Veneuze en arteri_le trombose zijn twee van de belangrijkste oorzaken van ziekte en sterfte in Westerse landen. Hoewel de laatste jaren is er veel bekend geworden over de oorzaken die de kans op... Show moreVeneuze en arteri_le trombose zijn twee van de belangrijkste oorzaken van ziekte en sterfte in Westerse landen. Hoewel de laatste jaren is er veel bekend geworden over de oorzaken die de kans op het krijgen van trombose verhogen, zijn er nog veel onduidelijkheden. In dit proefschrift hebben we getracht om naar aanleiding van eerder uitgevoerde genetische en observationele studies nieuwe risicofactoren voor deze twee soorten trombose op te zoeken. Tevens is de samenhang tussen arteri_le en veneuze trombose en de preventie voor trombose tijdens zwangerschap besproken. Show less
Human pregnancy is an interesting immunological paradox. The fetus is a semi-allograft, carrying paternal and maternal genes but is not rejected by the maternal immune system. The placenta is a key... Show moreHuman pregnancy is an interesting immunological paradox. The fetus is a semi-allograft, carrying paternal and maternal genes but is not rejected by the maternal immune system. The placenta is a key player in maintaining the pregnancy, since this fetus-derived organ is in direct contact with the mother. This thesis describes the results of investigations on the immune regulation at the fetal-maternal interface with emphasis on two immunological challenges during pregnancy. First, preeclampsia, which might be immunologically related to host versus graft disease as seen in solid organ transplantation and second, egg donation (ED) pregnancies, which show that even complete allogeneic fetal allografts can be tolerated by the mother. The immunological mechanisms involved in acceptance of the totally allogeneic fetus in ED pregnancies are not well understood yet. It is possible that it leads to differential immunological regulation. This hypothesis is tested in this thesis. We found differential immunological interactions in successful ED and in preeclamptic pregnancies compared with naturally conceived pregnancies. These results indicate that preeclampsia and ED pregnancies are indeed immunological challenges during pregnancy. It is a scientific challenge to further reveal the immunological mechanisms, contributing to precious information for the fields of immunology, transplantation and obstetrics. Show less
Recent studies have suggested that the fetus is capable of exhibiting a stress response to intrauterine needling, resulting in alterations in fetal stress hormone levels. Intrauterine transfusions... Show moreRecent studies have suggested that the fetus is capable of exhibiting a stress response to intrauterine needling, resulting in alterations in fetal stress hormone levels. Intrauterine transfusions are performed by inserting a needle either in the umbilical cord root at the placental surface (PCI), or in the intrahepatic portion of the umbilical vein (IHV). Aim of our study was to test the hypothesis that fetal hormonal changes during intrauterine transfusion are more pronounced when the needle is inserted in the fetal abdomen. Furthermore we aimed to evaluate the effect of fetal analgesia with remifentanil on the fetal stress hormone changes. Exploring the hemodynamic changes following a noxious stimulus, we saw no differences in transfusions through the IHV or the PCI. Remifentanil did not influence the stress hormone changes. We concluded that the stress hormone changes are independent of both site of transfusion and the use of remifentanil. Our results do not confirm nor deny that the fetus is capable to react to a potential painful stimulus, or to show signs of stress or even pain. However, previous research has suggested that presumably painful fetal conditions can lead to alterations in stress reactions after birth. This phenomenon is called ‘fetal programming’. Fetal programming could possibly lead to life-long changes in stress responses and even to increased susceptibility for certain diseases. With the current understanding of fetal pain and fetal analgesia we would advocate the following: 1. Fetal analgesia for invasive procedures should be provided from at least 20 weeks gestation onwards 2. All invasive fetal procedures warrant fetal analgesia, but in procedures involving more than just a single puncture with a thin needle it is obligatory. 3. Analgesics should be given intravenously to the mother. The drug of choice should be ultra-short working (like remifentanil) therefore minimising possible undesirable side-effects to both fetus and mother. Show less
This thesis describes the results of the LEMMoN study, a nationwide prospective cohort study into severe maternal morbidity in the Netherlands in which all hospitals in the Netherlands participated... Show moreThis thesis describes the results of the LEMMoN study, a nationwide prospective cohort study into severe maternal morbidity in the Netherlands in which all hospitals in the Netherlands participated. The main objectives of the study were to assess incidence, case fatality rate, risk factors and substandard care in severe maternal morbidity in the Netherlands. Cases of severe maternal morbidity were collected during a two-year period. All pregnant women in the Netherlands in the same period acted as reference cohort (n=371,021). Special attention was paid to the ethnic background. Substandard care was assessed in selected cases during audit meetings. Severe maternal morbidity was reported in 2552 cases, overall incidence being 7.1 per 1000 deliveries. Incidences of ICU admission, uterine rupture, eclampsia and major obstetric haemorrhage were 0.24%, 0.06%, 0.06% and 0.45% per 1000, respectively. Non-Western immigrant women had a 1.3 fold increased risk of severe maternal morbidity as compared with Western women. Jehovah__s witnesses had a 3.1-fold increased risk. Overall case fatality rate was 1 in 53. Substandard care was found in 80% of assessed cases during clinical audit. Since substandard care was found in the majority of assessed cases, reduction of severe maternal morbidity seems a mandatory challenge. Show less
