Godelieve C. M. L. Page-Christiaens

Reliability of Fetal Sex Determination Using Maternal Plasma

OBJECTIVE: To determine the diagnostic accuracy of noninvasive fetal sex determination in maternal plasma. METHODS: All consecutive patients for whom fetal sex determination in maternal plasma was performed in our laboratory from 2003 up to 2009 were included in the study. Real-time polymerase chain reaction was performed for the SRY gene and multicopy DYS14 marker sequence. A stringent diagnostic algorithm was applied. In the case of a positive result for both Y chromosome–specific assays, a male-bearing pregnancy was reported. In the case of a negative result, the presence of fetal DNA was ascertained through the use of 24 biallelic insertion/deletion polymorphisms or paternally inherited blood group antigens. Only if the presence of fetal DNA was confirmed was a female-bearing pregnancy reported. Results were compared with the pregnancy outcomes. RESULTS: A total of 201 women were tested. The median gestational age was 9 0/7 weeks (interquartile range 8 0/7 to 10 0/7 weeks). In 189 of 201 cases (94%), a test result was issued; in 10 cases, the presence of fetal DNA could not be confirmed; in two cases, an early miscarriage was observed. Pregnancy outcome was obtained in 197 cases, including 105 male-bearing and 81 female-bearing pregnancies and 11 miscarriages. Sensitivity and specificity of the test were 100% (95% confidence intervals 96.6–100% and 95.6–100%, respectively). In all 10 cases in which the presence of fetal DNA could not be confirmed, a female was born. CONCLUSION: Noninvasive fetal sex determination in maternal plasma is highly reliable and clinically applicable. LEVEL OF EVIDENCE: III

Noninvasive fetal blood group genotyping of rhesus D, c, E and of K in alloimmunised pregnant women: evaluation of a 7‐year clinical experience

Please cite this paper as: Scheffer P, van der Schoot C, Page‐Christiaens G, de Haas M. Noninvasive fetal blood group genotyping of rhesus D, c, E and of K in alloimmunised pregnant women: evaluation of a 7‐year clinical experience. BJOG 2011;118:1340–1348.

Adjustment to termination of pregnancy for fetal anomaly: a longitudinal study in women at 4, 8, and 16 months.

OBJECTIVE We studied psychological outcomes and predictors for adverse outcome in 147 women 4, 8, and 16 months after termination of pregnancy for fetal anomaly. STUDY DESIGN We conducted a longitudinal study with validated self-completed questionnaires. RESULTS Four months after termination 46% of women showed pathological levels of posttraumatic stress symptoms, decreasing to 20.5% after 16 months. As to depression, these figures were 28% and 13%, respectively. Late onset of problematic adaptation did not occur frequently. Outcome at 4 months was the most important predictor of persistent impaired psychological outcome. Other predictors were low self-efficacy, high level of doubt during decision making, lack of partner support, being religious, and advanced gestational age. Strong feelings of regret for the decision were mentioned by 2.7% of women. CONCLUSION Termination of pregnancy for fetal anomaly has significant psychological consequences for 20% of women up to > 1 year. Only few women mention feelings of regret.

Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels

OBJECTIVE The primary aim of this study was to investigate the correlation between pregnancy outcome and bile acid (BA) levels in pregnancies that were affected by intrahepatic cholestasis of pregnancy (ICP). In addition, correlations between maternal and fetal BA levels were explored. STUDY DESIGN We conducted a retrospective study that included women with pruritus and BA levels ≥10 μmol/L between January 2005 and August 2012 in 3 large hospitals in the Netherlands. The study group was divided in mild (10-39 μmol/L), moderate (40-99 μmol/L), and severe (≥100 μmol/L) ICP. Main outcome measures were spontaneous preterm birth, meconium-stained amniotic fluid, asphyxia, and perinatal death. Univariate and multivariate logistic regression analysis was used to study associations between BA levels and adverse outcome. RESULTS A total of 215 women were included. Gestational age at diagnosis and gestational age at delivery were significantly lower in the severe, as compared with the mild, ICP group (P < .001). Spontaneous preterm birth (19.0%), meconium-stained fluid (47.6%), and perinatal death (9.5%) occurred significantly more often in cases with severe ICP. Higher BA levels were associated significantly with spontaneous preterm birth (adjusted odds ratio [aOR], 1.15; 95% confidence interval [CI], 1.03-1.28), meconium-stained amniotic fluid (aOR, 1.15; 95% CI, 1.06-1.25), and perinatal death (aOR, 1.26; 95% CI, 1.01-1.57). Maternal BA levels at diagnosis and at delivery were correlated positively with umbilical cord blood BA levels (P = .006 and .012, respectively). CONCLUSION Severe ICP is associated with adverse pregnancy outcome. Levels of BA correlate between mother and fetus.

