In this thesis the aim was to study immune cell interactions at the maternal-fetal interface to understand the role for immune cells during healthy pregnancy development an pregnancy complications.... Show moreIn this thesis the aim was to study immune cell interactions at the maternal-fetal interface to understand the role for immune cells during healthy pregnancy development an pregnancy complications. Specifically in cases of recurrent pregnancy loss and chronic histiocytic intervillositis. Show less
Galbally, M.; Watson, S.J.; Lappas, M.; Kloet, E.R. de; Wyrwoll, C.S.; Mark, P.J.; Lewis, A.J. 2022
In examining maternal depression, placental 11 beta-HSD2 mRNA expression and offspring cortisol regulation as a potential fetal programming pathway in relation to later child emotional disorders,... Show moreIn examining maternal depression, placental 11 beta-HSD2 mRNA expression and offspring cortisol regulation as a potential fetal programming pathway in relation to later child emotional disorders, it has become clear that sex differences may be important to consider. This study reports on data obtained from 209 participants in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS) recruited before 20 weeks of pregnancy. Maternal depressive disorders were diagnosed using the SCID-IV and maternal childhood trauma using the Childhood Trauma Questionnaire. Placental 11 beta-HSD2 mRNA was measured using qRT-PCR. For assessment of stressinduced cortisol reactivity, salivary cortisol samples were taken at 12 months of age. At 4 years of age, measurement of Childhood Emotional Disorders (depression and anxiety) was based on maternal report using the Preschool Age Psychiatric Assessment (PAPA) and internalizing symptoms using the Child Behavior Checklist (CBCL). Maternal depression in pregnancy and postpartum, and infant cortisol reactivity, was associated with internalizing symptoms for females only. For female offspring only, increased 12-month cortisol reactivity was also associated with increased emotional disorders at 4 years of age; however, there was no association with placental 11 beta-HSD2 mRNA expression. In females only, the combination of lower placental 11 beta-HSD2 mRNA expression and higher cortisol reactivity at 12 months of age predicted increased internalising problems. These findings suggest there may be sex differences in prenatal predictors and pathways for early childhood depression and anxiety symptoms and disorder. Show less
Giesbers, S.; Bos, M.; Bulten, J.; Meeren, L. van der; Drongelen, J. van 2022
BackgrounBackground: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare fetal disease in which maternal antibodies directed toward fetal human platelet antigens (HPA) are formed... Show moreBackgrounBackground: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare fetal disease in which maternal antibodies directed toward fetal human platelet antigens (HPA) are formed during pregnancy and cause fetal thrombocytopenia. The diagnosis FNAIT is suspected when a fetus or neonate presents with signs of bleeding. Case: We describe a pregnancy complicated by a placental hematoma in the 20th week of gestation as the first manifestation of FNAIT. Further evaluation showed signs of germinal matrix hemorrhage and HPA-5b allo-antibodies. After the diagnosis, intravenous immunoglobulin was administered weekly and a healthy daughter was born at 37 weeks. Histopathological analysis revealed that the hematoma was caused by a sub-amniotic hemorrhage of fetal origin. Conclusion: A subamniotic hematoma appears to be the first manifestation of FNAIT. (c) 2022 The Author(s). Published by S. Karger AG, Basel Show less
Snoep, M.C.; Aliasi, M.; Meeren, L.E. van der; Jongbloed, M.R.M.; DeRuiter, M.C.; Haak, M.C. 2021
Impaired placentation is an important contributing factor to intra-uterine growth restriction and pre-eclampsia in fetuses with congenital heart defects (CHD). These pregnancy complications occur... Show moreImpaired placentation is an important contributing factor to intra-uterine growth restriction and pre-eclampsia in fetuses with congenital heart defects (CHD). These pregnancy complications occur more frequently in pregnancies with fetal CHD. One of the most important factors influencing the life of children with CHD is neurodevelopmental delay, which seems to start already in utero. Delayed neurodevelopment in utero may be correlated or even (partly) explained by impaired placentation in CHD cases. This systematic review provides an overview of published