Unexplained False Negative Results in Noninvasive Prenatal Testing: Two Cases Involving Trisomies 13 and 18.

Noninvasive prenatal testing (NIPT) validation studies show high sensitivity and specificity for detection of trisomies 13, 18, and 21. False negative cases have rarely been reported. We describe a false negative case of trisomy 13 and another of trisomy 18 in which NIPT was commercially marketed directly to the clinician. Both cases came to our attention because a fetal anatomy scan at 20 weeks of gestation revealed multiple anomalies. Karyotyping of cultured amniocytes showed nonmosaic trisomies 13 and 18, respectively. Cytogenetic investigation of cytotrophoblast cells from multiple placental biopsies showed a low proportion of nontrisomic cells in each case, but this was considered too small for explaining the false negative NIPT result. The discordant results also could not be explained by early gestational age, elevated maternal weight, a vanishing twin, or suboptimal storage or transport of samples. The root cause of the discrepancies could, therefore, not be identified. The couples involved experienced difficulties in accepting the unexpected and late-adverse outcome of their pregnancy. We recommend that all parties involved in caring for couples who choose NIPT should collaborate to clarify false negative results in order to unravel possible biological causes and to improve the process of patient care from initial counseling to communication of the result.

Evaluation of antenatal umbilical coiling index at 16-21 weeks of gestation as a predictor of trisomy 21 and other chromosomal defects.

OBJECTIVES: To determine whether there is an association between sonographically assessed hyper- or hypocoiling of the umbilical cord and the presence of trisomy 21, to provide reference values for the antenatal umbilical coiling index (aUCI) at a gestational age of 16-21 weeks and to determine whether these measurements are reliable and reproducible. METHODS: This was a prospective study of 737 pregnancies in which the aUCI was measured between 16 and 21 weeks of gestation by ultrasound at the time of amniocentesis. The aUCI was calculated as the reciprocal value of the mean length of one complete coil in centimeters. We created reference curves and studied the relationship with trisomy 21 and other chromosomal defects. In 30 pregnancies we studied the intra- and interobserver variation in measurements using Bland-Altman plots with associated 95% limits of agreement and intraclass correlation coefficients. RESULTS: aUCI was found to be non-linearly related to gestational age at 16-21 weeks and reference curves were created for the mean aUCI and the 2.3(rd) , 10(th) , 90(th) and 97.7(th) percentiles. There was no significant difference in aUCI values between the reference group (n = 714) and cases with trisomy 21 (n = 16) or other aneuploidies (n = 7) (one-way ANOVA, P = 0.716). There was good intra- and interobserver agreement in aUCI measurements. CONCLUSIONS: The aUCI can be measured reliably and varies according to gestational age at 16-21 weeks. The aUCI was not significantly associated with trisomy 21 or other chromosomal defects.

Complex cardiac defect with hypoplastic right ventricle in a fetus with valproate exposure.

We describe a fetus with a hypoplastic right ventricle detected by prenatal ultrasound examination. A possible causal relationship with prenatal valproate exposure is discussed.

Mosaic trisomy (8)(p22 --> pter) in a fetus caused by a supernumerary marker chromosome without alphoid sequences.

OBJECTIVE: Our objective was to characterise a marker chromosome in cultured amniocytes of a fetus with a mos 47,XX,+mar[3]/46,XX[14] karyotype. METHODS: The indication for prenatal cytogenetic analysis of cultured amniocytes was advanced maternal age. Classic banding techniques (GTG- and C-banding) were performed. Microdissection combined with reverse painting was used to disclose the exact origin of the marker; the result was confirmed by chromosome painting and FISH with band-specific probes. RESULTS: Analysis of GTG-banded chromosomes showed a small marker chromosome in 3 of the 17 colonies analysed. Subsequently, C-banding showed no alphoid sequences, suggesting the presence of a neocentromere. The parent's karyotypes were normal. After normal ultrasound findings, the parents decided to continue the pregnancy. Chromosome analysis in peripheral blood after birth demonstrated that the marker chromosome was present in 50% of the lymphocytes. Using microFISH, the marker was further characterised and appeared to be derived from chromosome region (8)(p22 --> pter). CONCLUSION: Accurate identification of the marker chromosome was very important for prenatal counselling. Combining the results of GTG- and C-banding analysis with the results of the (micro)FISH, we concluded that the patient's karyotype is: mos 47,XX,+mar.rev ish der(8)(p22 --> pter)[50]/46,XX[50].

Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency.

