Biomedical subjects

E J Wolf

Publications and source records attributed to E J Wolf.

At least 19 recordsLinked to original sources

PubMed1998

Increased affinity leads to improved selective tumor delivery of single-chain Fv antibodies.

Mr 25,000 single-chain Fv (scFv) molecules are rapidly eliminated from the circulation of immunodeficient mice, yielding highly specific retention of small quantities of scFv in human tumor xenografts. We postulated that the specific retention of scFv in tumor could be enhanced by engineering significant increases in the affinity of the scFv for its target antigens. Affinity mutants of the human anti-HER2/neu (c-erbB-2) scFv C6.5 were generated by site-directed mutagenesis, which target the same antigenic epitope with a 320-fold range in affinity (3.2 x 10(-7) to 1.0 x 10(-9) M). In vitro, the Kd of each scFv correlated closely with the duration of its retention on the surface of human ovarian carcinoma SK-OV-3 cells overexpressing HER2/neu. In biodistribution studies performed in scid mice bearing established SK-OV-3 tumors, the degree and specificity of tumor localization increased significantly with increasing affinity. At 24 h after injection, tumor retention of the highest affinity scFv was 7-fold greater than that of a mutant with 320-fold lower affinity for HER2/neu. Because the rapid renal clearance of scFv may blunt the impact of improved affinity on tumor targeting, the distributions were also assayed in the absence of renal clearance (e.g., in mice rendered surgically anephric). In this model, the peak tumor retentions of the two higher affinity scFv approximated that reported previously for IgG targeting the same SK-OV-3 tumors in scid mice with intact kidneys. In contrast, the mutant with the lowest affinity for HER2/neu failed to accumulate in tumor, indicating the presence of an affinity threshold that must be exceeded for active in vivo tumor uptake. These results indicate that affinity can significantly impact the in vivo tumor-specific retention of scFv molecules.

Adenocarcinoma↗

PubMed1998

Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu.

Single-chain Fv (scFv) molecules exhibit highly specific tumour-targeting properties in tumour-bearing mice. However, because of their smaller size and monovalent binding, the quantities of radiolabelled scFv retained in tumours limit their therapeutic applications. Diabodies are dimeric antibody-based molecules composed of two non-covalently associated scFv that bind to antigen in a divalent manner. In vitro, diabodies produced from the anti-HER2/neu (c-erbB-2) scFv C6.5 displayed approximately 40-fold greater affinity for HER2/neu by surface plasmon resonance biosensor measurements and significantly prolonged association with antigen on the surface of SK-OV-3 cells (t1/2 cell surface retention of > 5 h vs 5 min) compared with C6.5 scFv. In SK-OV-3 tumour-bearing scid mice, radioiodinated C6.5 diabody displayed a highly favourable balance of quantitative tumour retention and specificity. By as early as 4 h after i.v. administration, significantly more diabody was retained in tumour (10 %ID g(-1)) than in blood (6.7 %ID ml(-1)) or normal tissue (liver, 2.8 %ID g(-1); lung, 7.1 %ID g(-1); kidney, 5.2 %ID g(-1)). Over the next 20 h, the quantity present in blood and most tissues dropped approximately tenfold, while the tumour retained 6.5 %ID g(-1) or about two-thirds of its 4-h value. In contrast, the 24-h tumour retention of radioiodinated C6.5 scFv monomer was only 1 %ID g(-1). When diabody retentions were examined over the course of a 72-h study and cumulative area under the curve (AUC) values were determined, the resulting tumor-organ AUC ratios were found to be superior to those previously reported for other monovalent or divalent scFv molecules. In conclusion, the diabody format provides the C6.5 molecule with a distinct in vitro and in vivo targeting advantage and has promise as a delivery vehicle for therapeutic agents.

Animals↗

PubMed1997

Neonatal effects and serum cortisol levels after multiple courses of maternal corticosteroids.

