Reproductive counseling in facioscapulohumeral muscular dystrophy (FSHD) can be challenging due to the complexity of its underlying genetic mechanisms and due to incomplete penetrance of the... Show moreReproductive counseling in facioscapulohumeral muscular dystrophy (FSHD) can be challenging due to the complexity of its underlying genetic mechanisms and due to incomplete penetrance of the disease. Full understanding of the genetic causes and potential inheritance patterns of both distinct FSHD types is essential: FSHD1 is an autosomal dominantly inherited repeat disorder, whereas FSHD2 is a digenic disorder. This has become even more relevant now that prenatal diagnosis and preimplantation genetic diagnosis options are available for FSHD1. Pregnancy and delivery outcomes in FSHD are usually favorable, but clinicians should be aware of the risks. We aim to provide clinicians with case-based strategies for reproductive counseling in FSHD, as well as recommendations for pregnancy and delivery. Show less
Obstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However,... Show moreObstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and cli-nicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes. Show less
Background Pre-eclampsia has a major impact on renal function as shown by the development of proteinuria and podocyturia. How the systemic, soluble Fms-like tyrosine kinase-1 (sFlt-1)-driven... Show moreBackground Pre-eclampsia has a major impact on renal function as shown by the development of proteinuria and podocyturia. How the systemic, soluble Fms-like tyrosine kinase-1 (sFlt-1)-driven inhibition of vascular endothelial growth factor (VEGF) activity detected in pre-eclampsia directly affects renal function remains unknown. The aim of the study was to clarify whether a non-canonical, renal-centred escape from VEGF inhibition in the case of pre-eclamptic pregnancy might have a direct impact on renal function. Methods We evaluated plasma and urinary VEGF and placental growth factor (PlGF), plasma sFlt-1 and carbonic anhydrase IX (CAIX), albuminuria and podocyturia in 18 women with uncomplicated pregnancy, 21 with pre-eclampsia and 18 non-pregnant. The three groups were matched for age and the pregnant groups also for gestational age at enrolment. Results Plasma VEGF was reduced in uncomplicated (P = 0.001) and pre-eclamptic (P = 0.0003) pregnancies when compared with controls. In uncomplicated pregnancy, the dysfunction was balanced by an increase (P = 0.009) of plasma PlGF. Increased (P = 0.0001) plasma CAIX in pre-eclampsia was in line with hypoxia. Pre-eclampsia resulted in a paradoxical increase (P = 0.0004) of urinary excretion of VEGF. Urinary concentrations of VEGF and podocytes were correlated to each other (r(2) = 0.48, P < 0.0005) but also to plasma sFlt-1 (r(2) = 0.56, P < 0.0001 and r(2) = 0.23, P = 0.03, respectively). Conclusions In the case of pre-eclampsia, the systemic VEGF inhibition leads the kidney, possibly the podocyte, to increase the VEGF synthesis. The mechanisms leading to local VEGF overproduction or the overproduced VEGF itself are reasonably involved in the pathogenesis of podocyturia and, as a consequence, renal dysfunction in pre-eclampsia. Show less
van't Hof, L.J.; Schotvanger, N.; Haasnoot, G.W.; Keur, C. van der; Roelen, D.L.; Lashley, L.E.E.L.O.; ... ; Hoorn, M.L.P. van der 2021
IntroductionIn pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the... Show moreIntroductionIn pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the maternal-fetal interface directly interact with HLA-C on extravillous trophoblast cells for optimal placental development. In this study, we aimed to determine whether there is a preferential selection for HLA compatibility and specific KIR/HLA-C combinations in uncomplicated and preeclamptic naturally conceived pregnancies compared to what would be expected by chance.MethodsGenotyping for maternal and fetal HLA-A, -B, -C, -DR, and -DQ, and maternal KIR was performed for 451 uncomplicated pregnancies and 77 pregnancies complicated with preeclampsia. The number of HLA antigen (mis)matches between mother and fetus was calculated and compared to expected values obtained by randomization of the HLA haplotype, inherited from the father, over the existing maternal haplotype of the fetuses. A similar methodology was