literature on placental development in pregnancies with fetal CHD. A systematic search was performed and the Newcastle-Ottawa scale was used to access data quality. Primary outcomes were placenta size and weight, vascular and villous architecture, immunohistochemistry, angiogenic biomarkers and/or placental gene expression. A total of 1161 articles were reviewed and 21 studies were included. Studies including CHD with a genetic disorder or syndrome and/or multiple pregnancies were excluded. Lower placental weight and elevated rates of abnormal umbilical cord insertions were found in CHD. Cases with CHD more frequently showed microscopic placental abnormalities (i.e. abnormal villous maturation and increased maternal vascular malperfusion lesions), reduced levels of angiogenic biomarkers and increased levels of anti-angiogenic biomarkers in maternal serum and umbilical cord blood. Altered gene expression involved in placental development and fetal growth were found in maternal serum and CHD placentas. In conclusion, abnormal placentation is found in CHD. More extensive studies are needed to elucidate the contribution of impaired placentation to delayed neurodevelopment in CHD cases. Show less
Galbally, M.; Watson, S.J.; Lappas, M.; Kloet, E.R. de; Rossum, E. van; Wyrwoll, C.; ... ; Lewis, A.J. 2021
Placental 11fl-HSD2 has been a focus of research for understanding potential fetal programming associated with maternal emotional disorders. This study examined the pathway from antenatal mental... Show morePlacental 11fl-HSD2 has been a focus of research for understanding potential fetal programming associated with maternal emotional disorders. This study examined the pathway from antenatal mental health via placental 11flHSD2 mRNA to cortisol regulation in the infant offspring. This study reports on data obtained from 236 participants in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS). At term, placental tissue was collected within 30 min of birth from 52 participants meeting current criteria for a depressive disorder, and 184 control participants. Depressive disorders were diagnosed using the SCID-IV. In addition, antidepressant use, depressive and anxiety symptoms were measured in early and late pregnancy. Placental 11fl-HSD2 mRNA expression was measured using qRT-PCR. Infant salivary cortisol samples were taken at 12 months of age. Women on antidepressant medication and with higher trait anxiety had higher placental 11fl-HSD2 expression compared to women not taking medication. Furthermore, the offspring of women taking an antidepressant and who also had a current depressive disorder and high trait anxiety had high cortisol reactivity at 12 months of age and this was mediated through 11fl-HSD2 mRNA expression. In contrast, offspring of women not taking antidepressant medication with depressive disorder and high anxiety there was low cortisol reactivity observed. Our findings suggest that the relationship between maternal antenatal depression and anxiety and infant cortisol reactivity is mediated through placental 11fl-HSD2 mRNA expression. Furthermore, the direction differed for women taking antidepressants, where infant cortisol reactivity was high whereas when compared to those with unmedicated depression and anxiety, where infant cortisol reactivity was low. Show less
Twin anemia polycythemia sequence (TAPS) is a form of chronic imbalanced feto-fetal transfusion through minuscule placental anastomoses leading to anemia in the TAPS donor and polycythemia in the... Show moreTwin anemia polycythemia sequence (TAPS) is a form of chronic imbalanced feto-fetal transfusion through minuscule placental anastomoses leading to anemia in the TAPS donor and polycythemia in the TAPS recipient and has been reported only in monochorionic twins. We report a very unusual case of TAPS which developed in a dichorionic twin pair, born at a gestational age of 33(+2). Twin 1 (recipient) was polycythemic and had a hemoglobin value of 22.4 g/dL, whereas twin 2 (donor) was anemic with a hemoglobin value of 9.8 g/dL and an increased reticulocyte count (72 parts per thousand). Color dye injection of the placenta revealed the presence of a deep-hidden small veno-venous anastomosis. Dichorionicity was confirmed on histologic examination. Aside from respiratory distress syndrome, the donor twin had an uncomplicated neonatal course. The recipient twin developed a post-hemorrhagic ventricular dilatation requiring treatment with a ventriculoperitoneal shunt and Rickham reservoir. This report shows that in dichorionic twins, placental anastomoses can be present, which can lead to the development of TAPS with severe consequences. Therefore, when a pale and plethoric dichorionic twin pair is born, a complete diagnostic work-up is required, including a full blood count with reticulocytes and placental injection, to investigate the presence and nature of potential underlying feto-fetal transfusion. Once the diagnosis of TAPS has been established, cerebral ultrasound, hearing screening, and long-term follow-up are strongly recommended as these twins have increased risk for severe cerebral injury, hearing loss, and long-term neurodevelopmental impairment. Show less
