Recurrent pregnancy loss (RPL) is a poorly understood condition that comes with many uncertainties, both for affected couples and healthcare providers. Important goals are to provide answers to... Show moreRecurrent pregnancy loss (RPL) is a poorly understood condition that comes with many uncertainties, both for affected couples and healthcare providers. Important goals are to provide answers to these couples and to improve their pregnancy outcomes. To achieve this, we need a better understanding of contributing and predictive factors. Until now, the male role in RPL has been underexposed. In this thesis, we aimed to expand our knowledge regarding the ‘forgotten father’ in RPL. We have found strong clues that in RPL, male contribution really matters.The main conclusions are that advanced paternal age and paternal smoking are associated with an increased risk of pregnancy loss, that inclusion of paternal factors into a prediction model improves the accuracy of predicting ongoing pregnancy after RPL, and that impaired immunomodulatory effects of seminal plasma may play a role in RPL. At the same time, our studies have led to new questions and uncovered new challenges, which are excellent opportunities for further research. Show less
Fosse, N.A. du; Lashley, E.E.L.O.; Treurniet, T.T.; Lith, J.M.M. van; Cessie, S. le; Boosman, H.; Hoorn, M.L.P. van der 2021
Background International guidelines recommend to offer supportive care during a next pregnancy to couples affected by recurrent pregnancy loss (RPL). In previous research, several options for... Show moreBackground International guidelines recommend to offer supportive care during a next pregnancy to couples affected by recurrent pregnancy loss (RPL). In previous research, several options for supportive care have been identified and women's preferences have been quantified. Although it is known that RPL impacts the mental health of both partners, male preferences for supportive care have hardly been explored. Methods A cross-sectional study was conducted in couples who visited a specialized RPL clinic in the Netherlands between November 2018 and December 2019. Both members of the couples received a questionnaire that quantified their preferences for supportive care in a next pregnancy and they were asked to complete this independently from each other. Preferences for each supportive care option were analysed on a group level (by gender) and on a couple level, by comparing preferences of both partners. Results Ninety-two questionnaires (completed by 46 couples) were analysed. The overall need for supportive care indicated on a scale from 1 to 10 was 6.8 for men and 7.9 for women (P = 0.002). Both genders preferred to regularly see the same doctor with knowledge of their obstetric history, to make a plan for the first trimester and to have frequent ultrasound examinations. A lower proportion of men preferred a doctor that shows understanding (80% of men vs. 100% of women, P = 0.004) and a doctor that informs on wellbeing (72% vs. 100%, P = <= 0.000). Fewer men preferred support from friends (48% vs. 74%, P = 0.017). Thirty-seven percent of men requested more involvement of the male partner at the outpatient clinic, compared to 70% of women (P = 0.007). In 28% of couples, partners had opposing preferences regarding peer support. Conclusions While both women and men affected by RPL are in need of supportive care, their preferences may differ. Current supportive care services may not entirely address the needs of men. Health care professionals should focus on both partners and development of novel supportive care programs with specific attention for men should be considered. 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
Keller, C.C.; Eikmans, M.; Hoorn, M.L.P. van der; Lashley, L.E.E.L.O. 2020
Regulatory T cells (Tregs) are essential in tolerizing the maternal immune system toward the semi-allogeneic embryo. In this systematic review, we evaluated the association of levels and function... Show moreRegulatory T cells (Tregs) are essential in tolerizing the maternal immune system toward the semi-allogeneic embryo. In this systematic review, we evaluated the association of levels and function of Tregs in peripheral blood and decidua with recurrent miscarriage (RM), defined as two unexplained miscarriages. We included 18 studies. Ten studies showed a significantly decreased level of Tregs in peripheral blood of non-pregnant women with RM, compared to controls (p < 0.05). In pregnant women with RM, levels of Tregs in the peripheral blood were significantly lower compared to control groups (p = 0.0004), as shown in nine studies. Moreover, seven studies described a decrease of Treg levels in the