Robert H. Ball

Impact of maternal age on obstetric outcome

OBJECTIVE: To estimate the effect of maternal age on obstetric outcomes. METHODS: A prospective database from a multicenter investigation of singletons, the FASTER trial, was studied. Subjects were divided into 3 age groups: 1) less than 35 years, 2) 35–39 years, and 3) 40 years and older. Multivariable logistic regression analysis was used to assess the effect of age on outcomes after adjusting for race, parity, body mass index, education, marital status, smoking, medical history, use of assisted conception, and patients study site. RESULTS: A total of 36,056 women with complete data were available: 28,398 (79%) less than 35 years of age; 6,294 (17%) 35–39 years; and 1,364 (4%) 40 years and older. Increasing age was significantly associated with miscarriage (adjusted odds ratio [adjOR]2.0 and 2.4 for ages 35–39 years and age 40 years and older, respectively), chromosomal abnormalities (adjOR 4.0 and 9.9), congenital anomalies (adjOR 1.4 and 1.7), gestational diabetes (adjOR 1.8 and 2.4), placenta previa (adjOR 1.8 and 2.8), and cesarean delivery (adjOR 1.6 and 2.0). Patients aged 35–39 years were at increased risk for macrosomia (adjOR 1.4). Increased risk for abruption (adjOR 2.3), preterm delivery (adjOR 1.4), low birth weight (adjOR 1.6), and perinatal mortality (adjOR 2.2) was noted in women aged 40 years and older. CONCLUSION: Increasing maternal age is independently associated with specific adverse pregnancy outcomes. Increasing age is a continuum rather than a threshold effect. LEVEL OF EVIDENCE: II-2

Fetal growth in early pregnancy and risk of delivering low birth weight infant: prospective cohort study

Objective To determine if first trimester fetal growth is associated with birth weight, duration of pregnancy, and the risk of delivering a small for gestational age infant. Design Prospective cohort study of 38 033 pregnancies between 1999 and 2003. Setting 15 centres representing major regions of the United States. Participants 976 women from the original cohort who conceived as the result of assisted reproductive technology, had a first trimester ultrasound measurement of fetal crown-rump length, and delivered live singleton infants without evidence of chromosomal or congenital abnormalities. First trimester growth was expressed as the difference between the observed and expected size of the fetus, expressed as equivalence to days of gestational age. Main outcome measures Birth weight, duration of pregnancy, and risk of delivering a small for gestational age infant. Results For each one day increase in the observed size of the fetus, birth weight increased by 28.2 (95% confidence interval 14.6 to 41.2) g. The association was substantially attenuated by adjustment for duration of pregnancy (adjusted coefficient 17.1 (6.6 to 27.5) g). Further adjustments for maternal characteristics and complications of pregnancy did not have a significant effect. The risk of delivering a small for gestational age infant decreased with increasing size in the first trimester (odds ratio for a one day increase 0.87, 0.81 to 0.94). The association was not materially affected by adjustment for maternal characteristics or complications of pregnancy. Conclusion Variation in birth weight may be determined, at least in part, by fetal growth in the first 12 weeks after conception through effects on timing of delivery and fetal growth velocity.

First-trimester septated cystic hygroma: prevalence, natural history, and pediatric outcome.

Objective: To estimate prevalence, natural history, and outcome of septated cystic hygroma in the first trimester in the general obstetric population, and to differentiate this finding from simple increased nuchal translucency. Methods: Patients at 10.3–13.6 weeks of gestation underwent nuchal translucency sonography as part of a multicenter clinical trial. Septated cystic hygroma cases were offered chorionic villi sampling for karyotype, and targeted fetal anatomical and cardiac evaluations. Survivors were followed up for fetal and long-term pediatric outcome (median 25 months, range 12–50 months). Cases of septated cystic hygroma were also compared with cases of simple increased nuchal translucency. Results: There were 134 cases of cystic hygroma (2 lost to follow-up) among 38,167 screened patients (1 in 285). Chromosomal abnormalities were diagnosed in 67 (51%), including 25 trisomy-21, 19 Turner syndrome, 13 trisomy-18, and 10 others. Major structural fetal malformations (primarily cardiac and skeletal) were diagnosed in 22 of the remaining 65 cases (34%). There were 5 cases (8%) of fetal death and 15 cases of elective pregnancy termination without evidence of abnormality. One of 23 (4%) normal survivors was diagnosed with cerebral palsy and developmental delay. Overall, survival with normal pediatric outcome was confirmed in 17% of cases (22 of 132). Compared with simple increased nuchal translucency, cystic hygroma has 5-fold, 12-fold, and 6-fold increased risk of aneuploidy, cardiac malformation, and perinatal death, respectively. Conclusion: First-trimester cystic hygroma was a frequent finding in a general obstetric screening program. It has the strongest prenatal association with aneuploidy described to date, with significantly worse outcome compared with simple increased nuchal translucency. Most pregnancies with normal evaluation at the completion of the second trimester resulted in a healthy infant with a normal pediatric outcome. Level of Evidence: II-2