OBJECTIVE: To determine the effects of multiple courses of maternal betamethasone for fetal lung maturation on neonatal serum cortisol levels and clinical Cushing syndrome. METHODS: Seventy-nine mother-infant pairs delivered between 24 and 36 weeks' gestation were enrolled in the study. They were grouped according to the number of courses of betamethasone received between 24 and 34 weeks' gestation for fetal lung maturation: those receiving no courses, one course, and two or more courses. Physical examinations were performed and serum glucose, electrolyte, and cortisol levels were measured on days 1 and 3 of life. RESULTS: For those receiving multiple courses of betamethasone (n = 43), the mean (+/- standard error of the mean [SEM]) number of courses was 5.3 +/- 0.4, with a mean (+/-SEM) total dose of 125.0 +/- 10.7 mg. No neonates had findings suggestive of Cushing syndrome. Day 1 cortisol levels (pooled mean +/- SEM) were 12.6 +/- 2.4, 5.3 +/- 3.2, and 4.4 +/- 1.8 microg/dL in those receiving no courses, one course, and two or more courses, respectively (P = .03; no courses versus two or more courses, P = .03), but the differences were not significant when corrected for multiple variables. Differences among day 3 cortisol levels (pooled mean +/- SEM) were not significant: 8.3 +/- 1.6, 5.8 +/- 1.4, and 5.8 +/- 0.9 microg/dL in those receiving no courses, one course, and two or more courses, respectively. None of the neonates in the group receiving no courses of betamethasone had day 1 cortisol levels lower than normal, whereas 22% and 11% of the neonates receiving one and two or more courses, respectively, had day 1 levels lower than normal. On day 3, 15% of those receiving one course and 10% of those receiving two or more courses had serum cortisol levels lower than normal, whereas none of those who received no courses had a low cortisol level. Multivariate regression analysis could show no association between the number of courses or total dose of betamethasone and the day 1 or day 3 cortisol values. The day 1 cortisol level (log10) was most associated with the severity of respiratory distress syndrome (RDS) and day 3 cortisol level (log10) with race and severity of RDS. Only in neonates with absent or mild RDS did number of courses correlate with day 3 cortisol levels (log10), but this was a positive correlation. CONCLUSION: Serum cortisol levels either were independent of the number of courses or total dose of corticosteroids given or, in a subpopulation, were associated with increasing levels with increasing doses, suggesting that there is no suppressive effect with repeated dosing.

Betamethasone↗

PubMed1996

Binding characteristics and antitumor properties of 1A10 bispecific antibody recognizing gp40 and human transferrin receptor.

The bispecific murine monoclonal antibody (MAb) 1A10 has specificity for the human transferrin receptor (TfR) and the human tumor-associated antigen gp40. This antibody, therefore, functions as an "antigen fork" by binding to two distinct antigens on the same malignant cell. Highly purified 1A10 inhibits the growth of cells coexpressing high levels of human TfR and the tumor-associated antigen gp40 by binding to both target antigens. In SW948 cells, the majority of 1A10 binding is via its gp40 specificity, and half-maximal inhibition of cell growth by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay requires 20-30-micrograms/ml concentrations of 1A10. The binding of 1A10 correlates with growth inhibition in the cell lines HT-29, SK-OV-3, OVCAR-2, and OVCAR-3. The growth of OVCAR-10 cells, which express little gp40 and TfR, is not inhibited by 1A10. However, SK-BR-3 cells, which express abundant gp40 and extremely high levels of TfR, are insensitive to the effects of 1A10. In some cell lines, combined exposure to 1A10 and the iron chelator deferoxamine mesylate has synergistic antiproliferative effects. A single i.p. dose of 600 micrograms 1A10 is sufficient to achieve an estimated tumor concentration of at least 30 micrograms/ml for 7 days in C.B17/Icr-scid mice bearing SW948 human tumor xenografts. Treatment of scid mice bearing day 2 or day 4 SW948 xenografts with single or multiple 1A10 doses inhibits tumor growth in a dose-related fashion. Antitumor effects are not seen with therapy using either parental antibody of 1A10. The antiproliferative properties of 1A10 in tumor cells overexpressing gp40 and TfR suggest avenues for the development of new bispecific antibody-promoted treatment strategies.

