Increased propensity for amyloidogenesis in male mice.

BACKGROUND: The male sex is a risk factor for reactive amyloidogenesis in several disease entities. Environmental, socioeconomic or genetic factors may underlie this male preponderance. This study was aimed at discovering whether male sex predisposes to reactive amyloidosis also in mice and to elucidate some of the hormonal associations of this risk. METHODS: Male and female Swiss mice were subjected to an established amyloid induction protocol and the amount of their splenic amyloid was determined and compared. The effect of estrogen, progesterone, testosterone and adrenalin on amyloidogenesis was studied in both sexes by administering these hormnones during amyloid induction and comparing the amount of splenic amyloid of the study mice with the control mice which received the amyloid induction protocol alone. RESULTS: Amyloid deposition appeared to be more abundant in male mice. This gender difference was not associated with any of the 3 sex hormones tested. Despite an expected increment, adrenalin caused an attenuation of amyloid deposition. CONCLUSIONS: The preferential expression of reactive amyloidosis in male mice seems to be unrelated to the common sex hormones. Increased production of other hormones such as adrenalin, or perhaps an augmented susceptibility to their effect, may cause gender differences by suppressing female amyloidogenesis. Our study favors the hypothesis of genetic predisposition as the mechanism leading to sex differences in amyloidogenesis. Further validation of our findings in gonadal ablated models and other amyloid induction protocols is warranted.

Hepatic infarctions during pregnancy are associated with the antiphospholipid syndrome and in addition with complete or incomplete HELLP syndrome.

Antiphospholipid antibody syndrome (APS) is associated with adverse pregnancy outcomes and maternal complications including thrombotic events and early pre-eclampsia. HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) represents a unique form in the spectrum of pre-eclampsia. This report describes four patients with pregnancy-associated hepatic infarctions. All four had APS and HELLP syndrome, which was complete in one patient and incomplete in three patients, with elevated liver enzymes in all, and either thrombocytopenia or hemolysis in two. In the literature, we found descriptions of an additional 24 patients who had 26 pregnancies with concomitant hepatic infarction. Of the total 28 patients, anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LAC) were assessed in 16 patients, out of whom 15 were found to be positive. Hepatic infartction during pregnancy was associated almost always with APS, with HELLP (2/3 complete, 1/3 incomplete), and only in one-third of the pregnancies with pre-eclampsia (PE).

School-age children born to diabetic mothers and to mothers with gestational diabetes exhibit a high rate of inattention and fine and gross motor impairment.

OBJECTIVES: To study the neurobehavioral effects that pregestational and gestational diabetes might have on offspring at school age. STUDY DESIGN: We studied neurobehavioral function at school age of 57 children born to 48, well controlled, diabetic mothers and of 32 children born to 32 women with gestational diabetes. Their development was compared with 57 control children matched by age, birth order and parental socio-economic status, using a number of cognitive, behavioral, sensory and motor neurological tests. RESULTS: The IQ scores on the WISC-R and Bender tests of the children born to diabetic mothers were similar to those of control children, but the Bender scores of the children born to mothers with gestational diabetes were slightly lower. No differences were found between the study groups in various sensory-motor functions in comparison to controls. However, both study group children performed less well than controls in fine and gross motor functions as observed on the Bruininks-Oseretzki test of motor proficiency. The scores of children born to the mothers with pregestational diabetes were higher than controls on the Touwen & Prechtl neurological examination (worse function). The children from both research groups also performed worse on the Pollack taper test that is designed to detect inattention and hyperactivity. The children of the two study groups also had slightly higher scores on the Conners abbreviated parents-teachers questionnaire measuring hyperactivity and inattention, but the differences from controls were not statistically significant. We found a negative correlation between the performance of the children born to mothers with pregestational diabetes on various neurodevelopmental and behavioral tests and the severity of maternal hyperglycemia as assessed by blood glycosylated hemoglobin levels and acetonuria. CONCLUSIONS: Pregestational or gestational diabetes was found to adversely affect attention span and motor functions of offspring at school age, but not their cognitive ability. These effects were negatively correlated with the degree of maternal glycemic control, and were more pronounced in younger children.

