Maternal blood-pressure trends throughout pregnancy and development of pre-eclampsia in women receiving first-trimester aspirin prophylaxis.

OBJECTIVES: To study women who initiated aspirin in the first trimester for high risk of pre-eclampsia, and compare blood-pressure trends throughout pregnancy between those with normal outcome and those who subsequently developed pre-eclampsia. METHODS: Women were enrolled into a prospective observational study at 9-14 weeks' gestation. This was a secondary analysis of those who started daily doses of 81 mg of aspirin before 16 weeks for increased risk of pre-eclampsia based on maternal history and bilateral uterine artery notching. Enrollment characteristics and blood-pressure measurements throughout gestation were compared between women who did and those who did not develop pre-eclampsia. RESULTS: Of the 237 women who initiated first-trimester aspirin prophylaxis, 29 (12.2%) developed pre-eclampsia. A total of 2881 serial blood-pressure measurements obtained between 4 and 41 weeks' gestation (747 in the first trimester, 1008 in the second and 1126 in the third) showed that women with pre-eclampsia started pregnancy with higher blood pressure and maintained this trend despite taking aspirin (mean arterial blood pressure in women with pre-eclampsia = (0.13 × gestational age (weeks)) + 93.63, vs (0.11 × gestational age (weeks)) + 82.61 in those without; P < 0.005). First-trimester diastolic and second-trimester systolic blood pressure were independent risk factors for pre-eclampsia (ß = 1.087 and 1.050, respectively; r2  = 0.24, P < 0.0001). When average first-trimester diastolic blood pressure was >74 mmHg, the odds ratio for pre-eclampsia was 6.5 (95% CI, 2.8-15.1; P < 0.001) and that for pre-eclampsia before 34 weeks was 14.6 (95% CI, 1.72-123.5; P = 0.004). If, in addition, average second-trimester systolic blood pressure was >125 mmHg, the odds ratio for pre-eclampsia was 9.4 (95% CI, 4.1-22.4; P < 0.001) and that for early-onset disease was 34.6 (95% CI, 4.1-296.4; P = 0.004). CONCLUSION: In women treated with prophylactic aspirin from the first trimester, those who develop pre-eclampsia have significantly and sustained higher blood pressure from the onset of pregnancy compared with those who do not develop pre-eclampsia. This raises the possibility that mildly elevated blood pressure predisposes women to abnormal placentation, which then acts synergistically with elevated blood pressure to predispose such women to pre-eclampsia to a degree that is incompletely mitigated by aspirin. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Educational innovations in clinical pharmacogenomics.

Genetic and genomic discovery is revolutionizing medicine at an extraordinary pace, leading to a better understanding of disease and improved treatments for patients. This advanced pace of discovery presents an urgency to expand medical school curricula to include genetic and genomic testing (including pharmacogenomics), and integration of genomic medicine into clinical practice. Consequently, organizations and healthcare authorities have charged medical schools with training future physicians to be competent in their knowledge of genomic implementation.

External validity of first-trimester algorithms in the prediction of pre-eclampsia disease severity.

OBJECTIVE: To compare disease features in women with pre-eclampsia between those who are correctly identified (true positive) and those who are missed (false negative) when applying first-trimester prediction algorithms for pre-eclampsia to a prospectively enrolled population. METHOD: Six first-trimester early (requiring delivery < 34 weeks' gestation) pre-eclampsia algorithms were applied to a prospective cohort of singleton pregnancies enrolled at first-trimester screening. Maternal outcomes, neonatal outcomes and severity parameters for pre-eclampsia were compared between true-positive and false-negative predictions. RESULTS: Twenty of 2446 (0.8%) women developed early pre-eclampsia, with 65% of these developing severe features and 20% HELLP syndrome. At enrollment, true-positive cases were more likely to be African-American and chronically hypertensive, while false-negative cases were more likely to be Caucasian. At delivery, true-positive cases were more likely to have pre-eclampsia superimposed on hypertension, severely elevated blood pressure and creatinine level > 1.1 mg/dL. False-negative cases were more likely to have HELLP syndrome (all P < 0.05). CONCLUSION: In an urban population with a high prevalence of chronic hypertension, patients who are correctly identified by first-trimester screening models are more likely to develop pre-eclampsia superimposed on chronic hypertension with severely elevated blood pressure and evidence of renal failure. In contrast, patients who are missed by these algorithms are more likely to have HELLP syndrome. Further research is needed to confirm these findings and the algorithm adjustments that may be necessary to better predict pre-eclampsia phenotypes.

