17-Hydroxyprogesterone caproate in triplet pregnancy: an individual patient data meta-analysis.

BACKGROUND: Preterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective. OBJECTIVE: To determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-hydroxyprogesterone caproate (17OHPc). SEARCH STRATEGY: We searched literature databases, trial registries and references in published articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies. DATA COLLECTION AND ANALYSIS: Investigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32 weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at <24, <28 and <34 weeks of gestation. MAIN RESULTS: Three RCTs of 17OHPc versus placebo included 232 mothers with triplet pregnancies and their 696 offspring. Risk-of-bias scores and between-study heterogeneity were low. Baseline characteristics were comparable between 17OHPc and placebo groups. The rate of the composite adverse perinatal outcome was similar among those treated with 17OHPc and those treated with placebo (34 and 35%, respectively; risk ratio [RR] 0.98, 95% confidence interval [95% CI] 0.79-1.2). The rate of birth at <32 weeks was also similar in the two groups (35 and 38%, respectively; RR 0.92, 95% CI 0.55-1.56). There were no significant between-group differences in perinatal mortality rate, randomisation-to-delivery interval, or other specified outcomes. CONCLUSION: Prophylactic 17OHPc given to mothers with triplet pregnancies had no significant impact on perinatal outcome or pregnancy duration. TWEETABLE ABSTRACT: 17-Hydroxyprogesterone caproate had no significant impact on the outcome or duration of triplet pregnancy.

Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.

BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB). OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA). SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles. SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB. MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75). AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

Optimizing multiphoton fluorescence microscopy light collection from living tissue by noncontact total emission detection (epiTED).

A benefit of multiphoton fluorescence microscopy is the inherent optical sectioning that occurs during excitation at the diffraction-limited spot. The scanned collection of fluorescence emission is incoherent; that is, no real image needs to be formed on the detector plane. The nearly isotropic emission of fluorescence excited at the focal spot allows for new detection schemes that efficiently funnel all attainable photons to detector(s). We previously showed [Combs, C.A., et al. (2007) Optimization of multiphoton excitation microscopy by total emission detection using a parabolic light reflector. J. Microsc. 228, 330-337] that parabolic mirrors and condensers could be combined to collect the totality of solid angle around the excitation spot for tissue blocks, leading to ∼8-fold signal gain. Using a similar approach, we have developed an in vivo total emission detection (epiTED) instrument modified to make noncontact images from outside of living tissue. Simulations suggest that a ∼4-fold enhancement may be possible (much larger with lower NA objectives than the 0.95 NA used here) with this approach, depending on objective characteristics, imaging depth and the characteristics of the sample being imaged. In our initial prototype, 2-fold improvements were demonstrated in the mouse brain and skeletal muscle as well as the rat kidney, using a variety of fluorophores and no compromise of spatial resolution. These results show this epiTED prototype effectively doubles emission signal in vivo; thus, it will maintain the image signal-to-noise ratio at two times the scan rate or enable full scan rate at approximately 30% reduced laser power (to minimize photo-damage).

Two-photon excitation fluorescence pH detection using 2,3-dicyanohydroquinone: a spectral ratiometric approach.

The use of 2,3-dicyanohydroquinone (DCHQ) as an emission ratiometric probe of pH in vitro and in fibroblast cells was evaluated using two-photon excitation fluorescence microscopy (TPEFM). In addition, methods for spectrally calibrating the Zeiss LSM510 META spectroscopy system for TPEFM were also developed. The emissions of both the acid and base forms of DCHQ were detectable when using an 800-nm excitation in TPEFM, thereby allowing ratiometric determination of pH. These data suggest that, in contrast to most other emission ratiometric probes, both acid and base forms of DCHQ have similar two-photon cross-sectional areas at 800 nm. Acid (maximum at approximately 457 nm) and base (maximum at approximately 489 nm) DCHQ TPEFM emission spectra were similar to previously reported one-photon excitation emission spectra. Calibration curves for pH were successfully constructed using the ratio of DCHQ emission difference maxima at 460 nm and 512 nm in vitro and in cells. To our knowledge, DCHQ is currently the only effective emission ratiometric pH indicator for two-photon microscopy and may serve as a useful starting point for the development of other TPEFM ratiometric dyes for quantitative measurement of other cell parameters such as Ca2+, Mg2+ or Na+.

Direct imaging of dehydrogenase activity within living cells using enzyme-dependent fluorescence recovery after photobleaching (ED-FRAP).