First- and second-trimester evaluation of risk for Down syndrome

OBJECTIVE: To investigate the differences in costs and outcomes of Down syndrome screening using data from the First and Second Trimester Evaluation of Risk (FASTER) Trial. METHODS: Seven possible screening options for Down syndrome were compared: 1) Triple Screen—maternal serum alpha fetoprotein, estriol, and hCG; 2) Quad—maternal serum alpha fetoprotein, estriol, hCG, and Inhibin A; 3) Combined First—nuchal translucency, pregnancy-associated plasma protein A (PAPP-A), free &bgr;-hCG; 4) Integrated—nuchal translucency, PAPP-A, plus Quad; 5) Serum Integrated—PAPP-A, plus Quad; 6) Stepwise Sequential—Combined First plus Quad with results given after each test; and 7) Contingent Sequential—Combined First and only those with risk between 1:30 and 1:1,500 have Quad screen. The detection rates for each option were used given a 5% false-positive rate except for Contingent Sequential with a 4.3% false-positive rate. Outcomes included societal costs of each screening regimen (screening tests, amniocentesis, management of complications, and cost of care of Down syndrome live births), Down syndrome fetuses identified and born, the associated quality-adjusted life years, and the incremental cost-utility ratio. RESULTS: Based on the screening results derived from the 38,033 women evaluated in the FASTER trial, the Contingent Sequential screen dominated (lower costs with better outcomes) all other screens. For example, the Contingent Sequential cost 32.3 million dollars whereas the other screens ranged from 32.8 to 37.5 million dollars. The Sequential strategy led to the identification of the most Down syndrome fetuses of all of the screens, but at a higher cost per Down syndrome case diagnosed (

The physiologic mechanisms of variable decelerations

719,675 compared with

Effects of Propofol and Thiopental on Maternal and Fetal Cardiovascular and Acid-base Variables in the Pregnant Ewe

690,427) as compared with the Contingent Sequential. Because of the lower overall false-positive rate leading to fewer procedure-related miscarriages, the Contingent Sequential resulted in the highest quality-adjusted life years as well. The Contingent Sequential remained the most cost-effective option throughout sensitivity analysis of inputs, including amniocentesis rate after positive screen, rate of therapeutic abortion after Down syndrome diagnosis, and rate of procedure-related miscarriages. CONCLUSION: Analysis of this actual data from the FASTER Trial demonstrates that the Contingent Sequential test is the most cost-effective. This information can help shape future policy regarding Down syndrome screening.

Regional blood flow and metabolism in ovine fetuses during severe cord occlusion

OBJECTIVES The purpose of this study was to determine the cause and physiologic consequences of variable decelerations. STUDY DESIGN Previous studies of heart rate changes in human and experimental animals were critically reviewed with respect to the autonomic nervous system component, the cause of the increased vagal activity, and the role of cord compression or other stimuli in these heart rate changes. RESULTS There is abundant evidence from experimental and human studies that variable decelerations can be reproduced by either cord compression or head compression. The vagal reflex produced is probably caused by a combination of chemoreflex (earlier in the deceleration) and baroreflex (later). The variable deceleration is accompanied by an acidosis, primarily respiratory, and probably hypoxemia. Cord compression results in decreased umbilical blood flow. CONCLUSIONS Recent Doppler velocimetry studies suggest that even though the variable decelerations may be similar in duration and depth, the reduction of umbilical blood flow may be greater when the prime cause is cord compression than when the prime cause is vagal reflex from another source.

Comparison of serum markers in first-trimester down syndrome screening.