Animals↗

PubMed1996

Single-chain Fv radioimmunotargeting.

The availability of engineered antibody species has catalyzed new developments in radioimmunotargeting. This chapter summarized recent studies of single-chain Fv (sFv) proteins, which are minimal antibody binding sites engineered as single polypeptide chains. The single-chain Fv can be as small as 26 kDa monomers or may be engineered as larger fusion proteins designed to self-associate into dimeric or multimeric species. They typically exhibit rapid clearance that results in high targeting specificity within a matter of hours. We have compared different modes of administration to allow further manipulation of their biodistribution and targeting properties. Results of the present study comparing intravenous (i.v.) and intraperitoneal (i.p.) administration show comparable long-term retention in circulation, but the i.v. route showed an initially high peak blood level while i.p. injection did not. As with a single sFv dose, repeated bolus injections of sFv attained high target-to-background ratios, whereas continuous sFv infusion reached a steady state level of free sFv in blood and kidney that exceeded that in tumor xenografts. We observed improved localization of radioiodinated sFv in tumor xenografts if the radioiodine label resisted dehalogenation from the protein, which was accomplished, for example, through conjugation of a para-131I-benzoyl group to Iysyl epsilon-amino groups of the protein. Modification of the sFv by genetic incorporation of a cysteinyl peptide (to form sFv') provided a chelation site for radiometals that simplified incorporation of 99mTc with the opportunity for improved diagnostic imaging in cancer and other diseases. Therapeutic applications of sFv radioimmunotargeting could rely on sFv' complexed to 186Re or 188Re. Engineering sFv of sFv' with increased antigen-binding affinity and appropriately manipulating their mode of administration should promote sustained tumor retention conducive to clinically useful therapeutic indices.

Animals↗

PubMed1995

Targeting c-erbB-2 expressing tumors using single-chain Fv monomers and dimers.

Single-chain Fv proteins containing a COOH-terminal cysteine (sFv') were constructed by using an antidigoxin 26.10 sFv and an anti-c-erbB-2 741F8 sFv. The fully active sFv' proteins were prepared by expression in Escherichia coli as insoluble inclusion bodies, followed by in vitro refolding using glutathione redox buffers and purification. The COOH-terminal cysteines of the refolded sFv' proteins were protected by a blocking group presumed to be the glutathionyl peptide, which was easily and selectively removed by gentle reduction. Air oxidation of the reduced sFv' monomers resulted in the efficient formation of disulfide-linked sFv' homodimers, designated (sFv')2, which were stable under oxidizing conditions and relatively slow to be disrupted under reducing conditions. The (26-10-1 sFv')-(741F8-1 sFv') heterodimer was prepared and possessed dual-antigen specificity; the active bispecific (sFv')2 dimerized under native conditions, apparently as a manifestation of self-association by the 741F8 sFv' subunit. Biodistribution and imaging studies that were performed on mice bearing human SK-OV-3 tumor xenografts that express the c-erbB-2 as a cell surface antigen were reviewed. Radioiodinated 741F8-2 (sFv')2 homodimer localized to the tumors with high specificity, as evidenced by excellent tumor:normal tissue ratios. Sagittal section autoradiography of whole animals 24 h after administration of antibody species revealed that 741F8 (sFv')2 produced a stronger tumor image than comparable doses of the 741F8 Fab, monomeric sFv', and the 26-10 (sFv')2 control without the high nonspecific background distribution of the 741F8 IgG.

Amino Acid Sequence↗

PubMed1995

Optimization of in vivo tumor targeting in SCID mice with divalent forms of 741F8 anti-c-erbB-2 single-chain Fv: effects of dose escalation and repeated i.v. administration.

