Gestational age-dependent expression of insulin-like growth factor-binding protein-1 (IGFBP-1) phosphoisoforms in human extraembryonic cavities, maternal serum, and decidua suggests decidua as the primary source of IGFBP-1 in these fluids during early pregnancy.

The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of fetal and maternal tissue development during pregnancy. Posttranslational modification of IGFBP-1 yields up to six IGFBP-1 phosphovariants and a nonphosphorylated form, which in vitro, have some different properties. Nonphospho IGFBP-1 has less affinity for IGFs than the phospho isoforms and also may have IGF-independent actions. Herein, we have investigated the complement of IGFBP-1 phosphoisoforms present in extraembryonic coelomic (EEC) fluid, amniotic fluid (AF), and maternal serum (MS) throughout human gestation. Also, to determine potential tissue source(s) of IGFBP-1 in these fluids, we have quantified IGFBP-1 and examined IGFBP-1 phosphoisoforms in conditioned media (CM) from maternal decidua, fetal liver, and fetal kidney explants throughout gestation. Western immunodetection revealed that IGFBP-1, present in EEC and AF in early pregnancy and in CM from early pregnancy decidua, is primarily in the nonphosphorylated form. MS in this period contains primarily the nonphospho form and, as in nonpregnant adults, the highly phosphorylated form of IGFBP-1. The phosphorylation profile of IGFBP-1 in AF, MS, and decidua CM changes as pregnancy progresses. All the IGFBP-1 phosphoisoforms ultimately are produced by decidua and are present in midgestation MS, and all but the most highly phosphorylated form are present in AF. In late gestation, MS contains primarily the highly phosphorylated form. In contrast, profiles in CM from explants of fetal liver and kidney at different gestational ages remain unchanged. Nonphosphorylated IGFBP-1 is the primary form in fetal kidney CM, whereas fetal liver CM contains all IGFBP-1 phosphoisoforms. Concentrations of IGFBP-1 in fetal liver and kidney CM are significantly lower (482 +/- 146 and 120 +/- 32 ng/mL x 100 mg wet wt tissue, respectively) than in decidua CM (11,417 +/- 2,358 ng/mL x 100 mg wet wt tissue). The data cumulatively suggest that maternal decidua is the primary source of IGFBP-1 in EEC, AF, and MS in early pregnancy and that fetal liver and kidney are not likely significant contributors. The presence of nonphospho IGFBP-1 in AF, EEC, and MS suggests an important role for this isoform during early gestation.

The role of sonography in assessing severity of fetal anemia in Rh- and Kell-isoimmunized pregnancies.

Fetal hematocrit values of blood obtained by percutaneous umbilical blood sampling were correlated with ultrasound findings in 35 samples from 15 pregnancies undergoing evaluation for Rh or Kell sensitization. Intravascular fetal transfusion was performed after a low hematocrit was obtained on 29 of 35 occasions. All fetuses with sonographic evidence of hydrops had a hematocrit of 15% or less, although three fetuses with hematocrits below 15% showed no signs of hydrops. In patients followed with serial sonography, hydramnios was noted as the earliest sonographic abnormality in six of nine pregnancies. All six fetuses were anemic (hematocrit 14-26%) and required transfusion. However, in three pregnancies where the fetus was anemic (hematocrit 22%), there was no hydramnios or other sonographic abnormality. Increased placental thickness was observed in association with fetal hydrops and a hematocrit below 15% in four cases, as well as in three other cases with fetal hematocrit between 16-29% but no fetal hydrops. Measurements of umbilical vein diameter provided no useful information because no increase was observed in these measurements, even in pregnancies with advanced fetal disease evidenced by hydrops.

First-trimester transabdominal multifetal pregnancy reduction: a report of 85 cases.

Eighty-five cases of multifetal pregnancy reduction were performed transabdominally at 9.5-13 weeks' gestation. All pregnancies consisted of three or more fetuses (28 triplets, 47 quadruplets, four quintuplets, four sextuplets, one septuplet, and one nontuplet), and all except five were reduced to twins. Forty-five women have delivered viable infants and eight lost all of the fetuses; 32 pregnancies are ongoing. No temporal relationship was noted between the pregnancy losses and the procedures. The mean gestational age at delivery was 35.7 weeks; 16 women (35.5%) delivered at or after 37 weeks, 16 (35.5%) between 34.5-37 weeks, nine (20%) between 32-34.5 weeks, and four (9%) before 32 weeks. There were no perinatal deaths, and all infants are healthy except for one who developed sequelae of severe hyaline membrane disease.