Neonatal outcome in growth-restricted versus appropriately grown preterm infants.

The objective of this paper is to examine whether growth-restricted preterm infants have a different neonatal outcome than appropriately grown preterm infants. All consecutive, singleton preterm deliveries between 27-35 weeks' gestation were included over a 4-year period. Infants with congenital anomalies and infants of diabetic mothers were excluded. Infants were categorized as small-for-gestational-age (SGA) when birth weight was at or below the 10th percentile, and appropriate-for-gestational-age (AGA) when between the 11th and 90th percentiles. Outcome variables included: neonatal death, respiratory distress syndrome (RDS), sepsis, intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Neonatal morbidity and mortality were examined by univariate and stepwise multivariate logistic regression analyses. Factors controlled for during the analysis included: maternal age; gestational age; mode of delivery; presence of preeclampsia, HELLP syndrome, prolonged premature rupture of membranes (PROM), placental abruption, placenta previa, prenatal steroid exposure, infant gender, and low Apgar score. Seventy-six infants were included in the SGA group and 209 in the AGA group. SGA infants had a higher mortality rate (p = 0.003). They also had more culture-proven sepsis episodes (p = 0.001). No differences were found with respect to the other outcomes. The results were similar when analyzed separately for the group of infants born at or below 32 weeks' gestation. Growth-restricted preterm infants were found to have both higher mortality and infection rates compared with AGA preterm infants. Growth restriction in the preterm neonate was not found to protect against other neonatal outcomes associated with prematurity. When considering elective preterm delivery for this high-risk group of pregnancies, the increased risks in the neonatal period should be taken into account.

Anti-cardiolipin antibodies in fetal blood and amniotic fluid derived from patients with the anti-phospholipid syndrome.

The aim of this study was to investigate whether, in patients with antiphospholipid syndrome, anticardiolipin antibodies pass from mother to offspring sera and amniotic fluid. Eleven patients with antiphospholipid syndrome (study group) and 11 healthy controls, matched by maternal and gestational age (control group) were prospectively examined for the presence of anticardiolipin antibodies in the cord blood during labour, and amniotic fluid during vaginal or Caesarean delivery. Three neonates (27.3%) in the study group had anticardiolipin antibodies in the cord blood, while none had them in the control group. Anticardiolipin antibodies were detected in the amniotic fluid in six (54.5%) of the study group pregnancies, compared with none in the control group. No adverse neonatal outcome was noted except for significantly lower (P < 0.0006) mean birth weight in the study group. Anticardiolipin antibodies can pass the placenta and be detected in fetal cord blood and amniotic fluid. This finding might be used in the future for the assessment of pregnancies with antiphospholipid syndrome.

Comparison of the motor development of school-age children born to mothers with and without diabetes mellitus.

The objectives of this study were to examine the effects of diabetes during pregnancy on the long-term motor development of the offspring and to study possible correlations between glycemic control and motor development. We compared the motor development of 57 children, 5- to 12-years-of-age, born to 48 mothers with well-controlled diabetes, to the motor development of 57 control children matched by age, birth order, and parental socio-economic status. Children born to mothers with diabetes performed less well than controls in fine and gross motor functions on the Bruininks-Oseretsky Test of Motor Proficiency. A negative correlation existed between the test scores of the children whose mothers had diabetes and the severity of hyperglycemia as assessed by blood glycosylated hemoglobin levels and acetonuria. Motor ability of the children of mothers with diabetes had a high correlation with biological and environmental variables. These results suggest that diabetes during pregnancy may affect the developing brain, inducing long-term mild motor deficiency. The effects seem to result from the adverse effects of diabetic metabolic factors, and the effects correlate with the degree of diabetes control. The combination of metabolic functioning of women with diabetes and home environment may affect the motor development of their children.

Safety of low-molecular-weight heparin in pregnancy: a systematic review.