Single-chain Fv molecules in monovalent (sFv) and divalent [(sFv')2] forms exhibit highly specific tumor targeting in mice as a result of their small size and rapid systemic clearance. As a consequence, there is a rapid reversal of the sFv blood/tumor gradient, resulting in diminished retention of sFv species in tumors. In this report we investigate two distinct strategies, dose escalation and repetitive intravenous (i.v.) dosing, aiming to increase the absolute selective retention of radiolabeled anti-c-erbB-2 125I-741F8 (sFv')2 in c-erbB-2-overexpressing SK-OV-3 tumors in mice with severe combined immunodeficiency (SCID). A dose-escalation strategy was applied to single i.v. injections of 125I-741F8 (sFv')2. Doses from 50 micrograms to 1000 micrograms were administered without a significant decrease in tumor targeting or specificity. High doses resulted in large increases in the absolute retention of 125I-741F8 (sFv')2. For example, raising the administered dose from 50 micrograms to 1000 micrograms increased the tumor retention 24 h after injection from 0.46 microgram/g to 9.5 micrograms/g, and resulted in a net increase of greater than 9 micrograms/g. Over the same dose range, the liver retention rose from 0.06 microgram/g to 1 microgram/g, and resulted in a net increase of less than 1 microgram/g. The retention of 9.5 micrograms/g in tumor 24 h following the 1000-micrograms dose of (sFv')2 was comparable to that seen 24 h after a 50-micrograms dose of 125I-741F8 IgG, indicating that the use of large doses of (sFv')2 may partially offset their rapid clearance. When two doses were administered by i.v. injection 24 h apart, the specificity of delivery to tumor observed after the first dose was maintained following the second injection. Tumor retention of 125I-741F8 (sFv')2 was 0.32 microgram/g at 24 h and 0.22 micrograms/g at 48 h following a single injection of 20 micrograms, while 0.04 microgram/ml and 0.03 microgram/ml were retained in blood at the same assay times. After a second 20-micrograms injection at the 24-h assay time, tumor retention increased to 0.49 micrograms/g, and blood retention was 0.06 microgram/ml, at the 48-h point. These results suggest that multiple high-dose administrations of radiolabeled 741F8 (sFv')2 may lead to the selective tumor localization of therapeutic radiation doses.

Amino Acid Sequence↗

PubMed1995

In vitro and in vivo characterization of a human anti-c-erbB-2 single-chain Fv isolated from a filamentous phage antibody library.

BACKGROUND: Antibody-based reagents have failed to live up to their anticipated role as highly specific targeting agents for cancer therapy. Targeting with human single-chain Fv (sFv) molecules may overcome some of the limitations of murine IgG, but are difficult to produce with conventional hybridoma technology. Alternatively, phage display of antibody gene repertoires can be used to produce human sFv. OBJECTIVES: To isolate and characterize human single chain Fvs which bind to c-erbB-2, an oncogene product overexpressed by 30-50% of breast carcinomas and other adenocarcinomas. STUDY DESIGN: A non-immune human single-chain Fv phage antibody library was selected on human c-erbB extracellular domain and sFv characterized with respect to affinity, binding kinetics, and in vivo pharmacokinetics in tumor-bearing scid mice. RESULTS: A human single-chain Fv (C6.5) was isolated which binds specifically to c-erbB-2. C6.5 is entirely human in sequence, expresses at high level as native protein in E. coli, and is easily purified in high yield in two steps. C6.5 binds to immobilized c-erbB-2 extracellular domain with a Kd of 1.6 x 10(-8) M and to c-erbB-2 on SK-OV-3 cells with a Kd of 2.0 x 10(-8) M, an affinity that is similar to sFv produced against the same antigen from hybridomas. Biodistribution studies demonstrate 1.47% injected dose/g tumor 24 h after injection of 125I-C6.5 into scid mice bearing SK-OV-3 tumors. Tumor:normal organ ratios range from 8.9:1 for kidney to 283:1 for muscle. CONCLUSIONS: These results are the first in vivo biodistribution studies using an sFv isolated from a non-immune human repertoire and confirm the specificity of sFv produced in this manner. The use of phage display to produce C6.5 mutants with higher affinity and slower k(off) would permit rigorous evaluation of the role of antibody affinity and binding kinetics in tumor targeting, and could result in the production of a therapeutically useful targeting protein for radioimmunotherapy and other applications.