executed for analysis of the KIR/HLA-C data (n=309).ResultsIn uncomplicated pregnancies, the degree of maternal-fetal HLA matching was not different than expected-by-chance values. In preeclamptic pregnancies, the degree of maternal-fetal HLA matching was different in observed compared to expected-by-chance values (p=0.012). More specifically, the degree of maternal-fetal matching of HLA-C was higher in the actual preeclamptic pregnancies than was expected-by-chance (p=0.007). Preeclamptic pregnancies showed an overall tendency towards higher maternal-fetal HLA compatibility, for total HLA matches (p=0.021), HLA class I (p=0.038) and HLA-C (p=0.025) compared to uncomplicated pregnancies.ConclusionThe data suggest that there is no preferential selection of maternal-fetal HLA compatibility in uncomplicated pregnancies. In contrast, increased total HLA, HLA class I and, especially, HLA-C compatibility is associated with preeclampsia, suggestive for a role of HLA mismatches in immune regulation leading to uncomplicated pregnancy. Show less
Objective To report the prevalence of polyparasitism during pregnancy in the Lambarene region of Gabon and its association with newborn birth weight.Method Pregnant women in their third trimester... Show moreObjective To report the prevalence of polyparasitism during pregnancy in the Lambarene region of Gabon and its association with newborn birth weight.Method Pregnant women in their third trimester were recruited in a prospective study between November 2011 and March 2015. Parasite infection status was assessed microscopically in stool, urine and blood samples. Maternal demographic and obstetrical characteristics and newborns anthropometric data were collected. Multivariable logistic regression was used to assess the association between low birth weight and polyparasitism.Results 678 of 927 pregnant women were included for analysis with mean age (SD) of 25 (6.8) years. The analysis showed that 69% (468/678) were infected with at least one parasite (Plasmodium spp., Schistosoma spp., soil-transmitted helminths, filarial infections). This comprised of 38% with monoparasitism and 31% polyparasitism. The proportion of newborn babies with a weight below 2500 g (LBW) in our study was 21% (142/678). Compared to pregnant women without infection, women with monoparasitic infection had adjusted Odds Ratio confidence interval 95% CI (aOR [95%CI]) of 1.6 [0.95-2.73], those with two parasites had aOR 95%CI of 2.63 [1.51-4.62], and those with more than two parasites had aOR of 5.08 [2.5-10.38] for delivering a newborn with low birth weight.Conclusion In Lambarene, an endemic area for multiple parasite infections, there is a high prevalence of polyparasitism in pregnant women. Polyparasitism is associated with low birth weight. Therefore, there is an urgent need for active screening and treatment of parasite infections in pregnant women to assess the potential public health benefit of such interventions. Show less
Car, H.; Karahan, G.E.; Dreyer, G.J.; Brand-Schaaf, S.H.; Vries, A.P.J. de; Kooten, C. van; ... ; Heidt, S. 2020
Human leukocyte antigen (HLA) antibodies are induced by pregnancy, transfusion, or transplantation. Serum from transplant recipients is regularly screened for IgG HLA antibodies because of their... Show moreHuman leukocyte antigen (HLA) antibodies are induced by pregnancy, transfusion, or transplantation. Serum from transplant recipients is regularly screened for IgG HLA antibodies because of their clinical relevance for transplant outcome. While other isotypes of HLA antibodies, such as IgA may also contribute to the alloimmune response, validated detection assays for IgA HLA antibody detection are lacking. Therefore, we modified the commonly used luminex screening assay for IgG HLA antibody detection (IgG-LMX) into an IgA HLA antibody screening assay (IgA-LMX). Optimization and validation was performed with IgG, IgA1, and IgA2 isotype variants of HLA-specific human recombinant monoclonal antibodies (mAbs). Reactivity patterns of IgA1 and IgA2 isotype HLA-specific mAbs in IgA-LMX were identical to those of the IgG isotype. Cross-reactivity with IgG and IgM antibodies and nonspecific binding to the beads were excluded. Further assay validation showed the absence of IgA HLA antibodies in serum from individuals without alloantigen exposure (n = 18). When