First-trimester prediction of pre-eclampsia: external validity of algorithms in a prospectively enrolled cohort.

OBJECTIVE: To evaluate the performance of published first-trimester prediction algorithms for pre-eclampsia (PE) in a prospectively enrolled cohort of women. METHOD: A MEDLINE search identified first-trimester screening-prediction algorithms for early-onset (requiring delivery < 34 weeks) and late-onset (requiring delivery ≥ 34 weeks) PE. Maternal variables, ultrasound parameters and biomarkers were determined prospectively in singleton pregnancies enrolled between 9 and 14 weeks. Prediction algorithms were applied to this population to calculate predicted probabilities for PE. The performance of the prediction algorithms was compared with that in the original publication and evaluated for factors explaining differences in prediction. RESULTS: Six early and two late PE prediction algorithms were applicable to 871-2962 women, depending on the variables required. The prevalence of early PE was 1.0-1.2% and of late PE was 4.1-5.0% in these patient subsets. One early PE prediction algorithm performed better than in the original publication (80% detection rate (DR) of early PE for 10% false-positive rate (FPR)); the remaining five prediction algorithms underperformed (29-53% DR). Prediction algorithms for late PE also underperformed (18-31% DR, 10% FPR). Applying the screening cut-offs based on the highest Youden index probability scores correctly detected 40-80% of women developing early PE and 71-82% who developed late PE. Exclusion of patients on first-trimester aspirin resulted in DRs of 40-83% and 65-82% for early and late PE, respectively. CONCLUSION: First-trimester prediction algorithms for PE share a high negative predictive value if applied to an external population but underperform in their ability to correctly identify women who develop PE. Further research is required to determine the factors responsible for the suboptimal external validity.

Second-trimester maternal serum analyte levels associated with fetal trisomy 13.

The aim of this study was to determine whether pregnancies affected by fetal trisomy 13 are associated with second-trimester maternal serum analyte levels different from those typical of the unaffected population. Pregnancies with trisomy 13 were identified through cytogenetics laboratories. Those which had second-trimester maternal serum screening analyte measurements were further evaluated. Maternal serum analyte levels for each case and five matched controls were statistically analysed by matched ranked-sum analysis. 28 cases of fetal trisomy 13 were identified. The median AFP, uE3 and hCG levels were 1.35 MoM, 0.71 MoM and 0.90 MoM, respectively. Only uE3 levels were statistically different (p < 0.01) from those for the unaffected population. These data suggest that second-trimester maternal serum AFP, uE3 and hCG levels are not useful in detecting fetal trisomy 13 and protocols already existing for Down syndrome or trisomy 18 screening will not detect the majority of cases of this aneuploidy.

Molecular characterization of a unique patient with epimerase-deficiency galactosaemia.

Inherited deficiencies of UDP-galactose 4-epimerase (GALE) have been associated with two distinct phenotypes. The vast majority of North American patients are clinically asymptomatic, are identified through newborn screening programmes for classical galactosaemia, and are of African-American descent. At least two symptomatic patients have been reported, one Pakistani and the other Asian Muslim, both with severe complications in the neonatal period and subsequent mental retardation. Through newborn screening, we have identified a GALE-deficient patient who is of mixed Pakistani/caucasian ancestry. He was clinically well in the neonatal period on a lactose-containing diet, and biochemical studies, including urine reducing sugars and galactitol, were consistent with a diagnosis of peripheral GALE deficiency. Although early developmental milestones were met normally, he now shows significant developmental delays in both motor and language skills. Mutational analysis revealed this patient to be a compound heterozygote at the GALE locus, with mutations N34S and L183P identified in the patient and confirmed in the parents. This report represents the first characterization of specific mutations in a GALE-deficient patient in conjunction with biochemical and clinical phenotype, and facilitates further studies of the GALE enzyme and its role in the different clinical forms of epimerase-deficiency galactosaemia.

Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life.

OBJECTIVE: Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration. STUDY DESIGN: We analyzed 27 cases representing five FAO disorders and compared the results with those obtained in a retrospective blinded analysis of 418 cases of sudden infant death (313 SIDS, 45 infections, and 34 accidents and abuse). RESULTS: All cases of accidents and abuse correctly tested negative. Among the others, 25 (6%) showed at least two abnormal findings. Of these, 14 closely matched the biochemical profiles seen in specific FAO disorders. These included 2 cases with medium-chain acyl-CoA dehydrogenase deficiency, 4 cases consistent with glutaric acidemia type 2, 4 cases with either very long-chain acylcoenzyme A dehydrogenase deficiency or long-chain 3-hydroxy-acyl-coenzyme A dehydrogenase deficiency, and 4 cases predicted to be affected with carnitine uptake defect. CONCLUSION: The results of this study support the view that approximately 5% of all cases of sudden infant death are likely caused by an FAO disorder.

46,XY,i(21q) identified by maternal serum screening.

Maternal serum screening for the detection of fetal Down syndrome has become widespread. Prenatal detection of fetal Down syndrome has important implications not only for management of the current pregnancy, but also for recurrence risk counseling for future pregnancies. We report a case of fetal Down syndrome due to an isochromosome 21q detected after maternal serum screening using alpha-fetoprotein and human chorionic gonadotropin indicated an increased risk for fetal Down syndrome in a 19-year-old pregnant woman. This confirms that maternal serum screening can detect fetal Down syndrome due to rare chromosome rearrangements and illustrates the importance of cytogenetic studies for provision of appropriate genetic counseling.

Profound biotinidase deficiency in two asymptomatic adults.

Biotinidase deficiency is an autosomal-recessive disorder of biotin recycling. Children with profound biotinidase deficiency usually have neurological and cutaneous symptoms in early childhood, but they may not develop symptoms until adolescence. We now report on a man and a woman with profound biotinidase deficiency who are asymptomatic and who were diagnosed only because their biotinidase-deficient children were identified by newborn screening. These adults have never exhibited symptoms of the disorder and are homozygous for two different mutations resulting in different aberrant enzymes. There is no evidence of an increased dietary intake of biotin to explain why they have remained asymptomatic. Although these adults may still be at risk for developing symptoms, they could represent a small group of individuals with profound biotinidase deficiency who will never develop clinical problems. Their lack of symptoms suggests that there are probably epigenetic factors that protect some enzyme-deficient individuals from developing symptoms. These individuals broaden the spectrum of expression of biotinidase deficiency.

Risk-based prenatal screening for trisomy 18 using alpha-fetoprotein, unconjugated oestriol and human chorionic gonadotropin.

Nine centres collaborated to examine the feasibility of a screening method for trisomy 18 that was based on assigning individual risk, using a combination of maternal age and measurements of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Second-trimester measurements of these analytes were obtained from 94 trisomy 18 pregnancies. In the 89 pregnancies without an associated open defect, the median levels for AFP, uE3, and hCG were 0.65, 0.43 and 0.36 multiples of the unaffected population median, respectively. The strongest individual predictor of risk for trisomy 18 was uE3, followed by hCG, AFP, and maternal age, in that order. Using a method of individual risk estimation that is based on the three markers and maternal age, 60 per cent of pregnancies associated with trisomy 18 would be detected at a risk cut-off level of 1:100, with a false-positive rate of about 0.2 per cent. One in nine pregnancies identified as being at increased risk for trisomy 18 would be expected to have an affected pregnancy. This risk-based screening method is more efficient than an existing method that is based on fixed analyte cut-off levels. Even though the birth prevalence of trisomy 18 is low, prenatal screening can be justified when performed in conjunction with Down syndrome screening and when a high proportion of women offered amniocentesis have an affected fetus.