Amino Acid Sequence↗

PubMed1995

The very low birthweight infant: maternal complications leading to preterm birth, placental lesions, and intrauterine growth.

The placental lesions of the very low birthweight (VLBW) infant were investigated in relation to clinical complications leading to preterm birth and evidence of growth impairment. The 249 singleton gestations yielding infants less than 1500 g were grouped according to the clinical complications leading to preterm birth as premature membrane rupture (116/249, 47%) preterm labor (55/249, 22%), pregnancy-induced hypertension (PIH, 54/249, 22%), and normotensive abruption (ABR, 24/249, 10%). Specifically excluded from this data set were cases with greater than 2 weeks discordance, fetal congenital anomalies, placenta previa, and maternal medical or gestational diseases such as chronic hypertension and diabetes mellitus, and intrauterine growth retardation (IUGR) as a primary indication for delivery. Placental weight and lesions including decidual vasculopathy and related villous lesions, chronic villitis/intervillositis, and decidual plasmacytosis were considered as variables in analyses in which raw birthweight was the dependent variable and gestational age a confounder. Of the 195 VLBW, 79 (41%) infants from normotensive mothers had lesions of decidual vasculopathy or chronic inflammation. In the VLBW infants from hypertensive mothers, growth restriction was related to markers of decidual vasculopathy. In the absence of maternal hypertension the growth restriction was independently associated with chronic villitis. Decidual vasculopathy (characteristic of PIH) and chronic intrauterine inflammation underlie the complications of many normotensive VLBW infants. The placental lesions in VLBW-IUGR depend on the presence or absence of maternal hypertension. In the absence of maternal hypertension, VLBW-IUGR is associated with chronic inflammation and is independent of decidual vasculopathy. In the presence of maternal hypertension, VLBW-IUGR is directly related to decidual vasculopathy.

Abruptio Placentae↗

PubMed1995

Enhanced tumor specificity of 741F8-1 (sFv')2, an anti-c-erbB-2 single-chain Fv dimer, mediated by stable radioiodine conjugation.

UNLABELLED: The goal of this study was to determine if the stabilization of the radioiodine-protein bond by the N-succinimidyl p-iodobenzoate (PIB) method improved the degree and specificity of tumor localization of 125I-741F8-1 (sFv')2, an anti-c-erbB-2 sFv dimer, in an immunodeficient murine model. METHODS: Gamma camera images were acquired 21 hr after intravenous administration of 131I-741F8-1 (sFv')2 labeled by the p-iodobenzoate or chloramine T methods. The stability of the radioiodine-protein bond also was assessed in plasma samples after intravenous injection of 125I-741F8-1 (sFv')2 labeled by either the chloramine T or p-iodobenzoate methods. RESULTS: By 6 hr postinjection, 97% of the activity associated with the 125I-741F8-1 (sFv')2 labeled by the p-iodobenzoate method was protein bound compared with 61% after labeling with the chloramine-T method. These observations indicate that increasing the stability of the conjugation between the radioiodine and the sFv molecule can significantly increase the degree and specificity of tumor targeting. Significantly greater tumor retention (p < 0.005) and lower blood (p < 0.001), spleen (p < 0.001) and stomach (p < 0.005) retention were observed in biodistribution studies when the p-iodobenzoate conjugate was used. This resulted in superior tumor-to-organ ratios for all tissue samples studied. CONCLUSION: These observations may have clinical relevance for the use of radiolabeled sFv as imaging agents.

Animals↗

PubMed1994

Ultrasonographic measurement of fetal nuchal skin to screen for chromosomal abnormalities.