BackgroundThe effects of propofol on uterine blood flow are not understood well. This is a relatively new agent that is finding increased use for nonobstetric surgical procedures during pregnancy and induction of anesthesia for cesarean section. MethodsThe effects of induction and maintenance of anesthesia with propofol were studied on maternal and fetal cardiovascular and acid-base variables in a chronically instrumented pregnant sheep model. Anesthesia was induced with a 2 mg/kg bolus of propofol and maintained with of one of three continuous infusions: 150, 300, and 450 μg kg-1 min-1. The control group received thiopental for induction, and anesthesia was maintained with isoflurane. ResultsThe use of propofol did not adversely affect maternal or fetal mean arterial pressure, heart rate, or base excess, fetal heart rate variability, or uterine blood flow. Uterine blood flow transiently decreased during induction and intubation with thiopental but remained stable during induction with propofol. However, administration of succinychollne for intubation in the presence of propofol resulted in a transient, but severe, maternal bradycardia. Continuous infusion of 300 μg kg-1 min-1 of propofol appeared to provide satisfactory anesthesia in the ewe. ConclusionsAssuming the applicability of ovine data to humans, these findings suggest that induction and maintenance of anesthesia with propofol and 50% nitrous oxide in oxygen has no adverse fetal effects but warrants caution because of the potential risk of severe maternal bradycardia during induction of anesthesia using the combination of propofol and succlnylcholine.

Individualized norms of optimal fetal growth: Fetal growth potential

OBJECTIVE Our purpose was to compare the ovine fetal response to severe, damaging asphyxia resulting from umbilical cord occlusion with that seen in uterine artery occlusion. STUDY DESIGN Six ovine fetuses were exposed to severe asphyxia produced by partial umbilical cord occlusion for 90 minutes. Fetal blood pressure and heart rate, blood gases, acid base status, electrocorticogram, and electromyogram were recorded. Regional blood flow (radioactive microspheres) measurements were performed at control and 30, 60, and 90 minutes of occlusion and 30 minutes after release. RESULTS During the period of occlusion pH fell from 7.37 +/- 0.01 (mean +/- SEM) to 6.82 +/- 0.03 at 90 minutes, base excess from 5 +/- 1 to -22 +/- 2 mEq.L-1 and oxygen content from 3.3 +/- 0.4 mmol.L-1 to a nadir of 1.6 +/- 0.4 mmol.L-1 (p < 0.05). There was no significant long-term change in fetal heart rate or blood pressures. The fetal electrocorticogram was profoundly suppressed during asphyxia, and seizure activity was documented after release of occlusion in all surviving animals. Umbilical blood flow fell to 21% +/- 5% of control by 60 minutes of occlusion and remained depressed until release. Brain and adrenal blood flows increased during asphyxia. Heart and intestinal blood flows did not change significantly from control values. Combined ventricular output and spleen, kidney, and carcass blood flow fell during the insult. Oxygen uptake by the cerebral cortex remained stable during occlusion. Oxygen uptake by the lower carcass fell to 15% +/- 7% of control. CONCLUSION Umbilical cord occlusion produces similar levels of asphyxia and evidence of encephalopathy (seizures), compared with previous experiments with uterine artery occlusion. The fetal response with respect to blood flow redistribution and organ oxygen uptake, however, differs. These differences may signify that with uterine artery occlusion the brain may be more vulnerable, whereas with umbilical cord occlusion the heart may be at greater risk.

Maintaining quality assurance for sonographic nuchal translucency measurement : lessons from the FASTER Trial

OBJECTIVE: To estimate patterns of total hCG and inhibin A levels in the late first trimester of Down syndrome pregnancies, compare them with that of free &bgr;-hCG, and assess screening performance of these markers individually and in combination with pregnancy-associated plasma protein-A (PAPP-A) and nuchal translucency. METHODS: Seventy-nine matched case–control sets of maternal serum samples (each Down syndrome case matched to 5 controls) from 11 through 13 completed weeks of gestation were taken from the sample bank of the First and Second Trimester Evaluation of Risk Consortium, a population-based study, and assayed for levels of free &bgr;-hCG, total hCG, and inhibin A. Distribution characteristics and correlations of the multiples of the median values were estimated in cases and controls. Screening performance for each marker, alone and in combination with PAPP-A, nuchal translucency, and maternal age, was calculated. RESULTS: Median multiples of the median levels of free &bgr;-hCG, total hCG, and inhibin A in cases were more elevated as gestation increased from 11 to 13 weeks, with univariate detection rates of 31%, 23%, and 29%, respectively, at a 5% false-positive rate. At 12 weeks, the multivariate detection rates at a 5% false-positive rate for nuchal translucency and PAPP-A (with maternal age) with either free &bgr;-hCG, total hCG, or inhibin A were 84%, 83%, and 85%, respectively. The improvement in performance from nuchal translucency and PAPP-A to any of the three-marker tests was significant, while performance of any of the three-marker combinations was not significantly different from each other. CONCLUSION: Although levels of free &bgr;-hCG in affected pregnancies were higher earlier than the levels of either total hCG or inhibin A, there was no significant difference in screening performance when either of the three markers was used with nuchal translucency and PAPP-A at 11–13 weeks of pregnancy. LEVEL OF EVIDENCE: II-2