Insulin release from isolated human fetal pancreatic islets.

Pancreases were obtained from five human fetuses 12 to 16 weeks old. The islets of Langerhans were isolated with collagenase, and then incubated with buffer, glucose, tolbutamide, or glucagon added to the medium. The insulin released into the medium was measured by immunoassay. Glucagon produced the only significant increase above base line; glucose and tolbutamide failed to enhance secretion of insulin. The data suggest that isolated human fetal islets of this gestational age develop responsiveness to glucagon earlier than to glucose or tolbutamide.

Strain of mycoplasma associated with human reproductive failure.

A strain of mycoplasma not previously described has been isolated from the chorion, decidua, and amnion of a patient who sustained a spontaneous abortion during the middle trimester. The fetal membranes exhibited an inflammatory reaction, but no evidence of other infectious agents, bacterial or viral, was noted. The T strain identified is not a classical mycoplasma; it differs in growth and nutritional requirements from the T strains previously characterized.

Ureaplasma urealyticum incriminated in perinatal morbidity and mortality.

Perinatal morbidity and mortality are associated with colonization of the chorionic surface of the placenta by Ureaplasma urealyticum or Mycoplasma hominis or both. These organisms are more strongly associated with unfavourable gestational outcome than group B streptococci. Chlamydia trachomatis does not appear to be important in the etiology of reproductive casualties. The mechanisms linking the mycoplasmas to perinatal disorders and death are not clear but merit investigation.

Endocrine studies in anencephaly.

Endocrine function has been investigated in four anencephalic neonates to determine the influence of absence of cortical and hypothalamic tissue and of hypoplasia of the pituitary. Intravenous glucose administration resulted in higher peak values for blood sugar and more rapid glucose disposal rates than reported in normals. Intravenous insulin tolerance tests on two of the infants failed to evoke elevations in plasma growth hormone, and the infants showed a remarkable resistance to the hypoglycemic effect of insulin. Administration of lysine-vasopressin caused an active growth hormone release. Similarly, there was a large increase in serum thyrotropin after administration of synthetic thyrotropin-releasing hormone. Basal levels of both thyrotropin and growth hormone were low as compared with values reported for normal newborns. Prolactin values obtained on three of the infants were in the normal range. The results strongly suggest that anterior pituitary function mediated by the hypothalamus and its releasing factors is deficient in anencephaly. However, the anterior pituitary can release growth hormone and thyrotropin when stimulated directly and, in the case of thyrotropin release, may function autonomously. The normal prolactin values presumably reflect the absence of the hypothalamic prolactin inhibitory factor.

Oral contraceptive use and risk of gestational trophoblastic tumors.

BACKGROUND: Gestational trophoblastic disease refers to a spectrum of rare benign and malignant gynecologic disorders whose pathogenesis is not well understood. Recent studies from China and the United States have raised the hypothesis that long-term use of oral contraceptives before conception may increase the risk of gestational trophoblastic tumors. A multicenter case-control study of gestational trophoblastic tumors was undertaken to test this hypothesis. METHODS: Telephone interviews were conducted with 235 case patients, including 50 with gestational choriocarcinoma, and 413 control subjects matched on recentness of pregnancy, age at pregnancy, and area of residence. Relative risks (odds ratios) were computed by conditional logistic regression. Reported P values are two-sided. RESULTS: The relative risk estimate for ever having used oral contraceptives before the index pregnancy was 1.9 (95% confidence interval [CI] = 1.2-3.0), and the risk increased with duration of use (P for trend = .05). The estimate was highest for women who used oral contraceptives during the cycle in which they became pregnant (relative risk = 4.0; 95% CI=1.6-10), but there was no consistent pattern according to the time interval since last use. Separate analyses of choriocarcinoma and persistent mole yielded similar results, i.e., the relative risk estimates for oral contraceptive use were 2.2 (95% CI=0.8-6.4) and 1.8 (95% CI=1.0-3.0), respectively. Control for the number of sexual partners, which was independently associated with risk (P for trend = .05), did not materially change the results. CONCLUSIONS: This study, the largest to date, indicates that long duration of oral contraceptive use before conception increases the risk of gestational trophoblastic tumors. These findings may provide clues to the pathogenesis of this rare disease. Changes in use of oral contraceptives are not warranted, however, because the incidence attributable to oral contraceptive use is very low.