Unfractionated heparin (UFH) remains the anticoagulant of choice during pregnancy. Low-molecular-weight heparins (LMWH) are an attractive alternative to UFH due to their logistic advantages and their association with a lower incidence of osteoporosis and HIT. We reviewed all published clinical reports concerning the use of LMWH during pregnancy. In addition, participants of an international interest group contributed a cohort of pregnant women treated with LMWH. Pregnancies were divided into two groups; those with and those without maternal comorbid conditions. The number of adverse fetal outcomes and the occurrence of maternal complications were evaluated in the two groups. In the group of women with comorbid conditions (n = 290), 13.4% of the pregnancies were associated with an adverse fetal outcome. In contrast, in the group of women without comorbid conditions (n = 196), 3.1% were associated with an adverse outcome, which is comparable to that seen in the normal population. We conclude that LMWH appear to be a safe alternative to unfractionated heparin as an anticoagulant during pregnancy.

Neurodevelopmental outcome at early school age of children born to mothers with gestational diabetes.

AIMS: To study the metabolic derangements in the second half of pregnancy caused by gestational diabetes, on the long term development of children. METHODS: The neuropsychological function of 32 school age children born to 32 mothers with well controlled gestational diabetes and 57 control children matched by age, birth order, and parental socioeconomic status was studied. RESULTS: There were no differences in head circumference and height, but the children born to diabetic mothers were heavier. The verbal IQ scores of index children below the age of 9 years were lower than those of control children. No differences were found between the groups in various sensory and motor functions and in the Touwen and Prechtl neurological test. The young index group children performed less well than controls in fine and gross motor functions, as observed on the Bruininks-Oseretzky test of motor proficiency. The scores of young children born to mothers with gestational diabetes were also lower than controls on the Pollack tapper test, and there were more index group children who scored abnormally on the parents' Conners questionnaire. No correlation was found between the performance of the index group children on various neurodevelopmental tests and the severity of perinatal complications. The differences tended to disappear with age. CONCLUSIONS: Gestational diabetes, as a result of the metabolic abnormalities in the second half of pregnancy, induces long term minor neurological deficits which are more pronounced in younger children. There does not seem to be any direct relation between the appearance of congenital anomalies and neurodevelopmental outcome.

Progression of labor in twin versus singleton gestations.

OBJECTIVE: The aim of this study was to investigate whether labor curves of twin gestations differ from those of singleton gestations. STUDY DESIGN: Among 1821 twin deliveries at our institution (1984-1996), we found 69 nulliparous and 94 multiparous women who were delivered at term (>/=37 weeks) of a vertex twin A with a birth weight of >/=2500 g. We excluded women who had any of the following: induction of labor, oxytocin augmentation, cervical dilatation >6 cm on admission, tocolysis during the previous 14 days, height <150 cm, hypertension, and diabetes. Women with singleton gestations (n = 163) who met the same exclusion criteria were matched for parity and maternal age (+/-3 years). Stage 1 of labor was defined as the interval between 4 and 10 cm cervical dilatation. Kaplan-Meier survival analysis was used for comparison between the groups. RESULTS: The study and control groups were similar in mean maternal height; however, women with twins were significantly heavier than were those with singletons (79.3 +/- 11.2 kg vs 73.2 +/- 10.8 kg, P <.001), had a higher frequency of epidural anesthesia (82% vs 62%), and had a significantly lower birth weight of the presenting fetus (2779.1 +/- 242.5 g vs 3301.4 +/- 429.2 g, P <.001). The cervical effacements and vertex stations on admission were similar in the 2 groups. On admission the cervical dilatation of women delivered of twins was smaller than that of the control group. Twin gestations had a significantly shorter first stage of labor than did their matched singleton control gestations (3.0 +/- 1.5 hours vs 4.0 +/- 2. 6 hours, P <.0001). This difference was apparent only in nulliparous women. No statistical difference was noted in the mean length of the second stage of labor (0.8 +/- 0.5 hour for twins and 0.7 +/- 0.6 hour for singletons). CONCLUSION: Twin gestations have a significantly shorter first stage of labor than do singleton gestations. This difference may be the result of the birth weight of the presenting twin being lower than that of its singleton counterpart or to differences in uterine contractility in twin and singleton gestations. Different labor curves should be considered for managing twin deliveries.