3-phosphoglycerate-dehydrogenase (3-PGDH) deficiency is an L-serine biosynthesis disorder, characterised by congenital microcephaly, severe psychomotor retardation, and intractable seizures. We report prenatal diagnosis of an affected fetus by DNA mutation analysis. Ultrasound assessment showed a reduction in fetal head circumference from the 75th percentile at 20 weeks' gestation to the 29th percentile at 26 weeks. L-serine was then given to the mother, which resulted in an enlarged fetal head circumference to the 76th percentile at 31 weeks. At birth, the girl's head circumference was normal, and at 48 months' follow-up, her psychomotor development has been unremarkable. 3-PGDH deficiency is an inborn metabolic error that can be successfully treated antenatally.

[Vertical HIV-I-transmission. I. Risk and prevention in pregnancy]. / Verticale HIV-I-transmissie. I. Risico en preventie bij de zwangere.

Without anti-HIV treatment, mother to child HIV-I transmission occurs in 15-30% of HIV positive pregnancies. Transmission occurs mostly in the last trimester or at birth. The maternal virus load in the last trimester and around birth is strongly related to the risk of HIV transmission to the child. This risk can be reduced during pregnancy by anti-HIV treatment and in certain cases by performing a caesarean section. It is recommended to determine the plasma virus load several times during pregnancy. If the virus load is found to be high, measurement of plasma anti-HIV drug concentrations and anti-HIV drug resistance may prompt modification of the anti-HIV drug regimen with the objective of achieving maximal suppression of virus replication in the last trimester.

A longitudinal study of maternal hemodynamics during normal pregnancy.

OBJECTIVE: To investigate the maternal hemodynamic changes that occur during normal pregnancy. METHODS: Serial hemodynamic investigations were performed throughout normal pregnancy by thoracic electrical bioimpedance monitoring in 50 healthy women. Analysis of variance with repeated measurements was used to evaluate the time course of a number of hemodynamic indies. RESULTS: The mean heart rate (+/- standard error [SE]) increased gradually from 87 +/- 2 beats per minute at 10-18 weeks' gestation to 92 +/- 1 beats per minute at 34-42 weeks' gestation. Mean arterial pressure decreased significantly after 14 weeks' gestation and increased significantly after 29 weeks' gestation. During the third trimester, mean cardiac output and mean stroke volume decreased, and mean systemic vascular resistance increased significantly. The course of cardiac output during the third trimester was not uniform in all women; it increased in nine and decreased in 41 women. A significantly higher mean cardiac output was found in nulliparous women compared with multiparous women (mean difference +/- SE 0.76 +/- 0.33 L/minute). The mean (+/- SE) cardiac output increased significantly from 6 (5.49 +/- 0.16 L/minute) to 12 weeks' postpartum (5.91 +/- 0.19 L/minute). CONCLUSION: Mean cardiac output and mean stroke volume decreased in late pregnancy. A significant difference in mean cardiac output was observed between nulliparous and multiparous women. Cardiac output usually, but not invariably, declined during the third trimester.

Cardiac output in normal pregnancy: a critical review.

OBJECTIVE: To review the literature about the effect of normal pregnancy on cardiac output, with special attention to study design, measurement technique, position of the subject, and parity. DATA SOURCES: For studies from the period 1955-1987, we examined Cumulated Index Medicus (National Library of Medicine Cataloging in Publication. Chicago: American Medical Association). For studies from 1988 to May 1, 1994, we used Medline on Silver Platter (U.S. National Library of Medicine Silver Platter International, 1994). METHODS OF STUDY SELECTION: Thirty-three cross-sectional and 19 longitudinal studies on cardiac output measurement in normal pregnancy were retrieved and reviewed. Thirteen longitudinal studies were excluded from analysis because an unvalidated technique was used or because not all subjects were measured at each study interval. The six remaining studies of genuine longitudinal design with at least two measurements throughout pregnancy were used for the definitive analysis. The results of the cross-sectional studies were included only to demonstrate a trend. DATA EXTRACTION AND SYNTHESIS: By pooling data from cross-sectional studies, a tendency was shown toward a higher cardiac output in the second trimester compared with the first trimester, and a tendency toward lower cardiac output was found in the third trimester compared with the second trimester. After delivery, cardiac output was lower than at any time during pregnancy. Selected longitudinal studies showed that the rise in cardiac output occurred early in the first trimester, and a further rise occurred during the second trimester. During the third trimester, cardiac output rose, fell, or plateaued, irrespective of the method of measurement applied or conditions during measurement. CONCLUSIONS: Cardiac output during the third trimester was widely divergent among the studies and probably dependent on individual factors. The tendency to report cardiac output as averages negated these inter-individual differences.

Use of cardiac index in pregnancy: is it justified?