the IgA-LMX assay was applied to sera from 289 individuals with known alloantigen exposure through pregnancy (n = 91) or kidney transplantation (n = 198), IgA HLA antibodies were detected in 3.5% of individuals; eight patients on the kidney retransplant waitlist and two women immunized through pregnancy. The majority (90%) of IgA HLA antibodies were directed against HLA class II and were always present in conjunction with IgG HLA antibodies. Results of this study show that this validated IgA-LMX method can serve as a screening assay for IgA HLA antibodies and that the incidence of IgA HLA antibodies in alloantigen exposed individuals is low. Show less
Zwan, A. van der; Unen, V. van; Beyrend, G.; Laban, S.; Keur, C. van der; Kapsenberg, H.J.M.; ... ; Heidt, S. 2020
During healthy pregnancy, a balanced microenvironment at the maternal-fetal interface with coordinated interaction between various immune cells is necessary to maintain immunological tolerance.... Show moreDuring healthy pregnancy, a balanced microenvironment at the maternal-fetal interface with coordinated interaction between various immune cells is necessary to maintain immunological tolerance. While specific decidual immune cell subsets have been investigated, a system-wide unbiased approach is lacking. Here, mass cytometry was applied for data-driven, in-depth immune profiling of the total leukocyte population isolated from first, second, and third trimester decidua, as well as maternal peripheral blood at time of delivery. The maternal-fetal interface showed a unique composition of immune cells, different from peripheral blood, with significant differences between early and term pregnancy samples. Profiling revealed substantial heterogeneity in the decidual lymphoid and myeloid cell lineages that shape gestational-specific immune networks and putative differentiation trajectories over time during gestation. Uncovering the overall complexity at the maternal-fetal interface throughout pregnancy resulted in a human atlas that may serve as a foundation upon which comprehension of the immune microenvironment and alterations thereof in pregnancy complications can be built. Show less
Eikmans, M.; Zwan, A. van der; Claas, F.H.J.; Hoorn, M.L. van der; Heidt, S. 2020
Appropriate development of the placenta is required for healthy pregnancy to occur. After implantation of the fertilized blastocyst, fetal trophoblasts invade the endometrium and myometrium of the... Show moreAppropriate development of the placenta is required for healthy pregnancy to occur. After implantation of the fertilized blastocyst, fetal trophoblasts invade the endometrium and myometrium of the mother's uterus to establish placentation. In this process, fetal trophoblasts encounter maternal immune cells. In this review, we focus on the role of maternal T cells and myeloid cells (macrophages, dendritic cells) in pregnancy and their interaction with trophoblasts. To retain immunologic tolerization, trophoblasts evade immune recognition by T cells and produce factors that modulate their phenotype and function. On top of that, the local environment at the maternal-fetal interface favors expansion of regulatory T cells. Macrophages and dendritic cells are essential in maintaining a healthy pregnancy. They produce soluble factors and act as antigen-presenting cells, thereby interacting with T cells. Herein, M2 macrophages, immature dendritic cells, CD4(+)Th2 cells, and regulatory T cells represent an axis that maintains a local immune tolerant environment. We consider outstanding issues concerning these cell types and their pathways, which need to be addressed in future investigations. Data from recent single-cell sequencing experiments of the placental bed, to study heterogeneity of maternal immune cells and to predict cell-cell interactions, are discussed. Novel ways for long-term culturing of primary trophoblasts allow for cell-cell interaction studies in a functional way. Future directions should include study of the functionality of currently known and newly identified decidual immune cell subsets in healthy and complicated pregnancies, and their interaction with and modulation by trophoblast cells. Show less