Neurobehaviour of school age children born to diabetic mothers.

AIM: To study the neurobehavioural effects that diabetes during pregnancy might have on children by school age. METHODS: The neurobehavioural function of 57 school age children born to 48, well controlled diabetic mothers was compared with 57 control children matched for age, birth order, and parental socioeconomic status, using several cognitive, behavioural, sensory and motor neurological tests. RESULTS: The IQ scores of the index group children were similar to those of control children (117.7 +/- 13.4 vs 118.5 +/- 10.1). There were no differences between the groups in various sensory motor functions. However, the index group children performed less well than the controls on indices of fine and gross motor functions, as observed on the Bruininks-Oseretzky test of motor proficiency. The scores of children born to diabetic mothers were higher than controls on the Touwen and Prechtl neurological examination. They also performed worse in the Pollack tapper test which is designed to detect minor neurological deficits, inattention, and hyperactivity. The index children had higher scores on the Conners abbreviated parent-teacher questionnaire which measures hyperactivity and inattention. There was a negative correlation between the performance of the index group children on various neurodevelopmental and behavioural tests and the severity of hyperglycaemia, as assessed by blood glycosylated haemoglobin and acetonuria. CONCLUSIONS: Diabetes during pregnancy adversely affects some fine neurological functions in children at school age, but not their cognitive scores. These effects are not correlated with the degree of glycaemic control.

Adjustment of magnesium sulfate infusion rate in patients with preterm labor.

OBJECTIVE: Our purpose was to investigate factors that might influence serum magnesium levels during intravenous magnesium sulfate tocolytic therapy. STUDY DESIGN: Thirty-three women receiving magnesium sulfate for preterm labor participated in this prospective, observational study. Gestational ages were 24 to 34 weeks. Four groups of women were identified according to the maintenance magnesium infusion rate required for arresting preterm labor after 5 g of therapy induction: 1.5, 2, 2.5, and 3 g/h. Serum magnesium samples were drawn after a predefined period of at least 18 hours of arrested preterm labor, at a minimum of every 6 hours. Variables examined included serum albumin; serum protein; serum ionized calcium; serum creatinine; creatinine clearance; 24-hour urine output; maternal height, weight, body surface area; and body mass index. RESULTS: By use of a multivariate stepwise regression model we identified four variables that independently and significantly contributed to the model: magnesium infusion rate (P < .001); total serum protein level (P < .001); serum creatinine level (P = .009); and maternal weight squared (P = .026). Seventy-two percent of the variance was accounted for by use of these parameters. A predictive linear model, developed to relate these factors, produced the following formula: Suggested magnesium infusion rate = 0.89 x Serum magnesium concentration (mg/dL) - 3.16 x Serum creatinine (mg/dL) - 0.66 x Serum total proteins (g/dL) + 0.0001 x (maternal weight)2 (kg) + 2.30. CONCLUSIONS: Serum creatinine, serum protein, and maternal weight can be used to adjust the dose of magnesium sulfate in patients with premature labor to achieve therapeutic serum levels of magnesium more rapidly and safely.

New birth weight nomograms for twin gestation on the basis of accurate gestational age.

OBJECTIVE: Our purpose was to establish new nomograms for the birth weight of twins on the basis of accurate methods to validate gestational age. STUDY DESIGN: The medical records of 1632 consecutive twin gestations delivered between 1984 and 1996 were reviewed. Only pregnancies induced by ovulation induction techniques or that were measured ultrasonographically for crown-rump length during the first trimester were included. Excluded were those whose fetuses (one or both) were stillborn, or if the mother smoked, had a significant chronic illness, or was prescribed any regular medications. The study comprised 520 twin pregnancies at 28 to 41 gestational weeks at delivery. RESULTS: The median and 10th and 90th percentile birth weight curves were calculated for the studied twins and plotted against previously reported singleton nomograms. Fetuses of twin pregnancies were found to be growth restricted in comparison with previously reported singletons throughout the third trimester. This trend became more evident after the thirty-fourth to thirty-sixth weeks. CONCLUSIONS: We recommend these novel birth weight nomograms for clinical use in the management of twin pregnancies.