Reduced nicotine adenine dinucleotide (NADH) is a key metabolite involved in cellular energy conversion and many redox reactions. We describe the use of confocal microscopy in conjunction with enzyme-dependent fluorescence recovery after photobleaching (ED-FRAP) of NADH as a topological assay of NADH generation capacity within living cardiac myocytes. Quantitative validation of this approach was performed using a dehydrogenase system, in vitro. In intact cells the NADH ED-FRAP was sensitive to temperature (Q(10) of 2.5) and to dehydrogenase activation by dichloroacetate or cAMP (twofold increase for each). In addition, NADH ED-FRAP was correlated with flavin adenine dinucleotide (FAD(+)) fluorescence. These data, coupled with the cellular patterns of NADH ED-FRAP changes with dehydrogenase stimulation, suggest that NADH ED-FRAP is localized to the mitochondria. These results suggest that ED-FRAP enables measurement of regional dynamics of mitochondrial NADH production in intact cells, thus providing information regarding region-specific intracellular redox reactions and energy metabolism.

Sonographic EFW and macrosomia: is there an optimum formula to predict diabetic fetal macrosomia?

OBJECTIVE: To compare the accuracy of 31 published formulas for estimated fetal weight (EFW) in predicting macrosomia (birthweight 4,000 gm or more) in infants of diabetic mothers. METHODS: The study population comprised 165 women with gestational or pregestational diabetes who had sonograms to estimate fetal weight after 36 weeks of gestation and within 2 weeks of delivery. Three measures of accuracy were compared: 1) area under the receiver operating characteristic (ROC) curve relating EFW to macrosomia, 2) systematic error, and 3) absolute error. For each measure, the 31 formulas were rank-ordered from 1 (best) to 31 (worst). For each formula, the three rank scores were summed to give a total score. The formula with the lowest total score was considered the "best" formula. RESULTS: Macrosomia occurred in 49 cases (30%). Areas under the ROC curves ranged from 0.8361-0.8978. Differences in areas were not significantly different between the 31 formulas. The 1986 formula of Ott et al. had the lowest total score. Using this "best" formula, an EFW of 4,000 gm or more had a sensitivity of 45% to predict macrosomia and a positive predictive value of 81%. To achieve 90% sensitivity with this formula would have required diagnosis of macrosomia with an EFW of 3,535 gm or more, but this would have comprised 46% of the population with a 42% false-positive rate. All 31 formulas were better at predicting macrosomia than predictions based on gestational age alone, and 28 were better than predictions based on abdominal circumference alone. CONCLUSIONS: All 31 formulas for EFW had comparably poor accuracy for prediction of macrosomia. Delivery decisions based on EFW will often be in error. Future studies should determine whether specific sonographic measurements, ratios, or differences are better than EFW or birthweight as predictors of birth trauma.

Effect of muscle action and metabolic strain on oxidative metabolic responses in human skeletal muscle.

A recent report suggests that differences in aerobic capacity exist between concentric and eccentric muscle action in human muscle (T. W. Ryschon, M. D. Fowler, R. E. Wysong, A. R. Anthony, and R. S. Balaban. J. Appl. Physiol. 83: 867-874, 1997). This study compared oxidative response, in the form of phosphocreatine (PCr) resynthesis rates, with matched levels of metabolic strain (i.e., changes in ADP concentration or the free energy of ATP hydrolysis) in tibialis anterior muscle exercised with either muscle action in vivo (n = 7 subjects). Exercise was controlled and metabolic strain measured by a dynamometer and (31)P-magnetic resonance spectroscopy, respectively. Metabolic strain was varied to bring cytosolic ADP concentration up to 55 microM or decrease the free energy of ATP hydrolysis to -55 kJ/mol with no change in cytoplasmic pH. PCr resynthesis rates after exercise ranged from 31.9 to 462.5 and from 21.4 to 405.4 micromol PCr/s for concentric and eccentric action, respectively. PCr resynthesis rates as a function of metabolic strain were not significantly different between muscle actions (P > 0.40), suggesting that oxidative capacity is dependent on metabolic strain, not muscle action. Pooled data were found to more closely conform to previous biochemical measurements when a term for increasing oxidative capacity with metabolic strain was added to models of respiratory control.

Normalized metabolic stress for 31P-MR spectroscopy studies of human skeletal muscle: MVC vs. muscle volume.