placenta of pregnant women with RM (p < 0.0001) compared to controls. Accordingly, the median of the relative changes (MRC) between cases and controls in the non-pregnant group (peripheral blood), and the two pregnant groups (peripheral blood and decidua) were -0.18 (-0.27-0), -0.26 (-0.35 to -0.17), and -0.52 (0.63-0.31), respectively. In addition to the assessment of Tregs by phenotype, six out of the 18 included studies investigated the functionality of these cells. These studies showed a lower inhibitory effect of Tregs cells on the proliferation of effector T cells of women with RM compared to fertile women. Also, the expression of IL-10 and TGF-beta was diminished. This systematic review shows that Treg levels and their function are significantly decreased in peripheral blood and decidua of pregnant and non-pregnant women with RM. This underlines the hypothesis that Tregs play a role in the pathogenesis of RM. Show less
In normal pregnancy the fetus, although a semi-allograft, is tolerated by the maternal immune system. It has been suggested that an inadequate maternal allo-immune response to the paternal... Show moreIn normal pregnancy the fetus, although a semi-allograft, is tolerated by the maternal immune system. It has been suggested that an inadequate maternal allo-immune response to the paternal antigens of the fetus is responsible for a proportion of the unexplained recurrent miscarriage. In chapter 2 we provide an overview on the possible role of the HLA system in recurrent miscarriage. No consistent conclusions can be drawn since the observed odd ratios found were relatively small and the risk of bias in the selected studies was high. In chapter 3 we compared the genetic polymorphisms of HLA-G in women with recurrent miscarriage with women with uneventful pregnancy. The HLA-G UTR-4 haplotype was less frequently observed in women with recurrent miscarriage, suggesting an immunoregulatory role of this haplotype. The combined results from chapter 4, chapter 6 and chapter 7 suggest that in a portion of women with unexplained recurrent miscarriage antibody-mediated rejection of the fetal allograft may play a role. We showed in chapter 8 that human seminal plasma contains all kinds of immunoregulatory factors and has an immunomodulatory effect on T cells. In chapter 9 a matched case-control study practicing oral sex was negatively associated with the occurrence of recurrent miscarriage. Show less
Cardiovascular disease (CVD) is the leading cause of death in women in the Western world. In this thesis, several studies are presented examining the association between recurrent miscarriage and... Show moreCardiovascular disease (CVD) is the leading cause of death in women in the Western world. In this thesis, several studies are presented examining the association between recurrent miscarriage and cardiovascular disease. Main aim of this thesis was to assess whether miscarriages are independently associated with an increased risk of cardiovascular disease later in life. And, if this was true, to identify cardiovascular risk factors and predict long term cardiovascular disease risk in women with a history of recurrent miscarriage. We found an increased risk of ischemic heart disease in women with a history of two (multivariate analysis HR 1.82) and three or more miscarriages (HR 3.18), irrespective whether consecutive or not (chapter 2). Women with a history of recurrent miscarriage have significantly higher 10- and 30-year cardiovascular risk scores compared to women with a history of no miscarriage. These results indicate an opportunity for the early identification of women prone to cardiovascular disease later in life. Women with a history of two or more miscarriages must be made aware of their increased cardiovascular risk and appropriate risk factor modifications will have to be offered, for example life style advises; weight management and smoking control. Show less
Meuleman, T.; Drabbels, J.; Lith, J.M.M. van; Dekkers, O.M.; Rozemuller, E.; Cretu-Stancu, M.; ... ; Eikmans, M. 2018
This thesis describes the clinical significance of thebiomarker C4d, a split product of the complement system, in several manifestations of systemic autoimmunediseases such as SLE and... Show moreThis thesis describes the clinical significance of thebiomarker C4d, a split product of the complement system, in several manifestations of systemic autoimmunediseases such as SLE and antiphospholipid syndrome. The findings in this thesis suggest that this biomarker might be of use in unraveling disease mechanisms where complement activation is involved, as well as serving as a diagnostic tool to detect patients at risk of antibody mediated tissue injury Show less
