This thesis discusses the prenatal detection and outcome of fetal congenital heart defects. The first part of this thesis focuses to identify determinants for a prenatal diagnosis in fetus with a... Show moreThis thesis discusses the prenatal detection and outcome of fetal congenital heart defects. The first part of this thesis focuses to identify determinants for a prenatal diagnosis in fetus with a structural congenital heart defect. The second part provides evidence on the prognosis of specific congenital heart defects diagnoses in the fetus, as prenatal counseling remains difficult in some cases, due to the fact that little evidence is available on the outcome of congenital heart defects from a fetal perspective. Show less
Individuals having a genetic predisposition to cancer and their partners face challenging decisions regarding their wish to have children. This study aimed to determine the effects of an online... Show moreIndividuals having a genetic predisposition to cancer and their partners face challenging decisions regarding their wish to have children. This study aimed to determine the effects of an online decision aid to support couples in making an informed decision regarding their reproductive options. A nationwide pretest-posttest study was conducted in the Netherlands among 131 participants between November 2016 and May 2018. Couples were eligible for participation if one partner had a pathogenic variant predisposing for an autosomal dominant hereditary cancer syndrome. Participants completed a questionnaire before use (T0), and at 3 months (T3) after use of the decision aid to assess the primary outcome measure informed decision-making, and the secondary outcome measures decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy. T0-T3 comparisons show an overall positive effect for all outcome measures (allps < 0.05; knowledge (ES = - 1.05), decisional conflict (ES = 0.99), participants' decision self-efficacy (ES = -0.55), level of deliberation (ES = - 0.50), and realistic expectations (ES = - 0.44). Informed decision-making increased over time and 58.0% of the participants made an informed reproductive decision at T3. The online decision aid seems to be an appropriate tool to complement standard reproductive counseling to support our target group in making an informed reproductive decision. Use of the decision aid may lessen the negative psychological impact of decision-making on couples' daily life and wellbeing. Show less
Hemoglobinopathies (HbP) are recessive hereditary disorders of hemoglobin, characterized by microcytic hypochromic anemia. HbP diagnostics encompasses three specialties: hematological, biochemical... Show moreHemoglobinopathies (HbP) are recessive hereditary disorders of hemoglobin, characterized by microcytic hypochromic anemia. HbP diagnostics encompasses three specialties: hematological, biochemical and molecular testing. Results of all tests together form the complete diagnosis. The main objective of this thesis was to improve post- and prenatal diagnostics of the hemoglobinopathies. Several molecular assays have been designed, tested and validated. In addition, a number of informative hemoglobinopathy cases have been studied in detail. Diagnostics for hemoglobinopathies is strongly improved over the recent years. In particular the implementation of the MLPA technique made it possible to detect deletions and duplications in the globin gene clusters in patients who remain undiagnosed by applying the conventional techniques. The aCGH technology was developed in order to characterize the breakpoints of novel deletions detected by MLPA more precisely. This has led to the design of several relatively simple gap-PCR assays, which are useful in laboratories where MLPA and aCGH is not available. In addition, gap-PCR can be used for quick screening for the more locally occurring deletions or in family studies. A non-invasive prenatal diagnosis assay for hemoglobinopathies was developed by combining the PAP and MCA techniques. This method will be implemented in the current flow for prenatal diagnosis and will eventually make 50% of the invasive procedures redundant. Show less