A critical requirement of submaximal exercise tests is the comparability of workload and associated metabolic stress between subjects. In this study, 31P-magnetic resonance spectroscopy was used to estimate metabolic strain in the soleus muscle during dynamic, submaximal plantar flexion in which target torque was 10 and 15% of a maximal voluntary contraction (MVC). In 10 healthy, normally active adults, (PCr + Pi)/PCr, where PCr is phosphocreatine, was highly correlated with power output normalized to the volume of muscle in the plantar flexor compartment (r = 0.89, P < 0.001). The same variable was also correlated, although less strongly (r = 0.78, P < 0.001), with power normalized to plantar flexor cross-sectional area. These findings suggest that comparable levels of metabolic strain can be obtained in subjects of different size when the power output, or stress, for dynamic plantar flexion is selected as a function of plantar flexor muscle volume. In contrast, selecting power output as a function of MVC resulted in a positive linear relationship between (PCr + Pi)/PCr and the torque produced, indicating that metabolic strain was increasing rather than achieving constancy as a function of MVC. These findings provide new insight into the design of dynamic muscle contraction protocols aimed at detecting metabolic differences between subjects of different body size but having similar blood flow capacity and mitochondrial volume per unit of muscle.

Diabetic nephropathy and pregnancy.

Knowledge of the pathogenic mechanisms of diabetic nephropathy (by which hyperglycemia, hyperfiltration, and hypertension cause the gradual development of microproteinuria, mesangial expansion, and eventual glomerular closure) provides the basis for effective treatment. Intensified glycemic control and antihypertensive therapy that is safe for the fetus are crucial for success during pregnancy. Considered outcome measures include perinatal survival, size at birth, child development, and long-term maternal renal function.

Lack of effect of pregnancy on renal allograft survival or function.

To determine whether pregnancy had a long-term influence on the survival or function of renal allografts, a case-control study was conducted. Patients were selected from a pool of 915 patients transplanted at the University of Cincinnati from 1967 to 1990. The pregnancy group consisted of 18 women who became pregnant 3 months to 17 years after transplantation and who elected to continue pregnancy. There were 26 nonpregnant female controls, and 23 male control renal transplant recipients. Matching criteria were cause of end-stage renal disease (ESRD), donor source, age at transplantation, calendar year of transplantation, time from transplantation to pregnancy, and serum creatinine concentration at the time corresponding to conception. Matching was performed by one investigator, who had no knowledge of long-term outcome in any of the patients. The three groups were well-matched with regard to these criteria. Male controls had higher baseline creatinine clearances than pregnancy cases or female controls. During pregnancy, serum creatinine levels fell by 20%, and creatinine clearance rose by 53%. Immediately after pregnancy, these values returned to baseline. Graft survival, with a mean posttransplant follow-up of 11-12 years, was 77.8% in the pregnancy cases, 69.2% in the female controls, and 69.6% in the male controls. By life-table analysis, none of these differences was significant. Among surviving grafts, serum creatinine levels and creatinine clearances remained stable throughout the follow-up period. In this study, using well-matched male and nonpregnant female cohorts for comparison, pregnancy did not have an adverse long-term effect on renal allograft function or survival.

Graded intracellular acidosis produces extensive and reversible reductions in the effective free energy change of ATP hydrolysis in a molluscan muscle.

Phosphorus nuclear magnetic resonance spectroscopy was used to evaluate the impact of experimental reductions of intracellular pH on in vitro preparations of the radula protractor muscle of the marine gastropod, Busycon canaliculatum. The intracellular pH of radula refractor muscle bundles superfused with buffered artificial sea water (pH = 7.8) was 7.29. It was possible to clamp muscle intracellular pH at various acidotic states by changing the superfusate to 5, 10, and 15 mmol.l-1 5,5-dimethyl-oxazolidine-2,4-dione in buffered artificial sea water (pH = 6.5). Consistent and temporally stable reductions of intracellular pH were achieved (intracellular pH = 6.98, 6.79, and 6.62, respectively). During the acidotic transitions, arginine phosphate concentrations decreased and inorganic phosphate concentrations increased in a reciprocal manner and remained essentially constant after the intracellular pH stabilized. The extent of changes in arginine phosphate and inorganic phosphate was directly proportional to the magnitude of the imposed acidosis. Total adenosine triphosphate concentrations remained unchanged in all treatments. However, the magnesium adenosine triphosphate to total adenosine triphosphate ratio declined in direct relation to the extent of the acidosis. Intracellular free Mg2+ fell incrementally with reduced intracellular pH. All of the above effects were rapidly reversed when the 5,5-dimethyl-oxazolidine-2,4-dione was washed out by changing the superfusate to buffered artificial sea water (pH = 7.8). Mg-adenosine diphosphate concentrations were calculated in all treatments using equilibrium constants for the arginine kinase reaction corrected for pH and intracellular free [Mg2+]. The metabolite, intracellular pH, and [Mg2+] data were used to estimate the effective free energy of hydrolysis of adenosine triphosphate (dG/d xi ATP) under most experimental conditions. Experimental acidosis resulted in dramatic reductions in dG/d xi ATP which were fully reversible upon wash-out of 5,5-dimethyl-dioxazolidine-2,4-dione and recovery to normal intracellular pH conditions. Acidosis resulted in net hydrolysis of arginine phosphate, likely via a complex mechanism involving enhancement of rate of adenosine triphosphate hydrolysis and/or inhibition of adenosine triphosphate synthesis.