Use of bi-allelic insertion/deletion polymorphisms as a positive control for fetal genotyping in maternal blood: first clinical experience

Abstract:  Amplification of fetal DNA in maternal plasma is a new way for non‐invasive fetal genotyping in pregnancies at risk for disorders where the presence of a paternal DNA sequence contributes to the risk status of the fetus. We describe the use of a panel of 10 bi‐allelic highly polymorphic markers to ascertain the presence and amplification of fetal DNA in case the fetus is negative for the targeted paternal “disease” sequence.

Noninvasive fetal genotyping of human platelet antigen-1a

Please cite this paper as: Scheffer P, Ait Soussan A, Verhagen O, Page‐Christiaens G, Oepkes D, de Haas M, van der Schoot C. Noninvasive fetal genotyping of human platelet antigen‐1a. BJOG 2011;118:1392–1395.

Factors determining uptake of invasive testing following first-trimester combined testing.

This study aims to analyze differences in characteristics between women who opted for invasive testing after first‐trimester combined testing and those who did not.

Sensitivity of fetal RHD screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: Prospective cohort study of a nationwide programme in the Netherlands

Objective To determine the accuracy of non-invasive fetal testing for the RHD gene in week 27 of pregnancy as part of an antenatal screening programme to restrict anti-D immunoglobulin use to women carrying a child positive for RHD. Design Prospectively monitoring of fetal RHD testing accuracy compared with serological cord blood typing on introduction of the test. Fetal RHD testing was performed with a duplex real time quantitative polymerase chain reaction, with cell-free fetal DNA isolated from 1 mL of maternal plasma The study period was between 4 July 2011 and 7 October 2012. The proportion of women participating in screening was determined. Setting Nationwide screening programme, the Netherlands. Tests are performed in a centralised setting. Participants 25 789 RhD negative pregnant women. Main outcome measures Sensitivity, specificity, false negative rate, and false positive rate of fetal RHD testing compared with serological cord blood typing; proportion of technical failures; and compliance to the screening programme. Results A fetal RHD test result and serological cord blood result were available for 25 789 pregnancies. Sensitivity for detection of fetal RHD was 99.94% (95% confidence interval 99.89% to 99.97%) and specificity was 97.74% (97.43% to 98.02%). Nine false negative results for fetal RHD testing were registered (0.03%, 95% confidence interval 0.01% to 0.06%). In two cases these were due to technical failures. False positive fetal RHD testing results were registered for 225 samples (0.87%, 0.76% to 0.99%). Weak RhD expression was shown in 22 of these cases, justifying anti-D immunoglobulin use. The negative and positive predictive values were 99.91% (95% confidence interval 99.82% to 99.95%) and 98.60% (98.40% to 98.77%), respectively. More than 98% of the women participated in the screening programme. Conclusions Fetal RHD testing in week 27 of pregnancy as part of a national antenatal screening programme is highly reliable and can be used to target both antenatal and postnatal anti-D immunoglobulin use.

Analysis of false-positive results of fetal RHD typing in a national screening program reveals vanishing twins as potential cause for discrepancy.

We aim to elucidate causes of false‐positive fetal RHD screening results obtained with cell‐free DNA.

The influence of pregnancy termination on the outcome of subsequent pregnancies: a retrospective cohort study

Objective To compare the incidences of preterm delivery, cervical incompetence treated by cerclage, placental implantation or retention problems (ie, placenta praevia, placental abruption and retained placenta) and postpartum haemorrhage between women with and without a history of pregnancy termination. Design A retrospective cohort study using aggregated data from a national perinatal registry. Setting All midwifery practices and hospitals in the Netherlands. Participants All pregnant women with a singleton pregnancy without congenital malformations and a gestational age of ≥20 weeks who delivered between January 2000 and December 2007. Main outcome measures Preterm delivery, cervical incompetence treated by cerclage, placenta praevia, placental abruption, retained placenta and postpartum haemorrhage. Results A previous pregnancy termination was reported in 16 000 (1.2%) deliveries. The vast majority of these (90–95%) were performed by surgical methods. The incidence of all outcome measures was significantly higher in women with a history of pregnancy termination. Adjusted ORs (95% CI) for cervical incompetence treated by cerclage, preterm delivery, placental implantation or retention problems and postpartum haemorrhage were 4.6 (2.9 to 7.2), 1.11 (1.02 to 1.20), 1.42 (1.29 to 1.55) and 1.16 (1.08 to 1.25), respectively. Associated numbers needed to harm were 1000, 167, 111 and 111, respectively. For any listed adverse outcome, the number needed to harm was 63. Conclusions In this large nationwide cohort study, we found a positive association between surgical termination of pregnancy and subsequent preterm delivery, cervical incompetence treated by cerclage, placental implantation or retention problems and postpartum haemorrhage in a subsequent pregnancy. Absolute risks for these outcomes, however, remain small. Medicinal termination might be considered first whenever there is a choice between both methods.