The aim of prenatal diagnosis is to provide information on chromosomal abnormalities, in order to allow parents an informed choice on the course of pregnancy. Karyotyping is the diagnostic test... Show moreThe aim of prenatal diagnosis is to provide information on chromosomal abnormalities, in order to allow parents an informed choice on the course of pregnancy. Karyotyping is the diagnostic test used to detect chromosomal abnormalities. It is highly accurate, but labour-intense, costly and slow. Karyotyping detects chromosomal abnormalities with no, mild, or unclear clinical consequences. Rapid aneuploidy detection (RAD) techniques can detect the most common chromosomal abnormalities (trisomies 13, 18, 21, X and Y). Multiplex Ligation-dependent Probe Amplification (MLPA) is a RAD test. Its diagnostic accuracy, tested on 4585 amniotic fluid samples in routine clinical practice, is comparable to that of karyotyping (P<0.001) and it reduces waiting time with 14.5 days at lower costs (-__240 per sample). Patient quality of life does not differ significantly. While caregivers prefer RAD, experts prefer a test detecting all severe chromosomal abnormalities. Patients' preferences are equally divided; they value the detection of severe chromosomal abnormalities most. Since RAD and karyotyping both detect the most common chromosomal abnormalities with severe consequences, both tests are appropriate for prenatal diagnosis. Based on decision analytic considerations and our study results, women should be offered a choice, since they will bear the responsibility of raising the child. Show less
With the availability of prenatal diagnostics in the last century, the fetus became a patient. Obstetricians looked togheter with neonatologist and pediatric surgeons, who in the past needed to... Show moreWith the availability of prenatal diagnostics in the last century, the fetus became a patient. Obstetricians looked togheter with neonatologist and pediatric surgeons, who in the past needed to treat sick neonates, for an earlier moment of treatment. An example of such a shift towards an earlier moment of treatment is the treatment of fetal tachycardia. Allready in utero medication can be given to the fetus transplacentally or direct fetally. In order to convert the tachycardia into a sinus rhythm. Another example is the anemic fetus who can be given an intrauterine blood transfusion to treat the anemia. A further example is the monochorionic twin with twin to twin transfusion syndrome. It is possible to coagulate the pathologic bloodvessel connections which cause the syndrome. Fetal death can be prevented by performing this procedure. A condition for the introduction of new techniques in medicine is that they are tested on efficacy and safety. That’s why new diagnostic and therapeutic procedures demand proper follow-up. Unwanted side effects, such as clubfeet after early amniocentesis, can be detected through careful and thorough follow-up before new techniques are applied on larger scale. Because follow-up research is needed after introduction of new techniques and because prognosis of the future child is very important for the expectant parents, we conducted the following studies. Chapter one comprehends the introduction of the thesis with a brief history of prenatal medicine. The introduction of new intrauterine treatment options increased possibilities. Not only can we timely diagnose abnormalities that cannot be treated (eg Down syndrome) but we can also diagnose diseases timely and treat abnormalities. Abnormalities that otherwise would lead to intrauterine fetal death (eg hydrops fetalis). Even performing intrauterine procedures that will increase a better start in life and therefore better starting point for postnatal treatment (eg prune belly syndrome). The importance of follow-up at infancy is on the one hand for the evaluation of new techniques, and on the other hand to inform parents adequately in case the fetus has an abnormality. Information on prognosis is important in making difficult decisions on either terminating the pregnancy, start intrauterine treatment or expectant management. Chapter two describes the annual results from all centers for invasive prenatal diagnosis in the Netherlands over the period 1991-2000, with particular emphasis on indications, abnormal results, type of invasive procedures, and terminations of pregnancy. The percentage of invasive prenatal diagnosis increased from 5% of births in 1991 to 6% in 1996 and subsequently remained level. During the study period, the number of pregnant women aged 36 and older increased by 70%, but the number of procedures because of maternal age remained stable. The percentage abnormal test results was 4.7 and increased from 3.6 in 1991 to 5.4 in 2000. The detection rate for abnormal results varied from 2% for maternal age to 28% for abnormalities detected by ultrasound examination. Important trends were the relative decrease of cordocentesis (-82%) and chorionic villi biopsy (-18%) in