In summary, in this thesis it becomes clear that the intrauterine environment created by the mother during pregnancy not only has beneficial effects on the developing embryo / fetus. Although it is... Show moreIn summary, in this thesis it becomes clear that the intrauterine environment created by the mother during pregnancy not only has beneficial effects on the developing embryo / fetus. Although it is too early to draw definite conclusions, the first results of this research line show that maternal apoE-deficiency, in contrast to maternal Ldlr-deficiency, adversely affects the offspring, not only in late fetal stages but also in adult life. Our data indicate that the inflammatory status of the mother and the lack of maternal apoE itself may attribute to the increased cardiovascular disease risk observed in the adult offspring. Hypercholesterolemia and oxidative stress possibly play a more regulatory role. In a first attempt to elucidate the underlying mechanism we show that maternal apoE-deficiency leads to changes in the histone triple-methylation modifications in the vascular wall of the offspring. Thi s can be considered an important lead that needs to be investigated further. It does not mean, however, that we are close to complete elucidation of the underlying mechanism. A lot of research is needed to accomplish this and it is needed. Why? The fact that a hit so early in life exerts negative effects on cardiovascular disease risk in adulthood is worrisome. If we could succeed in elucidating the exact role of epigenetics in this process and are able to translate these data to the human situation, possibly we could reduce the incidence of cardiovascular disease. Show less
The term __chimerism__ originates from Greek mythology and refers to the creature Chimaera, whose body was in front a lion, the back a serpent and the midsection a goat. In medicine, the term... Show moreThe term __chimerism__ originates from Greek mythology and refers to the creature Chimaera, whose body was in front a lion, the back a serpent and the midsection a goat. In medicine, the term chimerism refers to an individual, organ or part consisting of tissues of diverse genetic constitution. Pregnancy, blood transfusion and organ transplantation are potential causes of chimerism. In this thesis the occurrence of chimerism is investigated in different organs of healthy women, of women with the autoimmune disease Systemic Lupus Erythematosus (SLE) and of women that received a renal allograft. To demonstrate chimerism, male cells were detected in female organs by using in situ hybridization of the Y chromosome. Chimerism was found in 18% of healthy organs, in about 50% of organs derived from women with SLE and in none of the skin tumors investigated from female renal allograft recipients. In various organ types and both in women with and without sons and women with and without a transfusion history, chimerism was present. In this thesis we describe these results and review data from the ancient and recent literature. With all these data in hand, we speculate about the sources of chimerism and its implications on immunity. Show less
Groep B streptokokken (GBS) zijn belangrijke veroorzakers van ernstige infecties rondom de bevalling. Ter preventie van GBS-ziekte bij het kind worden antibiotica aan ongeveer 20% van alle... Show moreGroep B streptokokken (GBS) zijn belangrijke veroorzakers van ernstige infecties rondom de bevalling. Ter preventie van GBS-ziekte bij het kind worden antibiotica aan ongeveer 20% van alle zwangeren toegediend. Ondanks de toediening van antibiotica worden er soms kinderen ziek. Onderzoek naar de farmacokinetiek (lotgevallen van geneesmiddelen in het lichaam) en de huidige dosering van deze antibiotica tijdens de bevalling werd nog niet eerder verricht. Antibiotica zoals amoxicilline en clindamycine, die tijdens de bevalling worden toegediend, moeten bij de moeder een voldoende tijd een werkzame bloedspiegel hebben, de moederkoek passeren en ook bij het kind een voldoende tijd een werkzame bloedspiegel bereiken. Uit ons onderzoek blijkt, dat voor amoxicilline de farmacokinetiek bij vrouwen met gebroken vliezen voor aanvang van de bevalling vergelijkbaar is met die bij niet-zwangeren. Verschillende situaties bleken geen invloed te hebben op de farmacokinetiek van amoxicilline. Wanneer gebruik wordt gemaakt van een farmacokinetisch computermodel, waarin de bloedspiegels van amoxicilline van moeder, de navelstreng en het kind verwerkt zijn, lijkt de begin dosis van 2 gram amoxicilline afdoende voor het voorkomen van GBS-ziekte. Doseringen penicilline G die gebruikt worden voor de behandeling van GBS-ziekte bij vroegtijdig geboren kinderen zijn ook afdoende. Over clindamycine kunnen geen definitieve conclusies getrokken worden. Show less
In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), a large population-based case-control study, we investigated lifestyle factors as risk... Show moreIn the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), a large population-based case-control study, we investigated lifestyle factors as risk factors for venous thrombosis. Overweight, smoking and alcohol consumption were addressed and pregnancy and the postpartum period were evaluated in women. Due to the large sample size of the study it was possible to investigate the joint effect of these risk factors with important genetic risk factors for venous thrombosis such as the factor V Leiden and the prothrombin 20210A mutation. In addition to these lifestyle related risk factors, two polymorphisms within the promoter region of the protein C gene were studied as risk factors for venous thrombosis and the influence of genotypic variation on plasma protein C levels was assessed. Finally, we described our experience with the inclusion of two different control groups in the MEGA study. Show less