Maternal renal artery Doppler velocimetry in normotensive pregnancies and pregnancies complicated by hypertensive disorders.

Hypertensive disorders in pregnancy contribute to substantial maternal and perinatal morbidity and mortality. Clinically, these disorders are characterized by hypertension and proteinuria. However, these signs appear some time after the physiologic derangements have been initiated. The primary objectives of this study were as follows: 1) to establish baseline values for the maternal renal artery systolic-diastolic ratio (S/D) as a function of gestational age in normal pregnancies, and 2) to determine whether renal artery blood flow indices can accurately identify those pregnancies complicated by, or destined to develop, hypertensive disorders. Using a pulsed Doppler scanner, maternal renal artery duplex evaluation was performed in four groups of women: normotensive nonpregnant, normotensive pregnant, chronic hypertensive pregnant, and preeclamptic. In 30 normotensive pregnant women followed longitudinally, no change was noted in the renal artery S/D as gestational age advanced, with mean (+/- SD) values of 2.5 +/- 0.20 and 2.6 +/- 0.21 for the left and right sides, respectively. No clinically meaningful discriminations were detected when the four groups were compared. We conclude that maternal renal artery Doppler waveforms are not significantly altered by either pregnancy or hypertensive complications in pregnancy.

Reliability of pleural fluid lymphocyte counts in the antenatal diagnosis of congenital chylothorax.

Two cases are presented in which fetal thoracentesis was performed to evaluate pleural effusions. In the first, a fetus with nonimmune hydrops had pleural effusions with lymphocyte counts consistent with congenital chylothorax. However, amniotic fluid cultures grew cytomegalovirus and the diagnosis of congenital cytomegalovirus infection was confirmed at autopsy. In the second, the pleural fluid lymphocyte count was lower than that considered to be diagnostic of congenital chylothorax. Nevertheless, the clinical course in this case and the patient's history of two previous infants who were presumed to have that disease suggest that this was the most likely diagnosis. These cases emphasize that pleural fluid lymphocyte counts alone are not reliable in establishing the cause of hydrothorax before birth.

Use of atracurium besylate to arrest fetal activity during intrauterine intravascular transfusions.

Prevention of movement during intrauterine transfusion is important to facilitate the procedure and to prevent injury to the fetus. We administered atracurium besylate to the fetus via the umbilical vein during 12 intrauterine intravascular transfusions. A dose of 0.2-0.4 mg/kg of estimated fetal weight was administered after needle entry into the umbilical vein. With a dose of 0.2 mg/kg, fetal movement was slowed transiently. Thereafter, 0.4 mg/kg was administered. All recipients were paralyzed for the duration of the procedure. Fetal activity returned 20-130 minutes later.

Comparison of continuous-wave and pulsed Doppler S/D ratios of umbilical and uterine arteries.

Continuous-wave and pulsed Doppler ultrasound measurements of blood flow velocity waveforms of both uterine and umbilical arteries were performed on 85 patients to assess the correlation between these two measurements techniques. Peak systolic to end-diastolic (S/D) ratios measured by continuous-wave devices were not statistically different (P greater than .05) from those measured by a pulsed Doppler device. The S/D ratios of the umbilical artery measured by each device showed a strong correlation, whether measured by one observer (r = 0.93) or two observers (r = 0.89). Uterine artery ratios showed a weaker, although still significant, correlation (r = 0.57). Pulsed Doppler is not routinely necessary for the identification and measurement of umbilical and uterine artery S/D ratios.

A prospective study of the accuracy of ultrasound in predicting fetal microcephaly.

A prospective study of the diagnostic accuracy of ultrasound in the prediction of fetal microcephaly was performed on a study population of 24 patients. An occipitofrontal diameter larger than the predicted mean -2 standard deviations (SD), a head perimeter larger than the predicted mean -2 SD, and a head perimeter/abdominal perimeter larger than the predicted mean -1 SD were found to exclude fetal microcephaly. An occipitofrontal diameter smaller than the predicted mean -4 SD, a head perimeter smaller than the predicted mean -5 SD, a head perimeter/abdominal perimeter smaller than the predicted mean -3 SD, and a femur length/head perimeter larger than the predicted mean +3 SD were found to cause no errors in the diagnosis of microcephaly. If neither of these two groups of tests is satisfied, fetal microcephaly cannot be reliably diagnosed or excluded on the basis of a single ultrasound examination.