OBJECTIVE: The aim of this study was to test the hypothesis that standardization of cardiac output in pregnancy by correcting for body surface area, and thus obtaining cardiac index, is justified. STUDY DESIGN: Cardiac output was determined by thoracic electrical bioimpedance monitoring in 78 pregnant women; recordings were made at 1-month intervals from the first antenatal visit and a further two were made during the sixth and twelfth weeks after delivery. In a separate group of 10 pregnant women, cardiac output was determined by Doppler echocardiography at 5, 10, 14, 25, and 35 weeks and at 12 weeks post partum. RESULTS: Irrespective of gestational age, the correlation between cardiac output and body surface area was poor, by either thoracic electrical bioimpedance monitoring (r = 0.15 to 0.39) or Doppler echocardiography (r = 0.00 to 0.29). Furthermore, strict proportionality between cardiac output and body surface area was in general not the best way of describing the (poor) relation between these two. CONCLUSION: Standardization of cardiac output in pregnancy by correcting for body surface area to compare cardiac performance between individuals and between groups of individuals is not justified.

Thoracic electrical bioimpedance: suitable for monitoring stroke volume during pregnancy?

To obtain normal values for maternal stroke volume and cardiac output during pregnancy, a non-invasive, accurate and reproducible method is required. The thoracic electrical bioimpedance (TEB) method may be suitable. However, this method is as yet only qualified for short-term trend recordings, since it assumes that body dimensions such as height, weight and thoracic circumference remain constant during the study. This may not be the case in long-term studies, especially during pregnancy. In this paper it is argued that changes in stroke volume (SV) during pregnancy are reflected most strongly when using the formula: SV = P VET (dZ/dt)max/Z0, where P is a personal factor to be determined at the beginning of pregnancy; VET the ventricular ejection time; (dZ/dt)max the maximum of the first derivative of the thoracic impedance during the cardiac cycle and Z0 the time average of this impedance during the cardiac cycle. Indexed parameters should not be used as this reduces sensitivity. Commercial equipment, based upon other algorithms, can be used by feeding the right parameters for each series of measurements. This enables calculation, trends in stroke volume and cardiac output for longitudinal studies for instance during pregnancy.

Reproducibility of estimated cardiovascular function by transthoracic bioimpedance cardiography in healthy volunteers.

In ten healthy volunteers, stroke index (SI), heart rate (HR), thoracic fluid conductivity (TFC) and index of contractility (IC) were estimated by transthoracic bioimpedance measurements (BoMed Noninvasive Continuous Cardiac Output Monitor, model 3, Revision 7 (NCCOM3-R7)). Intra- and inter-observer variability and the influence of time of day (morning or afternoon) were determined. The intra-observer variability was significantly smaller during the morning than during the afternoon. The mean differences +/- standard error between consecutive measurements for morning versus afternoon measurements were, respectively: SI, 0.8 +/- 1.2 vs. 4.6 +/- 1.2 ml/m2 (P = 0.057); HR, -1.0 +/- 0.6 versus -0.9 +/- 0.6 beats/min; TFC, -0.0 +/- 0.3 vs. 1.0 +/- 0.3 (= TFC x 1000.omega-1) (P = 0.031) and IC, -0.6 +/- 0.9 vs. 5.6 +/- 0.9 (= IC x 1000.s-1) (P = 0.001). The inter-observer variability for SI, HR, TFC and IC did not reach statistical significance. These data suggest that reproducible measurements can be obtained provided that only morning or afternoon measurements are compared. Since the reproducibility of measurements was better during the morning than during the afternoon, we recommend that measurements are performed in the morning.

A fetal cystic neck mass associated with maternal tuberous sclerosis. Case report and literature review.

Tuberous sclerosis is a single gene autosomal-dominant disorder, characterized by multiple hamartoma formation. It shows a wide variability of expression. Prenatal diagnosis by means of a DNA or biochemical marker is not yet possible. Ultrasound offers the only way to detect possible antenatal hamartoma formation, which is most commonly found in the central nervous system, the renal system, and the heart. We report a case of fetal involvement that appears unique because of the unusual location of a tumour in the neck of the fetus.

Conservative management of an ovarian cyst in late pregnancy.

We report a case of concomitant ovarian tumor and pregnancy. Sonographic examination indicated that the tumor was benign and obstructed the birth canal. After conservative treatment (puncture of the cyst), a normal vaginal delivery was possible. Two days after delivery, salpingo-oophorectomy was performed because of torsion of the cyst. Pathological examination confirmed the benign nature of the cyst.

Ectopic pregnancy: not only a tubal disease.

Case histories of women with an obstetrical history and a current ectopic pregnancy (EP) were studied. When causal factors for EP such as salpingitis or inadequate contraception were ruled out there was a higher incidence of spontaneous abortion, ectopic pregnancy, and early labor (P less than 0.01) compared to matched controls. When the results of the first pregnancy after EP were studied the incidence of spontaneous abortion and early labor was higher (P = 0.01) than in matched controls.