OBJECTIVE We sought to study long-term (neuro)developmental and behavioral outcome of pregnancies complicated by intrauterine growth restriction at term in relation to induction of labor or an... Show moreOBJECTIVE We sought to study long-term (neuro)developmental and behavioral outcome of pregnancies complicated by intrauterine growth restriction at term in relation to induction of labor or an expectant management. STUDY DESIGN Parents of 2-year-old children included in the Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) answered the Ages and Stages Questionnaire (ASQ) and Child Behavior Checklist (CBCL). RESULTS We approached 582 (89.5%) of 650 parents. The response rate was 50%. Of these children, 27% had an abnormal score on the ASQ and 13% on the CBCL. Results of the ASQ and the CBCL for the 2 policies were comparable. Low birthweight, positive Morbidity Assessment Index score, and admission to intermediate care increased the risk of an abnormal outcome of the ASQ. This effect was not seen for the CBCL. CONCLUSION In women with intrauterine growth restriction at term, neither a policy of induction of labor nor expectant management affect developmental and behavioral outcome when compared to expectant management. Show less
Wyk, L. van; Boers, K.E.; Post, J.A.M. van der; Pampus, M.G. van; Wassenaer, A.G. van; Baar, A.L. van; ... ; DIGITAT Study Grp 2012
Microchimerism is defined by the presence of low levels of nonhost cells in a person. We developed a reliable method for separating viable microchimeric cells from the host environment. For flow... Show moreMicrochimerism is defined by the presence of low levels of nonhost cells in a person. We developed a reliable method for separating viable microchimeric cells from the host environment. For flow cytometric cell sorting, HLA antigens were targeted with human monoclonal HLA antibodies (mAbs). Optimal separation of microchimeric cells (present at a proportion as low as 0.01% in artificial mixtures) was obtained with 2 different HLA mAbs, one targeting the chimeric cells and the other the background cells. To verify purity of separated cell populations, flow-sorted fractions of 1000 cells were processed for DNA analysis by HLA-allele-specific and Y-chromosome-directed real-time quantitative PCR assays. After sorting, PCR signals of chimeric DNA markers in the positive fractions were significantly enhanced compared with those in the presort samples, and they were similar to those in 100% chimeric control samples. Next, we demonstrate applicability of HLA-targeted FACS sorting after pregnancy by separating chimeric maternal cells from child umbilical cord mononuclear cells. Targeting allelic differences with anti-HLA mAbs with FACS sorting allows maximal enrichment of viable microchimeric cells from a background cell population. The current methodology enables reliable microchimeric cell detection and separation in clinical specimens. Show less
Drabbels, J.J.M.; Keur, C.V. van de; Kemps, B.M.; Mulder, A.; Scherjon, S.A.; Claas, F.H.J.; Eikmans, M. 2011
ABSTRACT: INTRODUCTION: Studies have shown that fetal progenitor cells persist in maternal blood or bone marrow for more than 30 years after delivery. Increased trafficking of fetal cells occurs... Show moreABSTRACT: INTRODUCTION: Studies have shown that fetal progenitor cells persist in maternal blood or bone marrow for more than 30 years after delivery. Increased trafficking of fetal cells occurs during pregnancy complications, such as hypertension, preeclampsia, miscarriage and intra-uterine growth restriction (IUGR). Women with these pregnancy complications are significantly more often HLA-class II compatible with their spouses. Women who later develop scleroderma also give birth to an HLA-class II child more often. From these prior studies we hypothesized that preeclampsia and other pregnancy complications could be associated with increased levels of fetal cell trafficking, and later be involved in the development of scleroderma. METHODS: This study was a retrospective multi-centre matched case-control study. One-hundred-and-three women with systemic sclerosis (SSc) and 103 women with no history of SSc or other autoimmune disease were given a questionnaire regarding complications during pregnancy, such as hypertension, intra-uterine growth restriction (IUGR) and miscarriage. Conditional logistic regression analysis was used to assess associations. RESULTS: We found a statistically significantly increased incidence of having had a pregnancy history