Twin anemia polycythemia sequence (TAPS) is a chronic form of unbalanced feto-fetal transfusion through minuscule placental anastomoses in monochorionic twin pregnancies, leading to anemia in the... Show moreTwin anemia polycythemia sequence (TAPS) is a chronic form of unbalanced feto-fetal transfusion through minuscule placental anastomoses in monochorionic twin pregnancies, leading to anemia in the donor twin and polycythemia in the recipient twin. TAPS can occur spontaneously in up to 5% of monochorionic twins or can arise in 2%-16% of cases after incomplete laser surgery for twin-twin transfusion syndrome. TAPS can develop across the entire second and third trimester. Antenatal diagnosis for TAPS is reached via Doppler measurement of the fetal middle cerebral artery peak systolic velocity, showing an increased velocity in the donor, combined with a decreased velocity in the recipient. Treatment options for TAPS include expectant management, preterm delivery, intrauterine blood transfusion with or without a partial exchange transfusion, fetoscopic laser surgery and selective feticide. The best treatment option is unclear and is currently being investigated in an international multicenter randomized trial (the TAPS trial). Spontaneous fetal demise occurs in 5%-11% of TAPS twins, more often in donors (8%-18%) than in recipients (2%-5%). Severe long-term neurodevelopmental impairment is seen in 9% of TAPS twins, with donors having an increased risk for cognitive impairment and hearing problems (15%). Show less
This thesis deals with various aspects of twin anemia polycythemia sequence (TAPS). TAPS is a condition that can develop due to unbalanced feto-fetal blood transfusion through minuscule vascular... Show moreThis thesis deals with various aspects of twin anemia polycythemia sequence (TAPS). TAPS is a condition that can develop due to unbalanced feto-fetal blood transfusion through minuscule vascular placental anastomoses in monochorionic twin pregnancies, causing the donor twin to become anemic and the recipient twin to become polycythemic. In this thesis we show that a difference in middle cerebral artery peak systolic velocity (MCA-PSV) > 0.5 Multiples of the Median (MoM) has a high diagnostic accuracy for the the antenatal diagnosis of TAPS. For postnatal diagnosis of the condition, inspection of the color of the maternal side of the placenta can be of great value. Furthermore, we present the results of a large international registry, and report on outcomes after different treatment options for TAPS. As the best treatment for TAPS is unclear, we propose the protocol of The TAPS Trial (a multicenter open-label international RCT) to investigate the potential beneficial effect of fetoscopic laser surgery for the outcome in TAPS twins . In the last chapters of this thesis we discuss short- and long-term outcome and show that TAPS donors show significantly higher rates of perinatal mortality and long-term neurodevelopmental impairment than their recipient co-twins. Show less
Pregnancy can be seen as an immunologic paradox. Even though the fetus expresses paternally inherited alloantigens it is protected from rejection by a proper regulation of the maternal immune... Show morePregnancy can be seen as an immunologic paradox. Even though the fetus expresses paternally inherited alloantigens it is protected from rejection by a proper regulation of the maternal immune system. With the studies described in this thesis, we want to get more insight in the immunologic mechanisms that play a role in pregnancy. The results of this research can help to identify underlying etiologies in patients with unexplained pregnancy complications, such as recurrent miscarriage. Identifying these causes is important for providing answers and taking away anxiety in these couples, and eventually for the development of effective therapies. Furthermore, elucidating the mechanism leading to survival or rejection of the fetal allograft is not only essential for our understanding of processes leading to normal and abnormal pregnancies, but may also result in important concepts in the field of transplantation and autoimmunity. Show less