OBJECTIVE: The purpose of this prospective investigation was to determine the utility of ultrasonographic measurement of the fetal nuchal skin in screening for chromosomal abnormalities. STUDY DESIGN: In 1510 patients undergoing genetic amniocentesis at 14 to 21 weeks' gestation, the fetal nuchal skin fold was measured. A measurement of > or = 6 mm was considered abnormal. RESULTS: In fetuses with normal karyotype the nuchal skin increased with advancing gestational age (r = 0.45, p < 0.001). Only 27 fetuses with normal karyotype (2.0%) had an abnormal nuchal skin thickness. Fifty-seven fetuses had abnormal karyotype. Eight of 14 fetuses with Down syndrome had abnormal ultrasonographic findings; four had increased nuchal skin as the only ultrasonographic abnormality. Increased nuchal skin alone, in the absence of other ultrasonographic dysmorphologic features, did not help to identify fetuses with other abnormal karyotypes. CONCLUSION: Nuchal skin thickness is a useful noninvasive measurement to screen for Down syndrome but does not help to identify fetuses with other chromosomal abnormalities.

Chromosome Aberrations↗

PubMed1994

Risk of eye splash in obstetric procedures.

A prospective cross-sectional study was designed to determine the rates of upper facial splash during obstetric deliveries. Macroscopic splashes on the attached eye shields of surgical masks, worn for obstetric deliveries were enumerated for a sample of parturients during a 3-month period. Masks were collected for 68 vaginal and 44 cesarean deliveries, 31% of all deliveries during the study period. For cesarean deliveries, 68% (30) of all masks worn by primary surgeons had at least one splash; 57% (17) of which were heavily contaminated (more than five splashes). For the first assistant, 68% (30) of all masks had at least one splash; 23% (7) of which were heavily contaminated. During vaginal deliveries 44% (30) of masks worn by the delivering physician had at least one splash; 20% (6) of which were heavily contaminated. The primary surgeon in a cesarean section was 1.6 times as likely to be splashed (P < 0.04) when compared with vaginal deliveries and 4.6 times as likely to be heavily contaminated (P < 0.003). Estimated blood loss and the rate of eye splash were linearly related. Method of delivery was not independently associated with eye splash. These findings suggest that the risk of contamination by splash during obstetric procedures is high, particularly for cesarean deliveries because these deliveries tend to have greater blood losses.

Adult↗

PubMed1994

Fetal oculocerebrorenal syndrome of Lowe associated with elevated maternal serum and amniotic fluid alpha-fetoprotein levels.

OBJECTIVE: To report an association between fetal oculocerebrorenal syndrome of Lowe and elevations in maternal serum alpha-fetoprotein (MSAFP) and amniotic fluid alpha-fetoprotein (AFAFP). METHODS: Case 1 was identified during routine MSAFP screening. Cases 2-5 were identified through review of a data base of individuals with oculocerebrorenal syndrome enrolled at the National Institutes of Health. To estimate the frequency of this association, only those whose mothers would have been in the early second trimester from February 1987 to August 1993 were enumerated. The MSAFP was assumed to be normal unless explicitly reported or unless information outside the data base confirmed that MSAFP was not determined. RESULTS: An elevated MSAFP (2.5 multiples of the median [MoM] or greater) was detected in five of 20 pregnancies with a fetus affected by oculocerebrorenal syndrome. Maternal serum alpha-fetoprotein was greater than 5.0 MoM in three pregnancies undergoing amniocentesis, and all had an elevated AFAFP without significant acetylcholinesterase activity. No abnormalities were found by ultrasound, and there was no other cause of elevated AFP identified postnatally. Family history was positive in three of the five cases. The mothers were carriers in four of the five cases, whereas the fifth case appeared to be a spontaneous mutation. CONCLUSIONS: Elevated MSAFP and AFAFP appear to occur at a higher than expected frequency in pregnancies carrying an oculocerebrorenal syndrome fetus. The mechanism of elevation of AFP may be related to fetal renal tubular dysfunction. A directed interview, focusing on a maternal family history of male relatives with unexplained mental retardation, early institutionalization, or congenital rubella, is appropriate with unexplained MSAFP elevations and, particularly, with unexplained AFAFP elevations without acetylcholinesterase activity.