Glycemic thresholds for spontaneous abortion and congenital malformations in insulin-dependent diabetes mellitus.

OBJECTIVE: To test the hypothesis that women with insulin-dependent (type I) diabetes have a threshold of glycemic control in early pregnancy for increased risks of spontaneous abortion and congenital malformations. METHODS: Receiver-operating characteristic (ROC) curves were formed for the occurrence of abortion and malformations as a function of the median first-trimester preprandial blood glucose concentration and the first measured glycohemoglobin concentration in pregnant women with type I diabetes. RESULTS: Fifty-two of the 215 women (24%) who enrolled before 9 weeks' gestation had spontaneous abortions. Six percent of the women enrolled before 14 weeks had infants with major congenital malformations. Thresholds for an increased risk of abortion and malformations were a median first-trimester blood glucose concentration of 120-130 mg/dL or an initial glycohemoglobin concentration of 12-13% (6.2-7.5 standard deviations above the normal mean). CONCLUSIONS: Type I diabetic women with initial glycohemoglobin concentrations in pregnancy above 12% or median first-trimester preprandial glucose concentrations above 120 mg/dL have an increased risk of abortion and malformations. Below these glycemic thresholds, the risks are comparable to those in nondiabetic women.

Early-pregnancy proteinuria in diabetes related to preeclampsia.

OBJECTIVE: To test the hypothesis that the risk of preeclampsia in diabetic mothers is increased with incipient diabetic nephropathy as well as with overt nephropathy. METHODS: Pregnancy outcome was studied in 311 women with class B-RF diabetes from two institutions. Using 104 women without chronic hypertension followed at the University of California, San Francisco, we constructed a receiver-operating characteristic curve relating 24-hour urinary total protein before 20 weeks' gestation to the subsequent development of preeclampsia. From the curve, a predictive cutoff level of proteinuria was selected and tested in two validation groups not used to construct the curve: 158 women without chronic hypertension followed at the University of Cincinnati and 49 women with chronic hypertension from both institutions. RESULTS: The receiver-operating characteristic curve showed an increased risk of preeclampsia with early-pregnancy proteinuria of 190 mg/day or more. In the Cincinnati validation group, the rate of preeclampsia was 7% in women with early-pregnancy proteinuria of less than 190 mg/day, 31% with proteinuria of 190-499 mg/day, and 38% with proteinuria of 500 mg/day or more. In the chronic-hypertension validation group, the rates were 0, 50, and 58%, respectively. By multiple logistic regression, the increased risk of preeclampsia with proteinuria above 190 mg/day persisted after controlling for the effects of parity, chronic hypertension, retinopathy, and glycemic control. CONCLUSIONS: Diabetic gravidas with early-pregnancy proteinuria of 190-499 mg/day are at increased risk for preeclampsia. The risk is comparable to that in women with overt diabetic nephropathy and is independent of chronic hypertension. We speculate that diabetic women with proteinuria in this range have incipient or subclinical diabetic nephropathy.

Pregnancy after mustard repair for transposition of the great arteries.

BACKGROUND: Since the introduction of surgical repair procedures, women with complete transposition of the great arteries are surviving into their reproductive years. Only three successful pregnancies in such women have been described previously. CASES: Three women with transposition of the great arteries repaired in childhood became pregnant in 1991. Two pregnancies were complicated by failure of the systemic ventricle and one by preterm labor. Labor was managed with antibiotic prophylaxis against endocarditis, clinical hemodynamic assessment, epidural anesthesia, avoidance of maternal expulsive efforts in the second stage, and low forceps delivery. Three healthy infants were delivered vaginally between 34-39 weeks' gestation. CONCLUSION: With close cooperation between the cardiologist and obstetrician, successful pregnancy is possible after surgical repair of transposition of the great arteries. However, failure of the systemic ventricle is common and should be diagnosed and treated promptly.

Poor glycemic control and antepartum obstetric complications in women with insulin-dependent diabetes.