During pregnancy a unique situation arises in which the mother's immune system accepts the fetus, which carries both maternal and paternal genes, and does not reject it as can occur in solid organ... Show moreDuring pregnancy a unique situation arises in which the mother's immune system accepts the fetus, which carries both maternal and paternal genes, and does not reject it as can occur in solid organ transplantation. The aim of this dissertation was to unravel the immunological mechanisms that ensure tolerance during a healthy pregnancy and uncover how alterations could contribute to the development of pregnancy complications, such as pre-eclampsia and preterm birth.We applied the new technique mass cytometry and the associated computational analyzes to map all immune cells of the mother during a healthy pregnancy. Furthermore, we demonstrated the presence of three types of functional regulatory CD4+ T cells, identified a phenotype of CD8+ T cells that can offer both tolerance and immunity against infections, and demonstrated potential cross-reactivity of T cells against fetal allo-antigens. The results described in this thesis have contributed to a better understanding of healthy pregnancies and form a basis on which further research can be built. Show less
In this thesis, Chapter 1 presents the state of the literature on early development in humans and mice. Chapter 2 describes the development of gonadal and extragonadal PGCs in humans. Chapter 3... Show moreIn this thesis, Chapter 1 presents the state of the literature on early development in humans and mice. Chapter 2 describes the development of gonadal and extragonadal PGCs in humans. Chapter 3 investigates the status of XCI in human pre-implantation embryos. One X chromosome is indicated to be inactive in E4-E6 cells and E7 trophectoderm cells, whereas it becomes reactivated in E7 epiblast and primitive endoderm cells. Chapter 4 describes the entering of EVTs in maternal circulation (via decidual veins and lymphatic vessels) starts since W5.5, much earlier than previously accepted W8 (via decidual spiral arteries). Chapter 5 studies the spatial imprinting pattern of IGF2/H19 in human first-trimester placental villi. A normal imprinting pattern of IGF2/H19 is revealed in multi-site villi collections as in the embryo. Chapter 6 explores different consequences of Turner syndrome in mouse placenta. The significantly larger area of glycogen cells in XpO placental outer zone and the significantly higher expression of Ldha in XpO labyrinth zone suggest a more severe placental phenotype in E18.5 XpO placentas than in XmO placentas. Finally, Chapter 7 provides general discussion about the findings and discusses the future perspectives on assisted reproduction and new treatment for infertility, pregnancy complications. Show less
Increasing body of evidence shows that perinatal outcomes in MC twins are strongly associated with the complications resulting from the unique angioarchitecture in MC placentas, in particular... Show moreIncreasing body of evidence shows that perinatal outcomes in MC twins are strongly associated with the complications resulting from the unique angioarchitecture in MC placentas, in particular the placental vascular anastomoses. Due to the extensive application of prenatal ultrasound examination, an increasing number and types of complication dedicated for MC twins are being diagnosed. Delineation of the placental characteristics classified by specific complications may shed light on the pathophysiology of various complications in MC twins. One of the great successes in fetal therapy is the introduction of fetoscopic laser coagulation of vascular anastomoses for the treatment of twin–twin transfusion syndrome (TTTS). The investigation on postoperative complications in TTTS placentas is crucial for the further improvement of fetoscopic laser surgery and improvement of perinatal outcome. Since 2002, all MC placentas delivered at the Leiden University Medical Center (LUMC) are consecutively being examined and injected with colored dye. This large database of MC placentas (n=940 in 2016) allows detailed investigation of the pathogenesis and clinical outcome of these rare diseases. Show less