of hypertension or a fetus with IUGR in women who subsequently developed SSc compared to healthy controls. We found an odds ratio of 2.6 (95% confidence interval (CI): 1.1 to 4.6) for hypertensive complications during pregnancy and an odds ratio of 3.9 (95% CI: 1.2 to 12.3) for intra-uterine growth restriction for women with SSc compared to healthy controls. CONCLUSIONS: This is the first study to show an association between hypertensive complications during pregnancy or IUGR and the development of SSc at a later age. We speculate that the pregnancy abnormalities may have resulted in increased fetomaternal trafficking, which may have played a role in the increased incidence of SSc. Further studies are indicated to examine this putative relationship. Show less
Lashley, L.E.E.L.O.; Hoorn, M.L.P. van der; Mast, B.J. van der; Tilburgs, T.; Lee, N. van der; Keur, C. van der; ... ; Scherjon, S.A. 2011
We analyzed peripheral blood from women at term pregnancy for leukocyte composition, in vitro proliferative responses and cytokine production after nonspecific and fetus-specific stimulation.... Show moreWe analyzed peripheral blood from women at term pregnancy for leukocyte composition, in vitro proliferative responses and cytokine production after nonspecific and fetus-specific stimulation. Maternal peripheral blood mononuclear cells (PBMCs) were collected and stimulated with umbilical cord blood (UCB) of the mother's own child, third-party UCB, nonspecific stimulus phytohemagglutinin, and anti-CD3 antibody, with PBMCs of nonpregnant women (cPBMC) as controls. Nine combinations of patient, child, third party child, and controls were selected on basis of sharing one human leukocyte antigen (HLA)-DR antigen. The response of mPBMC upon specific stimulation with fetal antigens was similar to that of cPBMC. No differences were found when comparing the mother's response upon stimulation to her own child with stimulation to that with a control child. Nonspecific stimulation with phytohemagglutinin and anti-CD3 antibody did not reveal a difference in proliferation rate between mPBMC and cPBMC. However, mPBMC contained a higher percentage of CD14(+) cells (p = 0.001) and activated T cells (CD25(dim), p < 0.0001), but a lower percentage CD16(-)CD56(bright) natural killer (NK) cells (p = 0.001) and CD16(+)CD56(+) NK cells (p = 0.003). mPBMC produced more interleukin (IL)-6, IL-10, and IL-17 compared with cPBMC (p < 0.05). We found differences in lymphocyte composition and cytokine production between mPBMC and cPBMC. These differences did not result in quantitative changes in proliferative responses during pregnancy compared with responses in nonpregnant controls. Show less
Lashley, L.E.E.L.O.; Hoorn, M.L.P. van der; Mast, B.J. van der; Tilburgs, T.; Lee, N. van der; Keur, C. van der; ... ; Scherjon, S.A. 2011
In egg donation (ED) pregnancies the fetus is allogeneic to the gestational carrier. During these ED pregnancies the mother has to cope with a higher degree of antigenic dissimilarity compared with... Show moreIn egg donation (ED) pregnancies the fetus is allogeneic to the gestational carrier. During these ED pregnancies the mother has to cope with a higher degree of antigenic dissimilarity compared with spontaneously conceived pregnancies. At the fetal-maternal interface maternal cells and fetal cells come in close contact. Understanding the immune mechanisms at this fetal-maternal interface gives more insight into the question why the (semi-)allogeneic fetus is accepted and not rejected by the mother. The degree of antigenic dissimilarity in ED pregnancies is comparable with that in solid organ transplantations with HLA mismatched unrelated donors. Therefore, the immunologic interactions between mother and child in successful ED pregnancies may be relevant for the induction of immunological tolerance in solid organ transplantation. Show less
Hoorn, M.L.P. van der; Scherjon, S.A.; Claas, F.H.J. 2011