favour of amniocentesis. There was a significant decrease in the percentage of pregnant women aged 36 or older who underwent invasive prenatal diagnosis without previous screening. Chapter three represents de results of a (semi) randomized controlled study that compared the effects of transabdominal chorionic villus sampling and early amniocentesis on fetal mortality and child morbidity. Women requesting early prenatal diagnosis for advanced maternal age were allocated to early amniocentesis or transabdominal chorionic villus sampling either by randomization or, if they declined randomization, by their own choice. Of the 212 women who entered the study, 117 were randomized, 70 chose early amniocentesis and 25 chose transabdominal chorionic villus sampling. Overall, 130 women underwent early amniocentesis and 74 underwent transabdominal chorionic villus sampling at a median gestation of 12 weeks. Mosaic karyotypes were found in 5.4% of the early amniocenteses and in none of the chorionic villus samples. All unintended fetal losses occurred after early amniocentesis with a frequency of 6.2%. Talipes equinovarus was only observed after early amniocentesis with a frequency of 3.1%. The results of this study are in the Cochrane Database. In the nineties the early amniocentesis was abandonded because of the results of 3 controlled studies, including our study, that showed an increased risk of miscarriages and higher incidence of clubfeet. The conclusion of this chapter is that chorionic villus sampling remains the method of choice if prenatal diagnosis is needed in the first trimester of pregnancy. In chapter four the outcome of pregnancies with prenatally diagnosed central nervous system (CNS) malformations are described. Maternal and neonatal records of prenatally diagnosed CNS malformations were retrospectively reviewed over a 6-year period (1993–1998). Information on current development of surviving children was obtained by contacting the care-giving pediatric neurologist. During the study period 124 fetuses were diagnosed with a CNS malformation. Data on pregnancy and delivery were available for 118 pregnancies. Additional malformations were present in 47% of fetuses. A total of 46% of pregnancies were terminated, and 15% ended in spontaneous intrauterine death. A total of 39% of pregnancies resulted in live birth, and 25% of the infants were still alive at the age of 3 months. One child was lost to follow-up, one infant died at the age of 4 months, and two children died at the age of 3 years. Psychomotor development of the remaining 25 children was normal for 5, slightly disabled for 7, moderately disabled for 5 and severely disabled for 8. The conclusion of this chapter is that due to the high rate of termination of pregnancy and to the frequent association with other anomalies, the survival rate of pregnancies in which a CNS defect had been diagnosed prenatally was only 25%. More than 50% of surviving children were moderately or severely disabled. Chapter five decribes the neurodevelopmental assessment in children born with an umbilical artery pH < 7 in the period 1991-1992. During the study period, 1614 umbilical artery pH measurements were performed. Thirty (1.9%) were < 7. Of all infants born with an umbilical artery pH < 7 obstetric, neonatal, and pediatric records were reviewed. From this group 23 infants were admitted to the neonatal intensive care unit, and 8 of them required intubation. Twenty-eight children survived the neonatal period. At an age of 1 to 3 years, children were visited at home for semi-structured questioning of the mother and a Denver Developmental Screening Test of the child.Three children experienced an episode of mild hypertonia. One child had a mild motor developmental delay. The conclusion of this study is that babies born with an umbilical artery pH < 7 are at great risk to experience considerable short-term morbidity. Those who leave the neonatal intensive care unit without major problems have good outcomes, and pessimism in counselling their parents is unwarranted. Chapter six describes the long-term neurodevelopmental outcome in 33 children after twin-to-twin transfusion syndrome (TTTS). Maternal and neonatal medical records of all TTTS-cases admitted to our center between 1990 and 1998 were reviewed. Neurological and mental development at school age was assessed during a home visit in all TTTS-survivors. A total of 33 pregnancies with TTTS were identified. Four couples opted for termination of pregnancy. All other pregnancies were managed conservatively, 18 (62%) with serial amnioreductions