Background: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ... Show moreBackground: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed. Methods: A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles. Results: As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac. Conclusions: Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged. Show less
Krop, J.; Heidt, S.; Claas, F.H.J.; Eikmans, M. 2020
In pregnancy, the semi-allogeneic fetus needs to be tolerated by the mother's immune system. Regulatory T cells (Tregs) play a prominent role in this process. Novel technologies allow for in-depth... Show moreIn pregnancy, the semi-allogeneic fetus needs to be tolerated by the mother's immune system. Regulatory T cells (Tregs) play a prominent role in this process. Novel technologies allow for in-depth phenotyping of previously unidentified immune cell subsets, which has resulted in the appreciation of a vast heterogeneity of Treg subsets. Similar to other immunological events, there appears to be great diversity within the Treg population during pregnancy, both at the maternal-fetal interface as in the peripheral blood. Different Treg subsets have distinct phenotypes and various ways of functioning. Furthermore, the frequency of individual Treg subsets varies throughout gestation and is altered in aberrant pregnancies. This suggests that distinct Treg subsets play a role at different time points of gestation and that their role in maintaining healthy pregnancy is crucial, as reflected for instance by their reduced frequency in women with recurrent pregnancy loss. Since pregnancy is essential for the existence of mankind, multiple immune regulatory mechanisms and cell types are likely at play to assure successful pregnancy. Therefore, it is important to understand the complete microenvironment of the decidua, preferably in the context of the whole immune cell repertoire of the pregnant woman. So far, most studies have focused on a single mechanism or cell type, which often is the FoxP3 positive regulatory T cell when studying immune regulation. In this review, we instead focus on the contribution of FoxP3 negative Treg subsets to the decidual microenvironment and their possible role in pregnancy complications. Their phenotype, function, and effect in pregnancy are discussed. Show less
Objective: We aimed to validate a food-frequency questionnaire (FFQ) for Dutch pregnant women, against three 24 h-recalls and blood concentrations of B-vitamins and fatty acids, using the method of... Show moreObjective: We aimed to validate a food-frequency questionnaire (FFQ) for Dutch pregnant women, against three 24 h-recalls and blood concentrations of B-vitamins and fatty acids, using the method of triads. Methods: We included 83 pregnant women from the general population of Rotterdam, the Netherlands, at a median gestational age of 15.6 weeks. Participants completed three non-consecutive 24 h-recalls, and subsequently filled out the 293-item FFQ. Participants provided blood samples from which we analyzed serum folate and vitamin B12, as well as red blood cell folate, linoleic acid, and total saturated, monounsaturated, and polyunsaturated fatty acids. Results: Estimated energy intake did not differ between the FFQ and 24 h-recalls. Deattenuated Pearson's correlation coefficients, between energy-adjusted nutrient intake estimates from the FFQ and the 24 h-recalls, ranged from 0.41 (fat) to 0.88 (fiber) for macronutrients, and were around 0.6 for most micronutrients, except for vitamin E (0.27). Using the triad method, we obtained validity coefficients of 0.86 (95% Confidence Interval (CI) 0.36, 1.00) for serum folate, 0.86 (95% CI 0.18, 1.00) for red blood cell folate, and 1.00 (95% CI 0.42, 1.00) for vitamin B12. Validity coefficients for serum fatty acids ranged from 0.22 to 0.67. Conclusion: This FFQ is a reliable tool for estimating intake of energy, macronutrients, folate and vitamin B12 among women in mid-pregnancy. Show less