Biochemical diagnosis of fatty acid oxidation disorders by metabolite analysis of postmortem liver.

At least 12 fatty acid oxidation disorders are known to be responsible for cases of sudden and unexpected death in early childhood. A specific diagnosis of these disorders is essential for genetic counseling and for the screening of siblings potentially at risk for life-threatening episodes of fasting intolerance. Postmortem blood and urine samples often are not available for further biochemical studies, and currently only medium-chain acyl-CoA dehydrogenase (MCAD) deficiency can be diagnosed by the molecular analysis of tissues. We developed a postmortem screening method for fatty acid oxidation disorders by the simultaneous measurement of C8-C20 fatty acids, glucose, lactate, and other metabolites from the methanol wash of a pellet obtained by ultracentrifugation of liver homogenate. Cis-4-decenoic acid was present in five confirmed cases with MCAD deficiency and in one case with glutaric aciduria type II and was absent in 97 of 100 randomly chosen sudden death cases, at least 81 of which were diagnosed as sudden infant death syndrome (SIDS). C14-C18 monounsaturated fatty acids were significantly elevated in the one examined case affected with long-chain acyl-CoA dehydrogenase (LCAD) deficiency. The metabolite profiles in two cases with carnitine uptake deficiency were less informative, but they shared with all the other disease controls a very low glucose concentration, a finding compatible with premortem hypoglycemia. This method is proposed as a simple and practical means of biochemical screening to follow up the postmortem finding of liver fat infiltration.

Intrafamilial variability in Hurler syndrome and Sanfilippo syndrome type A: implications for evaluation of new therapies.

Intrafamilial variability has not been reported previously in Hurler syndrome or Sanfilippo syndrome type A. We describe two families in which sibs with comparable deficiencies of alpha-iduronidase (Hurler) or sulfamidase (Sanfilippo type A) activities in vitro nonetheless have divergence in clinical severity and disease progression. These cases underscore the need for caution in counseling as well as the limitations of using sibs as controls in evaluating the outcome of treatment.

The presence of two different infantile Tay-Sachs disease mutations in a Cajun population.

A study was undertaken to characterize the mutation(s) responsible for Tay-Sachs disease (TSD) in a Cajun population in southwest Louisiana and to identify the origins of these mutations. Eleven of 12 infantile TSD alleles examined in six families had the beta-hexosaminidase A (Hex A) alpha-subunit exon 11 insertion mutation that is present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The mutation in the remaining allele was a single-base transition in the donor splice site of the alpha-subunit intron 9. To determine the origins of these two mutations in the Cajun population, the TSD carrier status was enzymatically determined for 90 members of four of the six families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggest that this mutation has been in the Cajun population since its founding over 2 centuries ago and that it may be widely distributed within the population. In contrast, the intron 9 mutation apparently was introduced within the last century and probably is limited to a few Louisiana families.

Congenital nephrosis: detection of index cases through maternal serum alpha-fetoprotein screening.

Congenital nephrosis is an autosomal recessive disorder with an incidence of 1 in 8000 in Finland, but it is quite rare in non-Finnish populations. In families known to be at risk, prenatal detection is possible by means of maternal serum and/or amniotic fluid alpha-fetoprotein levels. We report the antenatal diagnosis of four cases of congenital nephrosis, three of which were index cases, through maternal serum alpha-fetoprotein screening. The diagnosis was confirmed at birth in two infants. Two patients elected to terminate their pregnancies, and the diagnoses were confirmed pathologically (obliteration of foot processes on electron microscopy of fetal glomeruli) in both. In cases of elevated maternal serum alpha-fetoprotein, with unexplained and marked elevations of amniotic fluid alpha-fetoprotein and normal acetylcholinesterase levels, the diagnosis of congenital nephrosis must be considered regardless of ethnic origin.

Multiple-marker screening in pregnancies with hydropic and nonhydropic Turner syndrome.

