinogenesis in the rat.
The effect of dietary administration of 0.5% ethoxyquin (EQ) on the in vivo induction of enzymes and effect on aflatoxin B1 (AFB1)-DNA binding in liver and the consequent in vitro metabolism of AFB1 by male Fischer F344 rat liver-derived fractions have been examined. EQ increased microsomal cytochrome P-450s, in particular those isozymes classed as phenobarbital inducible, and the in vitro rate of metabolism of AFB1. The formation of the presumed detoxified metabolites, aflatoxins M1 and Q1, was enhanced to a greater extent than was the formation of the active metabolite, aflatoxin B1-8,9 epoxide (assessed by the level of aflatoxin B1-8,9-dihydrodiol). Prolonged feeding with EQ was accompanied eventually by a reduction in the initially elevated cytochrome P-450 content, but this was not reflected in any significant decrease in the rate of AFB1 metabolism in vitro. EQ increased the glutathione S-transferase activity of the liver cytosol fractions as assessed with the model substrate 1-chloro-2,4-dinitrobenzene. The capacity of these fractions specifically to catalyze the conjugation of AFB1 with glutathione was induced to a far greater extent than was the conjugation of 1-chloro-2,4-dinitrobenzene. gamma-Glutamyl transpeptidase was induced in the periportal areas of the liver lobule. Reduced in vivo binding of [3H]AFB1 to DNA of liver and kidney was found to result from EQ treatment. It is concluded that the reduced hepatocarcinogenesis which results from feeding EQ simultaneously with AFB1 is due to the reduction in DNA-adduct formation which in turn is due at least in part to increased detoxifying metabolism in the microsomal, cytosolic, and plasma membrane compartments of the liver cells.
Aflatoxin B1↗
Fibrinopeptide A increases after chorionic villus sampling.
Fibrinopeptide levels were measured in 20 women during transcervical chorionic villus sampling (CVS). Fibrinopeptide A, a sensitive indicator of fibrinogen cleavage by thrombin, significantly increased in five subjects, whereas there was no change in B beta peptide, an indicator of fibrinolysis. The data suggest that modest fibrin formation, uncompensated by fibrinolysis, may be induced in some women by CVS.
Adult↗
Low maternal serum alpha-fetoprotein and perinatal outcome.
Pregnancy outcome was followed prospectively in women showing maternal serum alpha-fetoprotein values less than 0.4 multiple of the median. Using a radioimmunoassay later shown by others to produce a disproportionate number of low values, we nonetheless detected all three cases of autosomal trisomy (+18, +18, +21) at amniocentesis in 1531 women screened. Although two fetal losses and two autosomal trisomies (trisomy 18) occurred among a subgroup of only 15 women having two values less than 0.25 multiple of the median, fetal losses were in general far less frequent among the 99 women with at least one maternal serum alpha-fetoprotein value less than 0.4 multiple of the median than among women in previous reports. Comparing women with maternal serum alpha-fetoprotein values less than 0.4 multiple of the median against those with normal values (0.4 to 2.49 multiples of the median) also revealed no significant differences with respect to presence or absence of a variety of antepartum or intrapartum complications. Birth weight, gestational age, arterial cord pH, and Apgar scores also failed to differ significantly (one-way analysis of variance, p greater than 0.05). Women with a viable pregnancy who show low maternal serum alpha-fetoprotein values have a more favorable prognosis than previously claimed.
Chromosome Aberrations↗
Abnormal sexual differentiation and neoplasia.