Doppler umbilical velocimetry in the prediction of adverse outcome in pregnancies at risk for intrauterine growth retardation.

Perinatal indicators of fetal compromise were assessed according to the results of continuous-wave Doppler umbilical velocimetry for 172 patients at risk for intrauterine growth retardation (IUGR). Forty-three (25%) of the patients delivered an infant with a birth weight below the tenth percentile for gestational age. The last Doppler study before delivery was abnormal in 48.8% of the growth-retarded infants but in only 13.2% of the infants without evidence of IUGR. Furthermore, in the growth-retarded group, early delivery, reduced birth weight, decreased amniotic fluid at birth, admission to the neonatal intensive care unit, neonatal complications associated with IUGR, and a prolonged hospital stay were observed more frequently in those who had an abnormal ratio than in those with a normal ratio. The sensitivity of the systolic/diastolic ratio for an adverse perinatal outcome (operative delivery for fetal distress, neonatal morbidity associated with IUGR, and/or perinatal death) was significantly better for the infants with IUGR (66.7%) than for the infants without IUGR (27.8%; P less than .05). The predictive value of an abnormal ratio was also higher for the pregnancies complicated with IUGR (57.1%) than for those without IUGR (29.4%), but not to a statistically significant degree. These data suggest that Doppler umbilical velocimetry studies are valuable in identifying those growth-retarded fetuses at increased risk for an adverse perinatal outcome.

Choroid plexus cysts in the fetus: a benign anatomic variant or pathologic entity? Report of 41 cases and review of the literature.

During a 22-month period, 6288 women undergoing prenatal sonographic studies in the second and third trimesters were evaluated prospectively to determine the incidence of choroid plexus cysts in the fetus, to follow the natural course of these cysts in intrauterine life, and to determine the association of chromosomal and anatomic anomalies in these fetuses. We diagnosed choroid plexus cysts in 41 fetuses, an incidence of 0.65%. Unilateral and bilateral cysts were equally frequent, and in most cases diagnosed by 21 weeks' gestation. On follow-up scans, the cysts had completely disappeared by 23-24 weeks in 80% of the cases, and by 28 weeks in another 10%. Once resolved, the cysts did not recur, and a normal sonogram in the late second trimester predicted normal scans in late pregnancy and in the neonate. One fetus had a chromosomal abnormality (trisomy 18). Associated anatomic anomalies were detected in three fetuses, including the one with trisomy 18. We believe that in the great majority of cases, fetal choroid plexus cysts are benign transient variants of normal intracranial anatomy. It is, however, important to conduct a careful sonographic search for associated anomalies. Chromosomal studies are strongly recommended whenever associated anatomic abnormalities are detected and when the choroid plexus cysts are large, bilateral, and persistent beyond 20-22 weeks' gestation.

Ultrasound detection of Down syndrome: is it really possible?

Several ultrasonographic signs have been described in second-trimester fetuses at high risk for Down syndrome. We examined these parameters in twin pregnancies in which one fetus was affected with Down syndrome and the other was normal. Biparietal diameter to femur length ratio was concordant (either normal or abnormal) in eight of nine sets of twins. Actual femur length to expected femur length ratio was concordant in seven of nine sets of twins. Nuchal fold thickening (6 mm or more) correctly identified five out of nine affected fetuses and was not present in any of the normal fetuses. In conclusion, neither ratio was helpful in differentiating the fetus with Down syndrome from its normal cotwin. A thickened nuchal fold was the most informative parameter examined.

Diagnosis and management of fetal holoprosencephaly.

The holoprosencephalies are a spectrum of cerebral and facial malformations resulting from incomplete division of the embryonic forebrain. Using ultrasound to search for structural defects in the fetal brain and to measure interorbital distances, the alobar variety can be diagnosed antenatally. A series of seven cases is presented. Criteria for diagnosis and guidelines for obstetric management are presented.

Diagnosis of ventriculomegaly before fetal viability.