Egg donation (ED) makes it possible for subfertile women to conceive. Pregnancies achieved using ED with unrelated donors are unique, since the entire fetal genome is allogeneic to the mother. The... Show moreEgg donation (ED) makes it possible for subfertile women to conceive. Pregnancies achieved using ED with unrelated donors are unique, since the entire fetal genome is allogeneic to the mother. The aims of this review were to evaluate the consequences of ED pregnancies and to place them in the special context of their atypical immunologic relationships. This review comprised an online search of English language publications listed in Pubmed/Medline, up to 29 January 2010. Seventy-nine papers met inclusion criteria. Using the literature and the authors' own experience, the relevant data on pregnancy outcome and complications, placental pathology and immunology were evaluated. Multiple studies document that ED pregnancies are associated with a higher incidence of pregnancy-induced hypertension and placental pathology. The incidence of other perinatal complications, such as intrauterine growth restriction, prematurity and congenital malformations, is comparable to conventional IVF. During pregnancy, both local and systemic immunologic changes occur and in ED pregnancies these changes are more pronounced. There is almost no information in the literature on the long-term complications of ED pregnancies for the mother. ED pregnancies have a higher risk of maternal morbidity. Owing to the high degree of antigenic dissimilarity, ED pregnancies represent an interesting model to study complex immunologic interactions, as the fully allogeneic fetus is not rejected but tolerated by the pregnant woman. Knowledge of the immune system in ED pregnancies has broader significance, as it may also give insight into immunologic aspects of tolerance in solid organ transplantation. Show less
Boers, K.E.; Vijgen, S.M.C.; Bijlenga, D.; Post, J.A.M. van der; Bekedam, D.J.; Kwee, A.; ... ; DIGITAT Study Grp 2010
Objective To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term. Design Multicentre randomised equivalence trial (the... Show moreObjective To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term. Design Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT)). Setting Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008. Participants Pregnant women who had a singleton pregnancy beyond 36+0 weeks' gestation with suspected intrauterine growth restriction. Interventions Induction of labour or expectant monitoring. Main outcome measures The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means. Results 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference -9.9 days, 95% CI -11.3 to -8.6) and weighed 130 g less (mean difference -130 g, 95% CI -188 g to -71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (61%) in the expectant monitoring group (difference -0.8%, 95% CI -4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI -5.0% to 5.6%). Conclusions In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth. Show less
Lochem, A. van; Ziji, L. van; Beelen, E. van; Claas, F.H.J.; Scherjon, S.A. 2010
During pregnancy, maternal lymphocytes at the fetal-maternal interface play a key role in the immune acceptance of the allogeneic fetus. Recently, CD4(+) CD25(bright) regulatory T cells have been... Show moreDuring pregnancy, maternal lymphocytes at the fetal-maternal interface play a key role in the immune acceptance of the allogeneic fetus. Recently, CD4(+) CD25(bright) regulatory T cells have been shown to be concentrated in decidual tissue, where they are able to suppress fetus-specific and nonspecific immune responses. Decidual CD8(+) T cells are the main candidates to recognize and respond to fetal HLA-C at the fetal-maternal interface, but data on the characteristics of these cells are limited. In this study we examined the decidual and peripheral CD8(+) T cell pool for CD45RA, CCR7, CD28, and CD27 expression, using nine-color flow cytometry. Our data demonstrate that decidual CD8(+) T cells mainly consist of differentiated CD45RA(-)CCR7(-) effector-memory (EM) cells, whereas unprimed CD45RA(+) CCR7(+) naive cells are almost absent. Compared with peripheral blood EM CD8(+) T cells, the decidual EM CD8(+) T cells display a significantly reduced expression of perforin and granzyme B, which was confirmed by immunohistochemistry of decidual tissue sections. Interestingly, quantitative PCR analysis demonstrates an increased perforin and granzyme B mRNA content in decidual EM CD8(+) T cells in comparison with peripheral blood EM CD8(+) T cells. The presence of high levels of perforin and granzyme B mRNA in decidual EM T cells suggests that decidual CD8(+) T cells pursue alternative means of EM cell differentiation that may include a blockade of perforin and granzyme B mRNA translation into functional perforin and granzyme B proteins. Regulation of decidual CD8(+) T cell differentiation may play a crucial role in maternal immune tolerance to the allogeneic fetus. The Journal of Immunology, 2010, 185: 4470-4477. Show less