PIP: Recent studies in the US and China have suggested that long-term use of oral contraceptives (OCs) before conception increases the risk of gestational trophoblastic tumors. This association was investigated further in a study conducted at 8 US medical centers that specialize in the treatment of this gynecologic disorder. 235 cases, including 50 women with gestational choriocarcinoma, were matched with 413 controls on recentness of pregnancy, age at pregnancy, and area of residence. The relative risk estimate for ever-use of OCs before the index pregnancy was 1.9 (95% confidence interval [CI], 1.2-3.0) and the risk increased with duration of OC use. The relative risk was highest (4.0; 95% CI, 1.6-10.0) for women who used OCs during the cycle in which they became pregnant, but there was no consistent pattern according to the time interval since last OC use. The relative risks for choriocarcinoma and persistent mole associated with OC use were 2.2 (95% CI, 0.8-6.4) and 1.8 (95% CI, 1.0-3.0), respectively. This study, the largest to date, suggests that a long duration of OC use before conception does, indeed, increase the risk of gestational trophoblastic tumors.

Developmental phase-specific alkaline phosphatase isoenzymes of human placenta and their occurrence in human cancer.

Alkaline phosphatase electrophoretic patterns characteristic of three phases in early human trophoblast development are described in this preliminary communication. Phase 1 (6 to 10 weeks) consists entirely of two heat-sensitive, L-homoarginine-inhibited bands, the slower one of which possesses antigenic determinants of live-bone-type alkaline phosphatase, whereas the fast band lacks any of the known alkaline phosphatase antigenic determinants. Phase 2 pattern (11 to 13 weeks) is that of a mixture of Phase 1 and Phase 3 isozyme components, the latter exhibiting two isozyme bands with the characteristics of term placental alkaline phosphatases correspond in order to non-Regan isoenzyme, a mixture of Regan and non-Regan isoenzymes and Regan isoenzyme in a variety of human cancer tissues. The biochemical profile characteristic of trophoblast developmental Phase 1 alkaline phosphatase is expressed as 78.5% heat-sensitive inhibition (5 min at 65 degrees), 66.3% L-homoarginine inhibition, and 17.3% L-phenylalanine inhibition where n = 12. It is hypothesized that the alkaline phosphatase of human tumor tissues reflects the expression of placental genes corresponding to one or more phases of trophoblastic development.

Pathologic findings in fetal GM1 gangliosidosis.

A 24-week fetus with GM1 gangliosidosis (type 1) was studied using biochemical and histopathologic methods. Foam cells in viscera and placenta demonstrated widespread accumulation of a lipidlike material. By microscopy, central nervous system storage appeared confined to the retina and dorsal root ganglia, but the brain ganglioside content was measurably elevated compared with that of age-matched controls. These data, along with those of others, imply that, if the observed pathologic findings are irreversible, any attempts at intrauterine therapy must commence prior to the middle of the second trimester.

Gestational trophoblastic neoplasms: morphologic considerations.

Abnormal trophoblastic proliferation is the hallmark of a spectrum of lesions constituting the gestational trophoblastic neoplasms. Rapid proliferation, infiltration, vascular invasion, hematogenous dissemination, and spontaneous regression are features of both normal and neoplastic trophoblast. Trophoblastic hyperplasia without hydrops, hydatidiform mole, invasive mole, and gestational choriocarcinoma are related lesions, characterized by increasingly aberrant trophoblastic growth and worsening prognosis, if untreated. Difficulties in diagnosis may arise with respect to the normal early implantation site, the hydropic abortus, and postgestational, involuting, residual trophoblast. Histologic grading or hydatidiform moles is relevant to their prognosis and biologic behavior. Trophoblastic neoplasia may begin at any stage of pregnancy or puerperally with immediate or late and local or distant manifestations in the mother or the child. Cognizance of the capricius potential behavior of trophoblast permits successful management of its proliferative lesions, monitored by serial measurement of gonadotropin secretion.

Nonimmune hydrops fetalis: a challenge in perinatal pathology.

Autopsies were performed in 40 cases of nonimmune hydrops fetalis during the period from 1975 to 1983. In 25 cases specific anatomic diagnoses, including hematologic disorders, infections, chromosomal abnormalities, congenital anomalies, and tumors, were made. In the majority the diagnosis of hydrops fetalis was made prenatally by ultrasonography. The mean gestational age at delivery was 30 weeks; 23 infants were stillborn, and 17 died during the neonatal period. Body weights were consistently increased; peripheral edema and ascites were present in all cases and pleural effusions in all but two cases. Hepatosplenomegaly, cardiomegaly, and pulmonary hypoplasia were frequent findings. The most consistent microscopic changes involved endocrine organs. Islet cell hyperplasia and Leydig cell hyperplasia were common, and thyroid hyperplasia was found occasionally. The fetal zone of the adrenal cortex was often thick and composed of swollen, vacuolated cells. Enhanced extramedullary erythropoiesis was observed in all cases. Thirty-nine placentas were examined; 34 were edematous (mean weight, 547 g), with villous edema, excess erythroblastemia and normoblastemia, and occasional intravillous hematopoiesis. Nonimmune hydrops fetalis has a range of known causes. Thorough autopsy, including placental examination, is the most useful approach for determining the etiology. In 23 cases the probable or possible cause was established in this manner. Antibody studies should also be performed in all cases to exclude an immunologic etiology. Synthesis of clinical, serologic, and pathologic data offers prospects for rational management and prediction of recurrence.