Thirteen cases of documented ventriculomegaly were diagnosed between 19 and 24 weeks of gestation. In 11 cases, the lateral ventricle/hemispheric width ratio was abnormally increased at the time of the first ultrasound examination, and in two, the lateral ventricle/hemispheric width ratios were initially in the high normal range. Severe ventriculomegaly was observed in both of the latter cases when repeat examinations were performed two weeks later. In 12 cases (92%), the biparietal diameter (BPD) was appropriate for gestational age, whereas the BPD was increased in only one. Two of the affected fetuses were found in conjunction with normal twins. This series suggests that fetal ventriculomegaly can be accurately diagnosed before fetal viability using the lateral ventricle/hemispheric width ratio.

The severely anemic and hydropic isoimmune fetus: changes in fetal hematocrit associated with intrauterine death.

Hydrops caused by isoimmune hemolytic anemia is frequently associated with fetal death following intrauterine intravascular transfusion. To identify possible predictors of procedure-related fetal death, we examined changes in fetal blood volume and hematocrit resulting from the initial transfusion performed on 19 severely anemic, hydropic fetuses. Seven fetuses (36.8%) died at 24-72 hours after transfusion, but in no case was the procedure associated with fetal distress. There were no significant differences between fetuses who died and those who survived in terms of total volume of blood transfused, volume transfused as a percentage of total fetoplacental blood volume, hematocrit of transfused blood, post-transfusion hematocrit, umbilical vein pH, or gestational age at transfusion. Significant differences were noted between hydropic fetuses who died compared with those who survived in the mean pretransfusion hematocrit, 6.7% (+/- 2.0) versus 8.7% (+/- 1.6) (P = .03), and the relative increase in post- over pre-transfusion hematocrit, 5.5-fold (+/- 1.4) versus 3.5-fold (+/- 0.8) (P = .001). Stepwise logistic regression analysis confirmed that only the relative increase in hematocrit was predictive of fetal loss. Moreover, six of seven fetal deaths occurred when the relative increase in hematocrit was greater than fourfold, whereas ten of 12 surviving fetuses had relative increases of less than fourfold. We conclude that large, acute increases in fetal hematocrit following intrauterine transfusion are associated with substantial mortality in hydropic fetuses.

Antenatal treatment of alloimmune thrombocytopenia.

OBJECTIVE: Neonatal alloimmune thrombocytopenia is caused by platelet antigen incompatibility between the mother and fetus. Affected fetuses may have severe thrombocytopenia leading to intracranial hemorrhage before or at birth. We sought to treat this condition in utero to prevent these hemorrhages. METHODS: Eighteen women who had previously delivered infants with severe alloimmune thrombocytopenia were treated with weekly infusions of intravenous gamma globulin from the diagnosis of fetal thrombocytopenia until birth; nine were also treated with corticosteroids. RESULTS: There were no intracranial hemorrhages in the treated fetuses, compared with ten cases among the 21 untreated siblings (48%). Only three treated fetuses, compared with 16 of 20 untreated siblings, had platelet counts of less than 30,000/microL, with no bleeding complications. CONCLUSION: Antenatal treatment of alloimmune thrombocytopenia with weekly gamma globulin effectively improves the fetal platelet count and prevents intracranial hemorrhage.

Intrauterine intravascular transfusion for severe erythroblastosis fetalis: how much to transfuse?

Intrauterine intravascular transfusion is now believed to be a more precise method for treating fetal anemia in erythroblastosis fetalis than is intraperitoneal transfusion. Previously established guidelines for the volume of blood to be given in intraperitoneal transfusion at a specific gestational age are not applicable for intravascular transfusion. In 28 patients, intravascular transfusion was performed on 81 occasions between 19-34 weeks' gestation. The total number of transfusions ranged from one to six per patient. The aim at each procedure was to achieve a final hematocrit of 35-50%. Factors examined as likely to determine the volume of blood required included pre-transfusion hematocrit, post-minus pre-transfusion hematocrit (hematocrit increase), the hematocrit of the transfused blood, gestational age, estimated fetal weight, and interval from last transfusion. The factors found to be most predictive of total volume of blood required for transfusion were the hematocrit increase and either estimated fetal weight or gestational age.

Selective second-trimester termination of the anomalous fetus in twin pregnancies.

Selective termination of the affected fetus was performed during the second trimester in 17 pregnancies in which one twin was diagnosed to be anomalous. The affected twin had a chromosomal aneuploidy in 14 cases, neural tube defect in two cases, and an inborn error of metabolism in one case. With increasing operator skill and improvement in technique, a striking improvement occurred in pregnancy outcome in the last 11 patients as compared with the first six. In four of the first six cases, the entire pregnancy was lost. Among the last 11 patients, on the other hand, no pregnancy was lost. All 11 women delivered healthy, viable infants; eight delivered at term and three delivered between 31-35 weeks. Of the various techniques used, we found intracardiac injection of potassium chloride to be the most effective, but it should not be used in monochorionic twin gestations.

