A new direction for prenatal chromosome microarray testing: software-targeting for detection of clinically significant chromosome imbalance without equivocal findings.

Purpose. To design and validate a prenatal chromosomal microarray testing strategy that moves away from size-based detection thresholds, towards a more clinically relevant analysis, providing higher resolution than G-banded chromosomes but avoiding the detection of copy number variants (CNVs) of unclear prognosis that cause parental anxiety. Methods. All prenatal samples fulfilling our criteria for karyotype analysis (n = 342) were tested by chromosomal microarray and only CNVs of established deletion/duplication syndrome regions and any other CNV >3 Mb were detected and reported. A retrospective full-resolution analysis of 249 of these samples was carried out to ascertain the performance of this testing strategy. Results. Using our prenatal analysis, 23/342 (6.7%) samples were found to be abnormal. Of the remaining samples, 249 were anonymized and reanalyzed at full-resolution; a further 46 CNVs were detected in 44 of these cases (17.7%). None of these additional CNVs were of clear clinical significance. Conclusion. This prenatal chromosomal microarray strategy detected all CNVs of clear prognostic value and did not miss any CNVs of clear clinical significance. This strategy avoided both the problems associated with interpreting CNVs of uncertain prognosis and the parental anxiety that are a result of such findings.

An assessment of predictive value of the biophysical profile in women with preeclampsia using data from the fullPIERS database.

INTRODUCTION: Pre-eclampsia is associated with increased risk to both the mother and fetus. Effective monitoring of the fetal condition is essential to the management of women with pre-eclampsia. The biophysical profile (BPP) is one monitoring tool available to clinicians. AIMS AND OBJECTIVES: To compare the BPP test with cardiotocography/non-stress test (CTG/NST) alone for their ability to predict fetal acidemia at birth or a composite adverse perinatal outcome among women with preeclampsia and to estimate the effect of BPP assessment on mode of delivery and birth outcome. METHODS: Secondary analysis of a prospective cohort of women with preeclampsia. The predictive ability of the tests was assessed based on sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-). Women assessed with the BPP were compared with matched controls not assessed with the BPP to determine the odds of Cesarean delivery or adverse perinatal outcomes after adjustment for potential confounders. RESULTS: Five out of 89 women (5.6%) had an abnormal BPP; 18 out of 89 (20.2%) had an abnormal CTG/NST. Fetal acidemia was diagnosed in 13 fetuses (14.6%); composite adverse perinatal outcome in 68 fetuses/infants (76.4%). Both tests had relatively poor predictive performance for both outcomes (LR+ between 2.50 and 3.90 and LR- between 0.64 and 0.93). Assessment with the BPP was positively associated with fetal acidemia (adjusted OR 4.84; 95% CI 1.33-17.66). CONCLUSION: The BPP and CTG/NST alone were poor predictors of perinatal outcome in this cohort; multiple tests should be considered when assessing fetal risk in women with preeclampsia.

PIERS proteinuria: relationship with adverse maternal and perinatal outcome.

OBJECTIVE: To examine the ability of three different proteinuria assessment methods (urinary dipstick, spot urine protein:creatinine ratio [Pr/Cr], and 24-hour urine collection) to predict adverse pregnancy outcomes. METHODS: We performed a prospective multicentre cohort study, PIERS (Preeclampsia Integrated Estimate of RiSk), in seven academic tertiary maternity centres practising expectant management of preeclampsia remote from term in Canada, New Zealand, and Australia. Eligible women were those admitted with preeclampsia who had at least one antenatal proteinuria assessment by urinary dipstick, spot urine Pr/Cr ratio, and/or 24-hour urine collection. Proteinuria assessment was done either visually at the bedside (by dipstick) or by hospital clinical laboratories for spot urine Pr/Cr and 24-hour urine collection. We calculated receiver operating characteristic area under the curve (95% CI) for each proteinuria method and each of the combined adverse maternal outcomes (within 48 hours) or adverse perinatal outcomes (at any time). Models with AUC ≥ 0.70 were considered of interest. Analyses were run for all women who had each type of proteinuria assessment and for a cohort of women ("ALL measures") who had all three proteinuria assessments. RESULTS: More women were proteinuric by urinary dipstick (≥ 2+, 61.4%) than by spot urine Pr/Cr (≥ 30 g/mol, 50.4%) or 24-hour urine collection (≥ 0.3g/d, 34.7%). Each proteinuria measure evaluated had some discriminative power, and dipstick proteinuria (categorical) performed as well as other methods. No single method was predictive of adverse perinatal outcome. CONCLUSION: The measured amount of proteinuria should not be used in isolation for decision-making in women with preeclampsia. Dipstick proteinuria performs as well as other methods of assessing proteinuria for prediction of adverse events.

Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model.