Isolated congenital renal tubular immaturity in siblings.

This paper describes two cases of an unusual renal abnormality discovered in anuric siblings (one male, one female) who were born at 36 and 34 weeks of gestation and died of systemic complications secondary to severe pulmonary hypoplasia shortly after birth. Both gestations were complicated by marked oligohydramnios. Antenatal ultrasound examinations showed slightly enlarged kidneys in the first case and normal kidneys in the second case, with no evidence of hydronephrosis or cystic disease in either. With the exception of enlargement of the first infant's kidneys, autopsies revealed grossly unremarkable kidneys and ureters. Microscopy, however, demonstrated increased glomerulogenesis with normal glomeruli and global immaturity of renal tubules and ducts without concomitant features of dysplasia. Immunoperoxidase staining for epithelial membrane antigen revealed the immaturity or complete absence of proximal convoluted tubules. This precise constellation of findings had not been described previously. One other similar family has been documented in a report implicating genetic factors. In the present cases, the possibility of a cocaine-associated etiology is also addressed.

Postmortem manifestations of echovirus 11 sepsis in five newborn infants.

Five cases of fatal neonatal echovirus type 11 infection were observed in the Boston area during the summer and fall of 1979. Four of the mothers experienced gastroenteritis with fever and abdominal cramps late in the third trimester of pregnancy. The clinical course of each case was characterized by jaundice, hepatosplenomegaly, and progressive hepatic failure; all five infants were severely hypotonic. At autopsy massive hepatic and adrenal hemorrhage and necrosis, with evidence of consumption coagulopathy, were found. Echovirus type 11 was isolated from various sites before and after death. The histopathologic features and epidemiologic aspects of these cases are briefly discussed.

Cardiac rhabdomyoma. Rare cause of fetal death.

Two cases of nonimmune hydrops fetalis and fetal death associated with cardiac rhabdomyoma are reported. Case 1 presented with fetal supraventricular tachycardia, and cardiac rhabdomyoma was accurately diagnosed by fetal echocardiography. Autopsy revealed multiple rhabdomyomata involving the right atrial free wall, the sinoatrial node, and the left ventricle. The left circumflex coronary artery was extrinsically compressed by adjacent tumor tissue, causing left ventricular myocardial infarction. Case 2 had a unique, pedunculated, ball-like rhabdomyoma that almost totally occluded the mitral orifice. The causes of fetal death in patients with cardiac rhabdomyoma are analyzed and the possibility of fetal surgical management is proposed.

Persistence of partial mole.

Between January 1979 and August 1984, 8 of 81 patients with partial molar pregnancy who were followed at the New England Trophoblastic Disease Center had persistent trophoblastic tumor develop. No significant clinical differences were noted between such patients and others whose partial moles did not persist. On microscopic examination, none of the initial molar specimens manifested an unusual degree of trophoblastic proliferation or atypia. In six patients, curettage immediately preceding the initiation of treatment for persistent disease revealed viable molar tissue. In four, this was associated with trophoblastic hyperplasia and atypia. All patients who had persistent gestational trophoblastic tumor achieved remission with single-agent chemotherapy. Monitoring of serum human chorionic gonadotropin levels after partial molar pregnancy is recommended to detect persistent disease and effect prompt therapy.

Invasive partial mole.

A case of invasive partial hydatidiform mole requiring chemotherapy and hysterectomy in a 30-year-old white woman is presented. This is the first histologically and cytogenetically documented partial mole with persistent elevation of human chorionic gonadotropin (hCG) level and invasion of myometrium. There was no evidence of distant spread.

Hydatidiform moles. Application of flow cytometry in diagnosis.

Hydropic chorionic villi are found in hydropic abortuses, partial hydatidiform moles (PM), and complete hydatidiform moles. Partial and complete moles have the potential for persistent trophoblastic disease. The vast majority of partial moles are triploid and generally follow a benign clinical course. Complete moles are diploid and distant metastasis and choriocarcinoma may develop. The authors determined the nuclear ploidy by flow cytometry of 31 placentas, 19 of which appeared hydropic either on obstetric ultrasonography or gross examination. Of ten complete moles classified by histologic criteria, ten were diploid, whereas five of seven histologically classified PM were triploid. The remaining two cases classified as PM were diploid; one most likely represented a regressing complete mole; the other a hydropic abortus. All 14 control placentas were diploid. In all cases in which karyotypic analysis was performed, the flow cytometric determination of ploidy was confirmed. It was concluded that DNA flow cytometric analysis is a rapid, accurate, and cost-effective means for assaying nuclear ploidy in these tissues, and as such, offers an informative supplement to the histological interpretation of hydropic placentas.

