Michael T. Mennuti

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel

Estimation of the Risk of Thrombocytopenia in the Offspring of Pregnant Women with Presumed Immune Thrombocytopenic Purpura

Abstract Background and Methods. The optimal management of immune thrombocytopenic purpura during pregnancy remains controversial because the risk of severe neonatal thrombocytopenia remains uncertain. We studied the outcome of the index pregnancy in 162 women with a presumptive diagnosis of immune thrombocytopenic purpura to determine the frequency of neonatal thrombocytopenia and to determine whether neonatal risk could be predicted antenatally by history or platelet-antibody testing. Results. Two maternal characteristics were identified as predicting a low risk of severe neonatal thrombocytopenia: the absence of a history of immune thrombocytopenic purpura before pregnancy, and the absence of circulating platelet antibodies in the women who did have a history of the condition. Eighteen of 88 neonates (20 percent; 95 percent confidence interval, 13 to 30 percent) born to women with a history of immune thrombocytopenic purpura had severe thrombocytopenia (platelet count <50×109 per liter at birth), as co...

Neonatal morbidity in pregnancy complicated by diabetes mellitus: Predictive value of maternal glycemic profiles

The relationship between glycemic control and perinatal outcome was assessed in a relatively uniform population of 75 White Class B through D pregnant diabetic women. All patients used glucose reflectance meter self-monitoring and performed a minimum of four determinations daily. Mean capillary blood glucose was calculated from a minimum of 16 weeks of determinations. Regression analysis confirmed a correlation between these values and third-trimester hemoglobin A1 (p less than 0.001). The study population was divided into two groups on the basis of mean capillary blood glucose values: group I, mean capillary blood glucose less than 110 mg/dl (43 patients) (mean = 96.8 +/- 7.1); group II, mean capillary blood glucose greater than 110 mg/dl (32 patients) (mean = 126 +/- 9.0). Of the 32 patients in group II, eight had mean capillary blood glucose greater than or equal to 130 mg/dl. The degree of maternal glycemic control appeared to affect perinatal outcome. At least one form of infant morbidity was present in 33% of group I infants compared with 53% of group II. Significant differences were observed for the incidence of hypoglycemia (p less than 0.05), macrosomia (p less than 0.05), and respiratory distress syndrome (p less than 0.01). One of six group I infants delivered at 35 to 36 weeks developed respiratory distress syndrome, compared with four of seven group II patients. The appearance of phosphatidylglycerol in amniotic fluid appeared delayed in group II patients at term. These data suggest that maintaining mean capillary blood glucose values less than 110 mg/dl may serve to reduce several major forms of morbidity in the infant of the diabetic mother. This information is helpful in establishing objectives for glycemic control in pregnant women using self-monitoring techniques.

Immune Thrombocytopenic Purpura and Pregnancy

Neonatal thrombocytopenia is a potentially life-threatening complication of immune thrombocytopenic purpura (ITP). We followed 23 pregnant women who had either a history of ITP (11 women) or clinically active disease (12 women) to delineate the factors responsible for neonatal thrombocytopenia. No relation was observed between maternal and neonatal platelet counts (P greater than 0.5). Eleven women delivered thrombocytopenic children; antiplatelet antibodies were detectable in each mother, including five who were in clinical remission at delivery. The level of platelet-associated IgG in the mothers did not identify the neonates at risk for thrombocytopenia (P greater than 0.05). However, the level of maternal circulating antiplatelet antibody correlated with both the presence and the extent of neonatal thrombocytopenia (P less than 0.005). A discrepancy between maternal platelet count and maternal antibody level may be especially notable in mothers treated with steroids or splenectomy. Monitoring the level of circulating antiplatelet antibody may help in identifying and managing pregnant women with ITP at risk of delivering neonates with serious thrombocytopenia.

Incidence and significance of chromosome mosaicism involving an autosomal structural abnormality diagnosed prenatally through amniocentesis: A collaborative study

Among 179 663 prenatal diagnosis cases collected from ten institutions and two publications, 555 (0·3 per cent) were diagnosed as having chromosome mosaicism. Of these, 57 (10·3 per cent) were mosaic for an autosomal structural abnormality, 28 (5 per cent) for a sex chromosome structural abnormality, and 85 (15·3 per cent) were mosaic for a marker chromosome. Ninety‐five cases of prenatally diagnosed mosaicism with a structural abnormality in an autosome and a normal cell line, and with a known phenotypic outcome, were collected for karyotype–phenotype correlations through our collaboration (40 cases), a prior survey (26 cases), and published reports (29 cases). They included 13 balanced reciprocal translocations, one unbalanced reciprocal translocation, four balanced Robertsonian translocations, four unbalanced Robertsonian translocations, four inversions, 17 deletions, three ring chromosomes, 19 i(20q), seven +i(12p), six other isochromosomes, and 17 partial trisomies resulting from a duplication or other rearrangement. All cases mosaic for a balanced structural rearrangement resulted in a normal phenotype. All cases of 46/46,i(20q) resulted in normal liveborns. Five of seven cases with 46/47,+i(12p) had an abnormal phenotype compatible with Killian–Pallister syndrome. The overall risk for an abnormal outcome for a mosaic case with an unbalanced structural abnormality, excluding 46/46,i(20q) and 46/47,+i(12p), is 40·4 per cent. In the same category, the study also suggested a correlation between the percentage of abnormal cells and an abnormal phenotype. For mosaicism involving a terminal deletion, the possibility of a familial fragile site should be considered.

Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy?