Acetylcholinesterase↗

PubMed1993

Do survival and morbidity of very-low-birth-weight infants vary according to the primary pregnancy complication that results in preterm delivery?

OBJECTIVE: This retrospective study was conducted to determine whether predischarge survival and morbidity of very-low-birth weight infants varied according to the principal pregnancy complication that led to preterm delivery. STUDY DESIGN: The hospital records of 535 consecutive live-born singleton infants who weighed between 500 and 1499 gm were reviewed, and five primary complications that resulted in preterm delivery were identified: (1) premature rupture of membranes (n = 244, 46%), (2) idiopathic preterm labor (n = 97, 18%), (3) antepartum hemorrhage (n = 58, 11%), (4) pregnancy-induced hypertension (n = 98, 18%), and (5) "other" complications (n = 38, 7%). Neonatal records were studied to identify the presence of respiratory distress syndrome, bronchopulmonary dysplasia, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, and infant death before hospital discharge. Logistic regression analysis was used to analyze the association of each pregnancy complication with the various forms of neonatal morbidity. RESULTS: There were no statistically significant differences in discharge survival rates (range 71% to 88%) among infants born to women who experienced one of the five types of primary complications. Independent of all confounders, premature rupture of membranes was associated with a decreased risk of respiratory distress syndrome, bronchopulmonary dysplasia, pulmonary interstitial emphysema, patent ductus arteriosus, and intraventricular hemorrhage. Preterm labor was associated with an increased risk of pulmonary interstitial emphysema, patent ductus arteriosus, and intraventricular hemorrhage. Pregnancy-induced hypertension was associated with an increased risk of respiratory distress syndrome, pulmonary interstitial emphysema, and patent ductus arteriosus. Antepartum hemorrhage was associated with an increased risk of patent ductus arteriosus. CONCLUSION: The principal pregnancy complication that led to preterm delivery significantly influenced predischarge morbidity but not the predischarge survival of live-born infants.

Female↗

PubMed1992

Transverse cerebellar diameter measurements in twin pregnancies and the effect of intrauterine growth retardation.

OBJECTIVES: Transverse cerebellar diameter measurements have been established for singleton but not twin pregnancies. In singleton pregnancies controversy exists on whether cerebellar growth is affected by intrauterine growth retardation. We undertook this retrospective study in twin pregnancies to establish a nomogram for the transverse cerebellar diameter in twins and to assess the effect of growth retardation on this measurement. STUDY DESIGN: A retrospective review was performed on 171 patients with twin pregnancies with reliable dating from 15 to 36 weeks' gestation who had been referred to our antenatal evaluation unit for routine ultrasonographic examination. Of the 342 fetuses, 322 were available for analysis and establishment of a nomogram for the transverse cerebellar diameter. Twenty-four twin, growth-retarded fetuses were analyzed separately. RESULTS: The transverse cerebellar diameter increased linearly with gestational age (r = 0.94, p < 0.001). Fifteen (63%) of the growth-retarded fetuses had a transverse cerebellar diameter of < or = 5th percentile for gestational age. CONCLUSION: We suggest that intrauterine growth retardation may affect cerebellar growth in twins.

Cerebellum↗

PubMed1992

A comparison of pre-discharge survival and morbidity in singleton and twin very low birth weight infants.