and 11 (38%) without intrauterine interventions. Mean gestational age at delivery was 28 (range: 20-37) weeks. Perinatal mortality was 50% (29/58). Birth weight of donor twins was less than recipient twins. Systolic blood pressure at birth was lower in donors than in recipients and donors required more frequently inotropic support postnatally than recipients. The incidence of hypertension at birth was higher in recipients than in donors. Abnormal cranial ultrasonographic findings were reported in 41% (12/29) of the neonates. All long-term survivors (n = 29) were assessed during a home visit. Mean gestational age at birth of the surviving twins was 31 (range: 25-37) weeks. Mean age at follow-up was 6 (range: 4-11) years. The incidence of cerebral palsy was 21% (6/29). Five out of six children with cerebral palsy had an abnormal mental development. The incidence of cerebral palsy in the group of survivors treated with serial amnioreduction was 26% (5/19). Four children were born after intrauterine fetal death of their co-twin: two of them had cerebral palsy. The conclusion therefore is: the incidence of adverse neurodevelopmental outcome in TTTS-survivors is high, especially after intrauterine fetal death of a co-twin. In chapter seven the long-term neurodevelopmental status of children treated with intrauterine red blood cell and platelet transfusion (IUT) for fetal hydrops caused by parvovirus B19 infection is described. Maternal and neonatal records of all intrauterine transfusions for congenital parvovirus B19 infection in our center between 1997 - 2005 were reviewed. A total of 25 IUT sessions were performed in 24 hydropic fetuses. Sixteen survivors aged 6 months to 8 years were included in the follow-up study. All children underwent a general pediatric, a neurological examination and a neurodevelopment examination (developmental index by Bayley Scales of Infant Development or Snijders-Oomen test). Eleven children (68%) were normal and 5 children (32%) demonstrated a delayed psychomotor development with a suboptimal neurological examination (mild delay n=3, severe delay n=2). Neurodevelopmental status did not correlate with pre-IUT hemoglobin, platelet, or blood pH values. Growth and general health status were normal in all. Two children had minor congenital defects. Neurodevelopmental status was abnormal in 5 out of 16 survivors and was not related with the severity of fetal anemia and acidemia. We hypothesize that fetal parvovirus B19 infection may induce central nervous system damage. Chapter eight describes the results of a retrospective cohort study of children with fetal arrhythmia. In the Leiden University Medical Center, 44 fetuses were diagnosed with fetal cardiac arrhythmia between January 1990 and December 2005. Twenty-eight with supravenricular tachycardia (SVT), 7 with atrial flutter (AF) and 9 with atrioventricular block (AVB). The incidence of cardiac anomalies was 18%. Hydrops was seen in 42-50%. Direct or transplacental fetal antiarrhythmic medication was given in 76% of cases. In the SVT group, 19 children needed medication postpartum. In 16/19 infants, the arrhythmia ceased within the first year of life. In the SVT and AF group mortality was 6%. In 21% of these cases Wolff Parkinson White (WPW) syndrome was diagnosed. Mental scores were normal in all survivors. Of the seven cases of AVB included in the follow-up there is no survivor. The other two cases were lost for long-term follow-up, but their medical records noted pacemaker therapy in one and severe mental retardation in the other. In conclusion, mortality in SVT and AF patients in our study was 6% but mental scores were normal in all survivors. Twenty-one per cent of survivors had WPW syndrome. Prognosis in AVB patients was poor. Chapter nine comprehends the general discussion. We look into the demands of follow-up after prenatal diagnosis and therapy. How does loss to follow-up influence outcome? What is the best age to test for follow-up? Which test to use. After prenatal therapy, follow-up should always be performed as a standard procedure. Follow-up needs to comprehend the review of the medical records, specific testing and standard neurologic and developmental tests. An example of a good test, and age of testing is to perform a Bayley Scale of Infant Development test at the age of 2 with neurologic testing (e.g. Touwen). At the age of 5-6 years a further examination can be performed. Follow-up at a later age looks less sensible because postnatal factors influence outcome and prenatal techniques are developing continuously. Show less