Testing cell-free DNA (cfDNA) in maternal blood samples has been shown to have very high sensitivity for the detection of fetal aneuploidy with very low false-positive results in high-risk patients who undergo invasive prenatal diagnosis. Recent observation in clinical practice of several cases of positive cfDNA tests for trisomy 18 and trisomy 13, which were not confirmed by cytogenetic testing of the pregnancy, may reflect a limitation of the positive predictive value of this quantitative testing, particularly when it is used to detect rare aneuploidies. Analysis of a larger number of false-positive cases is needed to evaluate whether these observations reflect the positive predictive value that should be expected. Infrequently, mechanisms (such as low percentage mosaicism or confined placental mosaicism) might also lead to positive cfDNA testing that is not concordant with standard prenatal cytogenetic diagnosis. The need to explore these and other possible causes of false-positive cfDNA testing is exemplified by 2 of these cases. Additional evaluation of cfDNA testing in clinical practice and a mechanism for the systematic reporting of false-positive and false-negative cases will be important before this test is offered widely to the general population of low-risk obstetric patients. In the meantime, incorporating information about the positive predictive value in pretest counseling and in clinical laboratory reports is recommended. These experiences reinforce the importance of offering invasive testing to confirm cfDNA results before parental decision-making.

Practice patterns of obstetrician-gynecologists regarding preconception and prenatal screening for cystic fibrosis.

Objective: To assess practices of obstetrician-gynecologists regarding carrier screening for cystic fibrosis (CF).Methods: A questionnaire investigating practice patterns and opinions pertaining to CF screening was mailed to 1165 members of the American College of Obstetricians and Gynecologists (ACOG), of whom 565 participate in the Collaborative Ambulatory Research Network (CARN) and 600 were randomly selected.Results: Of the questionnaires, 64% were returned. Statistical analyses were limited to the 632 respondents whose primary medical specialty was gynecology (Gyn Only) or obstetrics and gynecology (ObGyn). CARN membership was not a significant factor on any nondemographic measure. Almost one-half of physicians do not ask nonpregnant patients their family history of CF or provide them with information about CF screening. The majority of ObGyns (88.7%) ask obstetric patients their family history of CF, and offer CF carrier screening. Almost two-thirds (65.8%) offer screening to all prenatal patients. Among those ObGyns who selectively offer CF screening to pregnant patients, only 27.4% utilized all of the selection criteria in the guidelines. Liability for not offering screening, familiarity with CF, and the ability to interpret a positive screening test were important physician concerns.Conclusion: The results indicate a need for minimizing the complexity of clinical guidelines for population-based genetic screening, prospective assessment of implementation and focused continuing education for providers.

MR imaging of cerebral abnormalities in utero

In view of the lack of ionizing radiation, ability to image in a variety of planes, and high contrast resolution, magnetic resonance (MR) imaging may have a role in obstetrical management. Three fetuses with severe cerebral abnormalities were studied by MR in utero. The findings were correlated with ultrasound examinations and with autopsy results. Ventricular dilatation and progression of hydrocephalus were detected by MR. Although fetal motion may affect image quality, diagnostically useful images were obtained with imaging times of 2.5 min.

Management of the diethylstilbestrol-exposed pregnant patient: A prospective study

Over a 5-year period we have managed 63 diethylstilbestrol-exposed pregnant patients with a standardized protocol requiring weekly cervical examination and decreased physical activity of the patient. Twenty-six patients (42%) underwent a prophylactic cerclage for a history of second-trimester loss or a hypoplastic cervix on initial clinical examination (group I). Thirty-six patients (58%) were followed expectantly (group II). Sixteen patients (44%) in group II demonstrated cervical change and required an emergency cerclage. Twenty-one patients were managed expectantly with no cerclage. The gestational age at delivery for group I was 37.7 +/- 2.80 versus 34.5 +/- 6.9 weeks for patients without a cerclage (p = 0.04). There were no perinatal deaths if a cerclage was performed, whereas there were five deaths (24%) in the group without cerclage. The five deaths occurred at a mean gestational age of 24.40 +/- 4.0 weeks and a mean birth weight of 614.00 +/- 441.73 gm. Patients with a hypoplastic cervix or prior reproductive loss had a better outcome with early cerclage than patients with a normal cervix followed expectantly. We presently lack a reliable method to detect the diethylstilbestrol-exposed patient at greatest risk for perinatal loss. Based on our experience we believe that placement of a cerclage early in pregnancy should be a strong consideration.

Abnormalities in platelet antiglobulin tests in preeclamptic mothers and their neonates

We prospectively studied 40 women with preeclampsia and 26 women with normal pregnancy for the presence of platelet-bound and circulating platelet-bindable immunoglobulin and complement. Although only 12 patients with preeclampsia had a platelet count less than 150,000/mm3, 36 of 40 demonstrated an abnormal direct antiglobulin test, compared with only three of 26 control subjects (p less than 10(-8]. An abnormal indirect test was also detected in 30 of 40 patients with preeclampsia compared with five of 26 healthy pregnant control women (p = 9.3 X 10(-6]. Abnormal antiglobulin tests persisted for 2 to 6 weeks after delivery. Although each neonate had a platelet count greater than 200,000/mm3 at the time of delivery, 10 of 18 had an abnormal direct antiglobulin test compared with one of 14 control subjects (p = 0.0049). The high frequency of abnormal platelet antiglobulin tests in women with preeclampsia and their neonates may indicate an immune cause of certain aspects of the syndrome or may reflect the extent of platelet activation.