The perinatal mortality rate of twins is four to 11 times higher than that of singletons, and twins are widely reported to have more morbidity than singletons, mainly because of a higher preterm birth rate. However, it is not clear that live-born preterm birth rate. However, it is not clear that live-born preterm twins suffer greater morbidity than comparable singletons. In fact, twins have been reported to develop pulmonary maturity earlier than singletons, which might result in decreased morbidity relative to comparable preterm singletons. We conducted this retrospective review of 496 consecutive singleton and 104 twin infants weighing 500-1499 g and born alive at 24-31 weeks' gestation to determine whether pre-discharge survival and morbidity in very low birth weight (VLBW) twin infants were greater than those of comparable singletons. The mean (+/- standard deviation) gestational age of the singletons was 27.5 +/- 2.0 weeks and of the twins 27.6 +/- 2.0 weeks. There were no differences in mean gestational age, gestational age distribution, mean birth weight, birth weight distribution, gender, or maternal race between the two groups. The pre-discharge survival rate for twins (77%) was not significantly different than that of singletons (82%). There were no differences between twins and singletons in the incidences of neonatal respiratory distress syndrome (63 versus 71%), pulmonary interstitial emphysema (14 versus 16%), patent ductus arteriosus (28 versus 29%), necrotizing enterocolitis (3 versus 5%), intraventricular hemorrhage (11 versus 16%), and retinopathy of prematurity (11 versus 18%). The incidence of bronchopulmonary dysplasia was significantly less in twins (27 versus 46%; P = .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Birth Weight↗

PubMed1991

Relationship between fetal biophysical activities and umbilical cord blood gas values.

In a prospective study of 62 patients undergoing cesarean section before the onset of labor a fetal biophysical profile assessment was performed within 3 hours before the cesarean section. The presence or absence of the individual fetal biophysical activities (fetal heart rate reactivity, fetal breathing movements, fetal body movements, and fetal tone) were correlated with umbilical cord blood gas and acid-base measurements (artery and vein). Fetuses with nonreactive nonstress test results or the absence of breathing had significantly lower cord artery pH, PO2 bicarbonate, and base excess measurements but not a significantly different PCO2 level as compared with fetuses that had these activities present. Fetuses with the absence of movements or tone had lower pH, PO2 bicarbonate, and base excess levels and higher PCO2 levels as compared with fetuses with the presence of movements or tone, respectively. These blood gas and acid-base differences were observed in both umbilical cord artery and vein. Subsequent analysis of the blood gas and acid-base measurements of the fetuses with compromised biophysical activities revealed that there are different levels of acidemia, hypoxemia, and hypercapnia at which the individual biophysical activities are compromised. These data suggest that the first manifestations of fetal hypoxemia and acidemia are nonreactive nonstress test results and loss of fetal breathing; in advanced acidemia, hypoxemia, and hypercapnia fetal movements and fetal tone are compromised.

Carbon Dioxide↗

PubMed1991

Placenta previa is not an independent risk factor for a small for gestational age infant.

Previous studies have presented conflicting evidence on the association between intrauterine growth retardation (IUGR) and placenta previa, with some groups reporting rates of IUGR as high as 16-19%. However, most of these studies failed to include a control population, included patients with other factors known to be associated with IUGR (eg, chronic hypertension, fetal anomalies, pregnancy-induced hypertension, insulin-dependent diabetes mellitus, etc), and/or did not confirm the patient's estimated gestational age. During the study period of January 1, 1980 through June 30, 1990, 54,969 deliveries occurred at the three affiliated hospitals of the Maternal-Fetal Medicine Division of the University of Connecticut Health Center. Review of the delivery records revealed 179 singleton pregnancies with documented placenta previa and without the above exclusion factors. One hundred seventy-one of these 179 study patients were compared with 171 women without placenta previa matched for confirmed gestational age, race, parity, and fetal sex. The incidence of small for gestational age (SGA) infants was 4.1% (seven of 171) in the study group and 5.8% (ten of 171) in the control group. Mean birth weights were 2559 and 2476 g, respectively. Neither difference was statistically significant. These results suggest that the prenatal diagnosis of an SGA fetus in a pregnancy complicated by placenta previa should not simply be attributed to abnormal placental implantation. Furthermore, routine ultrasonic examinations for growth in pregnancies complicated by placenta previa are not indicated.

Birth Weight↗