BACKGROUND: Pre-eclampsia is a leading cause of maternal deaths. These deaths mainly result from eclampsia, uncontrolled hypertension, or systemic inflammation. We developed and validated the fullPIERS model with the aim of identifying the risk of fatal or life-threatening complications in women with pre-eclampsia within 48 h of hospital admission for the disorder. METHODS: We developed and internally validated the fullPIERS model in a prospective, multicentre study in women who were admitted to tertiary obstetric centres with pre-eclampsia or who developed pre-eclampsia after admission. The outcome of interest was maternal mortality or other serious complications of pre-eclampsia. Routinely reported and informative variables were included in a stepwise backward elimination regression model to predict the adverse maternal outcome. We assessed performance using the area under the curve (AUC) of the receiver operating characteristic (ROC). Standard bootstrapping techniques were used to assess potential overfitting. FINDINGS: 261 of 2023 women with pre-eclampsia had adverse outcomes at any time after hospital admission (106 [5%] within 48 h of admission). Predictors of adverse maternal outcome included gestational age, chest pain or dyspnoea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. The fullPIERS model predicted adverse maternal outcomes within 48 h of study eligibility (AUC ROC 0·88, 95% CI 0·84-0·92). There was no significant overfitting. fullPIERS performed well (AUC ROC >0·7) up to 7 days after eligibility. INTERPRETATION: The fullPIERS model identifies women at increased risk of adverse outcomes up to 7 days before complications arise and can thereby modify direct patient care (eg, timing of delivery, place of care), improve the design of clinical trials, and inform biomedical investigations related to pre-eclampsia. FUNDING: Canadian Institutes of Health Research; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction; Preeclampsia Foundation; International Federation of Obstetricians and Gynecologists; Michael Smith Foundation for Health Research; and Child and Family Research Institute.

Aetiology and pathogenesis of IUGR.

Intrauterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity. A complex and dynamic interaction of maternal, placental and fetal environment is involved in ensuring normal fetal growth. An imbalance or lack of coordination in this complex system may lead to IUGR. Animal studies have given us an insight into some aspects of the basic pathophysiology of IUGR, and recent technologies such as Doppler studies of maternal and fetal vessels have added further information. The aetiologies of IUGR are diverse, involving multiple complex mechanisms, which make understanding of the pathophysiology difficult. However, particular focus is placed on the mechanisms involved in uteroplacental insufficiency as a cause of IUGR, as (1) it is common, (2) outcome can be good if timing of delivery is optimal and (3) it may be amenable to therapy in the future. While the research into the pathophysiology of IUGR continues, there have been interesting discoveries related to the genetic contribution to IUGR and the intrauterine programming of adult-onset diseases attributed to IUGR.

Drugs and the fetus.

PURPOSE OF REVIEW: Few drugs are licensed in pregnancy, and data on drug use in pregnancy are mainly retrospective and uncontrolled. Pregnancy exposure has increased recently to new classes of drugs, as they have been shown to be effective and well tolerated outside of pregnancy. RECENT FINDINGS: Anti-nausea therapies, H2-receptor and proton pump inhibitors appear to be safe. Metformin is being trialed for treatment in gestational diabetes and initial reports appear encouraging. Concern has been raised about statins in early pregnancy and should be avoided. New antiepileptic medication appears effective with low risk of abnormality. However, when combined with valproate, risks are still high. Selective serotonin reuptake inhibitors for depression appear to be effective, with likely low risk for teratogenesis, although neonatal behavioural syndrome following their use in the third trimester is a concern. Angiotensin II inhibitors should be avoided in the second and third trimesters of pregnancy. Smoking cessation programmes need to be reevaluated. SUMMARY: Information about safety of drugs and caution about prescribing in pregnancy should continue. Until large clinical trials are performed, the risk/benefit ratio of drugs during pregnancy will remain uncertain.

Reassuring fetal middle cerebral artery doppler velocimetry in alloimmunised pregnancies: neonatal outcomes without invasive procedures.

OBJECTIVE: To assess the neonatal outcome in red blood cell alloimmunised pregnancies at increased risk of fetal anaemia where invasive testing was avoided based on reassuring middle cerebral artery (MCA) Doppler velocity results. METHODS: We included 28 alloimmunised pregnant women at significant risk of fetal or neonatal anaemia who did not have invasive testing because of reassuring MCA Doppler velocimetry. Women requiring invasive testing or intrauterine transfusion were excluded. Outcome measures were admission to neonatal intensive care unit, cord haemoglobin and bilirubin levels and neonatal therapy. RESULTS: Ten neonates (36%) were anaemic at birth while 18 (64%) had normal haemoglobin. Seven neonates (25%) did not require any form of neonatal therapy, 10 (36%) had phototherapy only, 7 (25%) required exchange transfusions and 4 (14%) top-up transfusions. There were no treatment-related complications. Mean cord haemoglobin was 13.9 g/dl (range 7-18.9) and mean bilirubin was 84.1 micromol/l (range 29-192). CONCLUSION: Avoiding invasive procedures in pregnancies at risk of fetal anaemia by relying on reassuring MCA Doppler velocimetry did not result in life-threatening fetal or neonatal morbidities. The extent of neonatal therapy was acceptable. The routine use of this test can lead to less unnecessary invasive procedures in at-risk fetuses.