Dexamethasone as an adjuvant therapy for anovulatory, normoandrogenic patients during ovulation induction with exogenous gonadotropins.

OBJECTIVE: The objective of our study was to explore the effect of dexamethasone (DEX), a highly potent, long-acting glucocorticoid, on the treatment outcome of 74 anovulatory women aged 21 to 29 years, with normal gonadotropins, androgen, and prolactin (PRL) serum levels who failed to conceive on antiestrogen therapy. METHODS: The patients received human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG) for ovulation induction. Starting on day 4 of the induced menstruation, hMG was administered in combination with DEX, 0.5 mg at night, or without DEX as an adjuvant treatment. The total amount of gonadotropins used, time required for stimulation, percentage of fertilization, serum estradiol levels, pregnancy rate, cumulative pregnancy rate, and abortions were recorded. RESULTS: There were no differences in either the cumulative pregnancy rate (54.1% in the DEX group and 52.7% in the untreated group) or the abortion rates (21.7% in the DEX group compared to 20.8% in the untreated group). The other parameters investigated also did not differ significantly between the groups. CONCLUSIONS: The overall results did not support DEX as a clinically useful adjuvant therapy for anovulatory, normoandrogenic patients.

Stretching of the cervix and stripping of the membranes at term: a randomised controlled study.

OBJECTIVE: To determine whether routine antepartum stretching of the cervix and stripping of the membranes at term would shorten the length of pregnancies, and whether this correlated with cervical status and fetal and maternal parameters. DESIGN: A prospective, randomised, controlled study of 293 term gravidas, free of medical complications, divided into two groups: stretching/stripping, and non-stretching/stripping. Digital separation of the fetal membranes from the lower uterine segment, and cervical stretching, were performed during routine vaginal examination of the first group. In the second group, only routine vaginal examination was performed. RESULTS: Of 293 patients, 152 underwent a trial of stretching and stripping; 141 served as a control group. The mean interval (hours to delivery after the procedure) was 136 h (S.D. 10), compared to 161 h (S.D. 11) in the control group (P = 0.095; not significant), but with only a trend towards the shorter interval in the first group. When patients were matched according to weeks of gestation and fetal and maternal parameters, only those at 41 weeks' gestation or more had a significant reduction in the interval from the procedure to delivery (mean 91 h (S.D. 8) compared to mean 125 h (S.D. 10) in the control group; P < 0.007). This observation was independent of cervical status and other maternal or fetal parameters. CONCLUSIONS: Only patients > or = 41 weeks' gestation benefitted from stretching of the cervix and stripping of the fetal membranes. The effect was not dependent on the cervical status or other maternal and fetal parameters.

Intraumbilical vein injection of prostaglandin F2 alpha in retained placenta.

A randomized protocol was used to study the effect of intraumbilical prostaglandin F2 alpha (Hembate, Upjohn) and oxytocin injection in women with retained placenta. Prostaglandin F2 alpha, 20 mg, diluted to 20 ml in normal saline solution (10 women, group 1), 30 IU of oxytocin, diluted to 20 ml in normal saline solution (11 women, group 2), or 20 ml of normal saline solution alone (7 women, group 3), were injected into the umbilical vein 1 h after delivery. Nine women (group 4, controls) underwent manual removal of the retained placenta. In group 1, placental expulsion occurred in all patients and the duration of the placental expulsion after prostaglandin F2 alpha injection was 6.8 +/- 1.36 (mean +/- SE) min: in group 2, six placental expulsions occurred after 13.3 +/- 1.97 min (mean +/- SE); and in group 3, no effect was recorded after intraumbilical saline injection. We suggest that intraumbilical vein injection of prostaglandin F2 alpha might be a beneficial, non-surgical method for treating retained placenta. Oxytocin might reduce the incidence of manual lysis of the placenta and achieve partial success.