OBJECTIVE: The purpose of this study was to test the hypothesis that the rate of complications of pregnancy in women with insulin-dependent diabetes is higher than in nondiabetic women and is associated with poor glycemic control and microvascular disease. METHOD: Women who enrolled in a multidisciplinary program of diabetes in pregnancy prior to 20 weeks' gestation were included in the study and matched 1:2 by age, race and parity to a control group of nondiabetic women. Complications of pregnancy were retrospectively analyzed and compared between groups. The association of complications with glycemic control and microvascular disease was analyzed within the diabetic group. RESULT: Women with diabetes had significantly higher rates of pregnancy-induced hypertension (PIH), polyhydramnios, pyelonephritis, preterm delivery and meconium-stained amniotic fluid. Poor glycemic control, particularly during the first and second trimesters of pregnancy, was associated with all complications, except pyelonephritis. Microvascular disease was associated with PIH and preterm delivery prior to 34 weeks. CONCLUSION: Women with insulin-dependent diabetes are at high risk for complications of pregnancy. Glycemic control during the first and second trimesters may affect events later in pregnancy.

Maternal and perinatal implications of diabetic nephropathy.

Nephropathy is a serious and challenging complication of diabetes with regard to maternal health, fetal well-being, and outcome of infants. This article describes the available information and the controversies regarding clinical course, pregnancy complications, and treatment.

Sonographic estimation of fetal weight based on a model of fetal volume.

OBJECTIVES: To derive a formula for sonographic estimated fetal weight (EFW) based on a two-compartment model of fetal volume and to test it against two widely used formulas, especially at the extremes of fetal weight for which existing formulas are generally inaccurate. METHODS: We analyzed 865 consecutive sonograms that met the following inclusion criteria: singleton pregnancy, normal anatomy, delivery within 3 days of sonography, and measurements of biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL). The weight of the fetal head was modeled to be proportional to HC3, and the weight of the trunk proportional to AC2 x FL. The proportionality constants were found by multiple linear regression on 380 sonograms performed in 1990 (the "derivation set"). The new formula was tested for accuracy of prediction of actual birth weight against the formulas of Hadlock et al and Shepard et al using 485 sonograms from 1991-1992 (the "validation set"). RESULTS: In the derivation set, the formula EFW = (0.23718 x AC2 x FL) + (0.03312 x HC3) was fit; the correlation with actual birth weight had an r value of 0.996. In the validation set, the new formula produced smaller systematic errors and smaller absolute errors than either the Hadlock or Shepard formula both overall and in fetal weight strata from less than 1000 g to over 4000 g. CONCLUSION: The new formula makes geometric sense and provides accurate estimates of fetal weight across a broad range of weights.

Experimental preeclampsia produced by chronic constriction of the lower aorta: validation with longitudinal blood pressure measurements in conscious rhesus monkeys.

OBJECTIVES: Our goals were (1) to determine whether hypertension, proteinuria, and glomerular endotheliosis can be produced by chronic reduction of lower aortic pressure in pregnant rhesus monkeys and (2) to study the time course of the development of hypertension by means of longitudinal arterial blood pressure measurements in conscious, unrestrained pregnant rhesus monkeys. STUDY DESIGN: Indwelling arterial catheters were placed at 103 +/- 4 days of gestation (term 160 days) for measurement of arterial pressure before and after reduction of lower aortic pressure. At 116 +/- 7 days lower aortic pressure was reduced by 24 +/- 11 mm Hg in 11 monkeys (experimental group) by a stricture on the aorta just below the renal arteries; six monkeys (controls) underwent a sham operation. Resting on the aorta just below the renal arteries; six monkeys (controls) underwent a sham operation. Resting pressures were measured three to five times per week by a tether-and-swivel system. RESULTS: Baseline arterial pressure averaged 81 +/- 6 mm Hg. In the experimental group four monkeys had adverse outcomes (one maternal death with severe hypertension, one abruptio placentae with stillbirth, and two spontaneous preterm deliveries with hypertension). There was one preterm delivery in the control group. Of the seven monkeys with aortic stricture who continued to term, four developed sustained hypertension (mean pressure 18 +/- 6 mm Hg above baseline), proteinuria, and moderate-to-severe glomerular endotheliosis. None of the controls had hypertension or proteinuria, but two had endotheliosis. CONCLUSION: These observations confirm that a syndrome resembling preeclampsia can be produced by a reduction of lower aortic pressure, and they demonstrate that the associated hypertension is not an artifact of anesthesia. This model may prove useful in studying the pathophysiologic mechanisms of preeclampsia.