Safety of fetal blood sampling by cordocentesis in fetuses with single umbilical arteries.

OBJECTIVES: To examine the safety of cordocentesis in fetuses with single umbilical arteries. METHODS: Retrospective analysis of all cases of cordocenteses in fetuses with single umbilical arteries over a five-year period at one centre. We analysed the records for pregnancy details, outcomes, and procedure-related complications, and compared these to similar data for cordocenteses procedures performed, during the same period, for similar indications in fetuses with three-vessel cords. RESULTS: Twenty-nine eligible cases were identified. All procedures were performed for the indication of fetal structural abnormalities, and seven fetuses (24%) had abnormal karyotypes. The median gestational age at the time of the procedure was 21 weeks (range 19-34 weeks). There were no procedure-related fetal losses but the umbilical artery was inadvertently punctured in one case, resulting in prolonged bradycardia with spontaneous recovery. These outcomes compare favourably to those of a total of 134 cordocenteses procedures in fetuses with three-vessel cords. CONCLUSION: Cordocentesis in cases with single umbilical arteries does not appear to carry more risk than in cases with three-vessel cord, and should continue to be performed by adequately trained specialists when indicated. Extra care should be undertaken to avoid puncturing the umbilical artery.

Fetal serum alpha-fetoprotein in alloimmunised pregnancies.

OBJECTIVES: Maternal serum alpha-fetoprotein (AFP) levels have been known to be increased in red blood cell alloimmunisation. Since AFP is now thought be a pro-erythropoietic factor, we wished to evaluate fetal serum levels of AFP in cases of alloimmunised pregnancies. METHODS: We studied AFP levels in 32 fetal serum samples from women with red blood cell alloimmunisation at the time of the first fetal blood sampling. We expressed the levels of AFP and haemoglobin as absolute numbers and as delta values (number of SDs by which the observed value differed from the normal mean for the same gestation). Main outcome measures were fetal serum AFP levels and fetal haemoglobin concentration. RESULTS: Overall, fetal AFP level was higher than normal in the cases (delta values 2.4 +/- 5.5 SD). However, mildly affected non-hydropic cases had higher levels than severely affected fetuses with hydrops. CONCLUSIONS: Fetuses affected by red blood cell alloimmunisation have increased levels of serum AFP but these levels fall back to low levels in severe anaemia especially with hydrops, which could represent the failing of a compensatory erythropoietic mechanism. Our results suggest that fetal haematopoiesis is activated early in red blood cell alloimmunisation but was subsequently impaired.

Prediction of chorionicity in twin pregnancies at 10-14 weeks of gestation.

OBJECTIVE: To examine the accuracy of sonographic determination of chorionicity in twin pregnancies at 10-14 weeks of gestation. DESIGN: Prospective study on the sonographic prediction of chorionicity at 10-14 weeks of gestation. PARTICIPANTS: During a 30 month period, from October 1997 to May 2000, 165 women attending the departments of fetal medicine or ultrasound. METHODS: Sonographic criteria used in the diagnosis of chorionicity were the number of placental sites, the lambda (lambda) and T signs and the thickness of the inter-twin membrane. The diagnosis of chorionicity was made at the time of the ultrasound examination using all these features and subsequently compared with the postnatal diagnosis, confirmed either by placental histology or discordancy in infant sex. RESULTS: In 150 cases with confirmation of chorionicity following delivery, 116 were postnatally classified as dichorionic and 34 monochorionic. Prenatal ultrasound examination correctly identified chorionicity in 149 (99.3%) cases. The most reliable indicator for dichorionicity was a combination using the lambda sign or two separate placentae with a sensitivity and specificity of 97.4% and 100%, respectively. The most useful test in predicting monochorionicity was the T sign with a sensitivity of 100% and specificity of 98.2%. Measurement of the inter-twin membrane thickness was a less reliable indicator where the sensitivity for dichorionicity and specificity for monochorionicity was only 92.6%. CONCLUSIONS: Ultrasound examination of twin pregnancies at 10-14 weeks of gestation predicts chorionicity with a high degree of accuracy using a combination of the number of placentae, lambda and T signs and inter-twin membrane thickness. All hospitals should encourage departments providing ultrasound services to undertake chorionicity determination when examining women with twin pregnancies at this gestation.