OBJECTIVE: The combination of maternal serum alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin levels and maternal age has been used to increase the sensitivity of screening for fetal Down syndrome and trisomy 18 in early-second-trimester pregnancies. We hypothesized that a unique pattern of these analytes also may be characteristic of fetal Turner syndrome, with or without hydrops. STUDY DESIGN: We studied preamniocentesis, second-trimester maternal serum specimens from seven hydropic and eight nonhydropic cases of fetal Turner syndrome. Clinical and pathologic records were reviewed. Statistical analysis of the data was performed by the rank sum test. RESULTS: In both hydropic and nonhydropic cases, alpha-fetoprotein levels were slightly reduced, and unconjugated estriol levels were markedly reduced. In hydropic pregnancies human chorionic gonadotropin levels were elevated, and nonhydropic pregnancies had low human chorionic gonadotropin levels (p = 0.001). CONCLUSIONS: The results suggest that the morphologic defect of hydrops, rather than the aneuploidy itself, is responsible for the elevation in human chorionic gonadotropin. In conjunction with the low unconjugated estriol levels, the elevation in human chorionic gonadotropin levels will result in the prenatal identification of hydropic fetal Turner syndrome pregnancies as being at increased risk for fetal Down syndrome.

Detection of cocaine and its metabolites in human amniotic fluid.

The dramatic rise in maternal drug abuse and the incidence of positive drug findings during neonatal testing has increased the need for prenatal toxicological testing for drugs of abuse. Human amniotic fluid samples collected after 13-39 weeks of pregnancy were screened for cocaine metabolite (benzoylecgonine) by fluorescence polarization immunoassay (FPIA). All positive samples, as well as any accompanying maternal serum, were confirmed by gas chromatography/mass spectrometry (GC/MS) for cocaine and its metabolites. Five samples out of 450 were positive for cocaine, benzoylecgonine, and ecgonine methyl ester by GC/MS. In addition, one sample was also positive for cocaethylene. Two maternal serum samples were positive for benzoylecgonine and ecgonine methyl ester. The presence of cocaine, benzoylecgonine, ecgonine methyl ester, and cocaethylene in the amniotic fluid suggests that the fetus is exposed to cocaine and its metabolites through maternal circulation. The impact of this exposure on the health of the newborn is unknown.

Tay-Sachs disease as a model for screening inborn errors.

In the absence of treatments for most inborn errors of metabolism, the goal of both geneticists and health care providers has been the prevention of disease through identification of at-risk couples. When the enzyme deficiency responsible for a disorder is known, heterozygotes can frequently be identified by enzyme assay. The presence or absence of specific mutations in the genes coding for these enzymes may be determined directly if the gene of interest has been identified and characterized. Because the inherited metabolic disorders are rare, these approaches are useful only for individuals with a family history of a specific disease or for populations in which the gene frequency for a specific disease is increased. Tay-Sachs disease is a fatal, autosomal recessive, metabolic disease caused by deficient activity of the lysosomal enzyme Hex A. Although it is rare in the general population, in which the heterozygote frequency is approximately 1/167, it is elevated in a few populations, including the Ashkenazi Jewish community, in which the heterozygote frequency is 1/30. The ability to detect TSD heterozygotes reliably and to diagnose TSD prenatally using a simple and rapid enzyme assay has made prevention of this disorder possible through education and carrier screening. The identification of specific TSD mutations at the DNA level enables laboratories to provide more accurate screening and diagnosis in some families. The success of TSD screening in the Ashkenazi Jewish population has made it the prototype for screening among the inborn errors of metabolism. The TSD example becomes increasingly relevant as heterozygote detection becomes possible for other genetic disorders that are increased in well-defined populations. Cystic fibrosis is such a disease in the caucasian population.

Study of the relationship between elevated maternal serum alpha-fetoprotein and adverse pregnancy outcome.

In a study of 1,703 pregnancies, adverse clinical outcomes associated with unexplained elevated maternal serum alpha-fetoprotein (MSAFP) included intrauterine growth retardation (IUGR), prematurity, IUGR and prematurity, prematurity without IUGR, spontaneous abortion, and stillbirth. These findings have significant implications for careful obstetrical management of patients with elevated MSAFP.