Effects of prenatal maternal estrogen on the male urogenital system.

Effects of in utero exposure to estrogens on the testis and prostate were assessed in male perinates. Exposure to diethylstilbestrol alone or combined with other female sex hormones correlated with hypertrophy and squamous metaplasia of the prostatic utricle and ducts, and with high ratios of Leydig cells to spermatogenic cells in the testis. These changes were not correlated with maternal diabetes, other congenital abnormalities, exposure to progestogens and steroidal estrogens, or thyroid hormones. Within the affected group an interaction was found between the hormones administered and the trimester during which treatment was started. These findings suggest that exogenous female sex hormones may interfere with the action of müllerian inhibiting factor in the human male fetus. The prostatic ducts also respond to maternal estrogen treatment. Relevance to later health is unknown.

Thrombocytopenia complicating preeclampsia: data to support a new model.

Thrombocytopenia can be associated with preeclampsia without evidence of consumptive coagulopathy and may contribute to placental insufficiency. In the case reported here, the patient's platelets agglutinated in vitro in the presence of her serum when the serum had been preincubated with her placental cells. The reaction was calcium and, probably, complement dependent. Mixtures of sera and placentas from normal APO-matched control pregnancies caused no agglutination of the patient's platelets. The capacity of her serum and placental cells to agglutinate her own platelets was not found in the sera obtained 60 days post partum. These findings suggest that in some cases of preeclampsia the platelets may be involved in an immune-mediated phenomenon that can induce platelet agglutination and is probably accentuated in the placenta, thus attenuating placental blood flow.

Production of experimental toxemia in the pregnant dog.

The aortas of 14 pregnant bitches were treated 1 to 3 weeks before term, producing a stricture that reduced the lumen from an average normal of 7-11 mm to 2.1 mm in diameter. Nine animals developed hypertension, 3 had significant proteinuria, and 1 had fluid retention. Light microscopy revealed moderate or severe glomerular lesions in 9 animals characterized by endotlial cell swelling, mesangial cell proliferation, and focal basement membrane thickening; electron microscopy revealed mesangial enlargement and electron-dense deposits. Immunofluorescence with rabbit anti-dog fibrinogen showed glomerular deposition of fibrinogen or its breakdown products in 11 of 12 cases so studied. Focal necrosis was seen in the liver in 5 cases, and diffuse hemorrhagic infarction of the placenta was present in all animals. None of these changes was found in nonpregnant or in sham-operated controls.

Vaginal adenosis in stillborns and neonates exposed to diethylstilbestrol and steroidal estrogens and progestins.

A histologic study was conducted of sagittal sections of the genital tracts of 281 autopsied female stillborns and neonates. The prevalence of vaginal adenosis among 43 offspring exposed in utero to diethylstilbestrol (DES) was 70%, a frequency 18 times greater than the 4% prevalence among 159 unexposed offspring. The relationship of the prevalence of vaginal adenosis to the gestational age at initial exposure was highly significant: 81% of those first exposed during the period of vaginogenesis had adenosis, whereas none exposed after 21 weeks' gestation had adenosis (P1 = 1 X 10(-4)). The relationship of the prevalence of vaginal adenosis to the total dose of DES prior to 22 weeks' gestation also was significant (P1 = 0.02), and this relationship was independent of gestational age at first exposure (P1 =0.01). In contrast, the prevalence of adenosis among 23 offspring exposed to steroidal estrogens and progestins was about the same as that among the unexposed offspring. Vaginal adenosis was unrelated to the complications of pregnancy for which the hormones were given, the calendar year of birth, and the gestational age at delivery.

Clinical experience with placental site trophoblastic tumors at the New England Trophoblastic Disease Center.

From 1982-1986, seven patients with pathologically confirmed placental site trophoblastic tumors underwent treatment at the New England Trophoblastic Disease Center. All seven patients presented with nonmetastatic disease; the presenting symptom was vaginal bleeding in six patients and amenorrhea in one patient. Mitotic counts of the tumor may vary among endometrial curettings, hysterectomy specimens, and metastatic lesions. When placental site trophoblastic tumor is diagnosed on endometrial curettage, a thorough metastatic workup should be undertaken. Because of this tumor's poor response to chemotherapy, a diagnosis of nonmetastatic placental site trophoblastic tumor should be followed by prompt hysterectomy.