The prevalence of neoplasia is increased in individuals with certain disorders of sexual differentiation. Etiology and frequency of neoplasia vary with the particular disorder. In uncomplicated cryptorchidism, the testis is at least 10 times more likely to undergo neoplastic transformation than a normal scrotal testis. Neoplasia probably is a function of both testicular location (intraabdominal) and underlying dysgenetic structure. If cryptorchidism is unilateral, and if orchiopexy has not been performed prior to age 6-10 years, orchiectomy should be encouraged. In those forms of gonadal dysgenesis not associated with a Y chromosome (e.g., 45,X; 45,X/46,XX; 46,XX) there is no definite increase in neoplasia, suggesting that elevated gonadotropin levels per se are not carcinogenic. Gonadal tumors are found in at least 30% of individuals with XY gonadal dysgenesis and are particularly frequent (55%) in H-Y antigen-positive patients. These tumors are almost always gonadoblastomas or dysgerminomas. Similar tumors are found in 15%-20% of 45,X/46,XY individuals. In either situation the neoplastic transformation could be a) secondary to the existence of XY gonadal tissue in an inhospitable environment, or b) integrally related to that process--genetic or cytogenetic--producing the dysgenetic gonads. The risk of neoplasia is sufficiently high that most of these patients should be offered early gonadal extirpation. The prevalence of gonadal tumors is not increased in Klinefelter's syndrome, further indicating that gonadotropins are not carcinogenic per se. However, Klinefelter patients are 20 times more likely to develop a carcinoma of the breast than are 46,XY males. Extragonadal germ cell tumors also are more common. In female pseudohermaphrodites there is probably no increased risk of neoplasia, whereas, in true hermaphrodites neoplasia is unusual but does occur. Neoplasia occurs in patients with complete testicular feminization (complete androgen insensitivity) but rarely in those with incomplete testicular feminization/Reifenstein's syndrome, 5 alpha-reductase deficiency, anorchia, agonadia, or testosterone biosynthetic defects. In complete testicular feminization the risk of malignant tumors is small prior to age 25. After age 25, it is about 2%-5%. Orchiectomy is recommended after pubertal feminization.
Disorders of Sex Development↗
Induction of gamma-glutamyl transpeptidase mRNA by aflatoxin B1 and ethoxyquin in rat liver.
We have studied the induction of rat liver gamma-glutamyl transpeptidase (GGT) mRNA by the antioxidant ethoxyquin and during aflatoxin B1-induced carcinogenesis. Using a rat kidney GGT cDNA probe, Northern blot analysis revealed that GGT mRNA induced in liver by either compounds was slightly larger than that found in untreated kidney. GGT mRNA was not detected in untreated liver or freshly isolated hepatocytes, but induction of the message in treated tissues correlated with the increase in enzymic activity observed by histochemistry and quantitative assay. Slot-blot analysis of poly(A)+ mRNA indicated that constitutive GGT mRNA levels in kidney were at least 5-fold greater than those in the most GGT-positive liver-derived tissue examined.
Aflatoxin B1↗
Verification of early pregnancy tests in a multicenter trial.
Tests for the diagnosis of early pregnancy have been available since 1974. However, no studies have systematically verified the accuracy of routine clinical laboratories in measuring human chorionic gonadotropin (hCG) prior to the time that pregnancy is clinically evident. We have conducted such a study in association with the NICHD-funded Diabetes in Early Pregnancy Study (DIEP). The purpose of this study was to elucidate the etiology of malformations in pregnancies complicated by diabetes mellitus, which probably occurs within the first few weeks of pregnancy, and therefore uniformity of pregnancy testing was necessary among the five centers to find an association of a teratogen at the time of organogenesis. We confirmed that routine clinical laboratories, in fact, could measure accurately hCG at the time of the missed menses; however, detection was not necessarily possible prior to that time. We conclude that in order to assure accurate diagnosis of early pregnancy, tests should ordinarily be delayed until time of the missed menses. When the test is used at this time, it is a reliable tool for early pregnancy testing and thus can be used to resolve questions relating to early pregnancy pathophysiology.
Chorionic Gonadotropin↗
Maternal serum alpha-fetoprotein screening in 1987.
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Adult↗
Prenatal effects of maternal-fetal HLA compatibility.
Both retrospective studies of idiopathic aborters, as well as prospective studies of normal couples, have shown reduced fertility among couples sharing HLA antigens. However, the effects of maternal-fetal histocompatibility on surviving embryos are largely univestigated. We thus prospectively studied 53 healthy, fertile women whose timed pregnancies were verified within 21 days of conception. Maternal-fetal histocompatibility status was determined for HLA-A,-B, and -DR locus antigens. Fetal growth rates were monitored by ultrasound at 8, 12, and 20 weeks gestation. Neonates were weighed, measured (birthlength, chest circumference, head circumference), and examined within 72 h of delivery (116 major and minor anomalies) in standardized fashion by one of two geneticists. Although no significant differences were found between infants compatible and incompatible at the HLA-A or HLA-B locus, significant differences were observed between HLA-DR compatible and incompatible infants for sex ratios (p less than .003) and minor anomaly rates (p less than .05). Although differences in mean birthweights between HLA-DR compatible and incompatible infants were not significant in this sample, HLA-DR compatible infants were on average 200 grams smaller than HLA-DR incompatible infants. We interpret these findings as evidence for selection against histocompatible fetuses throughout gestation, particularly with respect to HLA-DR compatibility. Potential immunologic and genetic mechanisms are discussed.
Adult↗
Gender testing in the Olympics.
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Humans↗