High-dose intravenous gamma globulin: does it have a role in the treatment of severe erythroblastosis fetalis?

The role of high-dose intravenous (IV) gamma globulin in the treatment of erythroblastosis fetalis was assessed in five pregnancies with severe Rh (four) or Kell (one) isoimmunization. These women were treated with IV gamma globulin (1.0 g/kg body weight) once a week. In addition, fetal blood transfusions were performed when indicated. In four patients with Rh sensitization, high-dose IV gamma globulin treatment had no apparent effect on the total number of intrauterine transfusions required, the interval between transfusions, or the volume of blood required at each transfusion. The treatment did not prevent fetal hydrops and had no effect on maternal antibody titers. In one patient with Kell sensitization, however, the course of the disease was less severe than anticipated, suggesting that IV gamma globulin treatment may have modified the severity of the disease. We conclude that high-dose IV gamma globulin does not appear to be useful in the treatment of severe Rh disease. Its role in Kell and other types of red-cell isoimmunization deserves further evaluation.

Randomized comparison of intravenous nitroglycerin and magnesium sulfate for treatment of preterm labor.

OBJECTIVE: To compare the safety and efficacy of high-dose intravenous (IV) nitroglycerin with those of IV magnesium sulfate for acute tocolysis of preterm labor. METHODS: Thirty-one women with preterm labor before 35 weeks' gestation were assigned randomly to IV magnesium sulfate or IV nitroglycerin for tocolysis. Preterm labor was defined as the occurrence of at least two contractions in 10 minutes, with cervical change or ruptured membranes. Acute tocolysis was defined as tocolysis for up to 48 hours. Magnesium sulfate was administered as a 4-g bolus, then at a rate of 2-4 g/h. Nitroglycerin was administered as a 100-microg bolus, then at a rate of 1- to 10-microg/kg/min. The primary outcome measure was achievement of at least 12 hours of successful tocolysis. RESULTS: Thirty patients were available for analysis. There were no significant differences in gestational age, cervical dilation, or incidence of ruptured membranes between groups at the initiation of tocolysis. Successful tocolysis was achieved in six of 16 patients receiving nitroglycerin, compared with 11 of 14 receiving magnesium sulfate (37.5 versus 78.6%, P = .033). Tocolytic failures (nitroglycerin versus magnesium sulfate) were due to persistent contractions with cervical change or rupture of previously intact membranes (five of 16 versus two of 14), persistent hypotension (four of 16 versus none of 14), and other severe side effects (one of 16 versus one of 14). Maternal hemodynamic alterations were more pronounced in patients who received nitroglycerin, and 25% of patients assigned to nitroglycerin treatment had hypotension requiring discontinuation of therapy. CONCLUSION: Tocolytic failures were more common with nitroglycerin than with magnesium sulfate. The hemodynamic alterations noted in patients receiving nitroglycerin, including a 25% incidence of persistent hypotension, might limit the usefulness of IV nitroglycerin for the acute tocolysis of preterm labor.

Central nervous system lupus and pregnancy: 11-year experience at a single center.

OBJECTIVE: To describe the pregnancy outcomes in women with central nervous system (CNS) manifestations of lupus. METHODS: Between 1991 and 2002, the outcome of five pregnancies in four patients with CNS lupus were retrospectively reviewed. All patients had an established history of systemic lupus erythematosus (SLE), and either a history of CNS lupus or active CNS lupus. Pregnancy outcomes assessed included term and preterm birth, intrauterine growth restriction, abnormal antepartum testing, perinatal mortality, pre-eclampsia and other maternal morbidities. RESULTS: Evidence of active CNS lupus symptoms developed in three of the five pregnancies. Two pregnancies were complicated by early onset pre-eclampsia, abnormal antepartum testing and extreme prematurity, with one subsequent neonatal death. The remaining three pregnancies had good neonatal outcomes, but were complicated by severe maternal post-pregnancy exacerbations, and the eventual death of one patient. CONCLUSIONS: CNS lupus in pregnancy represents an especially severe manifestation of SLE, and may involve great maternal and fetal risks.