Intravenous immunoglobulin treatment in the prevention of childbirth-associated acute exacerbations in multiple sclerosis: a pilot study.

Acute exacerbations frequently occur after childbirth in patients with relapsing-remitting multiple sclerosis (MS). The present pilot study was initiated in an attempt to reduce the number of childbirth-associated acute exacerbations in the postpartum period. We treated nine MS patients with a history of 12 childbirth-associated acute exacerbations that had occurred 2-9 weeks after previous deliveries. The patients were administered intravenous immunoglobulin (IVIg) at a dose of 0.4 g/kg per day for 5 consecutive days during the 1st week after childbirth and at 6 and 12 weeks thereafter. None of the treated patients relapsed during the 6-month period after delivery. However, three patients had a remote relapse, two at 8 months and one at 10 months after childbirth, but these probably represented the natural course of disease and were not associated with childbirth. We conclude that IVIg treatment may prevent acute childbirth-associated exacerbations in relapsing-remitting MS patients.

Combined vaginal-abdominal delivery of twins.

All cases of combined vaginal-abdominal deliveries at the Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, over an eight-year period (1984-1991) were reviewed. During this period a total of 38,821 deliveries took place. Of 722 (1.9%) twin deliveries, 354 (48.8%) were by cesarean section; 19 were combined deliveries, including 5% of all twins delivered by cesarean section and 2.6% of all twins delivered. High transverse lie and prolapse of the umbilical cord were the main indications for delivery by cesarean section of the second twin. In order to diminish the number of combined deliveries and to increase obstetric skills and experience, a program or protocol for vaginal twin deliveries is indicated.

The clinical value of umbilical artery Doppler velocimetry in the management of intrauterine growth-retarded fetuses before 32 weeks' gestation.

The objective of this study was to investigate the clinical utility of umbilical artery Doppler velocimetry in the management of very premature growth-retarded fetuses. The study comprised 34 fetuses between 26 and 34 weeks' gestation, diagnosed ultrasonically as suffering from intrauterine growth retardation. Based on the umbilical artery Doppler findings, patients were divided into 3 groups: group 1 (10 fetuses) with normal Doppler systolic/diastolic (S/D) ratios (within 2 SD of the mean for gestational age); group 2 (9 fetuses) with significant abnormal umbilical artery S/D ratios (above 2 SD of the mean for gestational age), and group 3 (15 fetuses) with absent or reverse end-diastolic flow. Fetal outcome was assessed in terms of neonatal mortality and morbidity, i.e. low umbilical artery pH (pH < 7.20) and Apgar scores. In group 1, all fetuses had a stable, normal S/D ratio; in group 2, 2 fetuses (22%) showed deterioration in the Doppler findings and were transferred to group 3, while in group 3, 3 of 15 fetuses (20%) showed improvement in the absence of end-diastolic flow and were thus transferred to group 2. Emergency cesarean section due to antenatal deterioration of the biophysical profile occurred in only 1 patient (10%) in group 1, compared to 33 and 87% in groups 2 and 3, respectively (p < 0.05). The other 9 patients in group 1 had normal vaginal deliveries at 36-37 weeks' gestation, with no perinatal complications. The mean expectant interval from admission to delivery in group 3 was 8.2 days, while in groups 1 and 2 it was 23.8 and 22.2, respectively (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Laparoscopic laser surgery of primary ovarian pregnancy.

We present a rare case in which therapy of primary ovarian pregnancy, using laparoscopic laser surgery (videolaseroscopy), was successfully performed without the need of laparotomy. Because operative laparoscopy has the benefits of reduced morbidity, reduced hospitalization and rapid recovery, and because it has the advantage of reducing postoperative adhesions as compared to laparotomy, it is the preferable technique for treatment of ovarian gestation after a laparoscopic diagnosis, especially for a woman who desires to preserve her fertility potential.