Hypertension during pregnancy and preeclampsia are associated with increased arterial thrombotic risk in later life. Whether these complications are associated with risk of venous thromboembolism ... Show moreHypertension during pregnancy and preeclampsia are associated with increased arterial thrombotic risk in later life. Whether these complications are associated with risk of venous thromboembolism (VTE) on the short term after pregnancy and on the long term, that is, outside pregnancy, is largely unknown. We conducted a nationwide cohort study in women with at least 1 pregnancy and their first VTE risk by linking the Dutch perinatal registry (Perined) to anticoagulation clinics. We used Cox proportional hazard models to estimate hazard ratios (HRs) and corresponding 95% CI for VTE risk in women with hypertension during pregnancy, women with preeclampsia, compared with women with uncomplicated pregnancies (reference). A total of 1 919 918 women were followed for a median of 13.7 (interquartile range, 7.6-19.2) years for a total of 24 531 118 person-years in which 5759 first VTEs occurred; incidence rate: 2.3 (95% CI, 2.3-2.4) per 10 000 person-years. In the first pregnancy and 3-month postpartum period, VTE risk was higher in women with hypertension, HR, 2.0 (95% CI, 1.7-2.4), and highest among women with preeclampsia, HR, 7.8 (95% CI, 5.4-11.3), versus the reference group. On the long term, women with hypertension during pregnancy and preeclampsia had a higher VTE risk: HR, 1.5 (95% CI, 1.4-1.6) and HR, 2.1 (95% CI, 1.8-2.4), respectively, versus the reference group. When excluding events during pregnancy and postpartum, these HRs were 1.4 (95% CI, 1.3-1.5) and 1.6 (95% CI, 1.4-2.0), respectively. In conclusion, hypertension during pregnancy and preeclampsia are associated with an increased VTE risk during pregnancy and postpartum period and in the 13 years after. Show less
The embryo of an oocyte donation (OD) pregnancy is completely allogeneic to the mother, which leads to a more serious challenge for the maternal immune system to tolerize the fetus. It is thought... Show moreThe embryo of an oocyte donation (OD) pregnancy is completely allogeneic to the mother, which leads to a more serious challenge for the maternal immune system to tolerize the fetus. It is thought that macrophages are essential in maintaining a healthy pregnancy, by acting in immunomodulation and spiral arterial remodeling. OD pregnancies represent an interesting model to study complex immunologic interactions between the fetus and the pregnant woman since the embryo is totally allogeneic compared to the mother. Here, we describe a narrative review on the role of macrophages and pregnancy and a systematic review was performed on the role of macrophages in OD pregnancies. Searches were made in different databases and the titles and abstracts were evaluated by three independent authors. In total, four articles were included on OD pregnancies and macrophages. Among these articles, some findings are conflicting between studies, indicating that more research is needed in this area. From current research, we could identify that there are multiple subtypes of macrophages, having diverse biological effects, and that the ratio between subtypes is altered during gestation and in aberrant pregnancy. The study of macrophages' phenotypes and their functions in OD pregnancies might be beneficial to better understand the maternal-fetal tolerance system. Show less
Craenmehr, M.H.C.; Haasnoot, G.W.; Drabbels, J.J.M.; Spruyt-Gerritse, M.J.; Cao, M.; Keur, C. van der; ... ; Eikmans, M. 2019
Background: A reliable screening tool that could contribute to the identification of women with an increased risk of postpartum hemorrhage would be of great clinical significance.Objectives: The... Show moreBackground: A reliable screening tool that could contribute to the identification of women with an increased risk of postpartum hemorrhage would be of great clinical significance.Objectives: The aim of this study was to examine the added predictive value of a bleeding assessment tool for postpartum hemorrhage exceeding 1000mL.Patients/Methods: Prospective two-center cohort study among 1147 pregnant women visiting the outpatient clinic or the maternity ward who completed a bleeding assessment tool prior to birth. The condensed MCMDM-1VWD bleeding assessment tool was adjusted to a questionnaire that could be used as a self-assessment bleeding tool. A score of 4 was considered to be abnormal.Results: In the 1147 pregnant women in our cohort, bleeding scores ranged from -3 to 13, with a median of 1 (IQR -1 to 3); 197 (17%) women developed postpartum hemorrhage. Among women with a history of postpartum hemorrhage 29% developed postpartum hemorrhage. Among 147 women with an abnormal bleeding score (4), 27 (18%) developed postpartum hemorrhage, whereas the remaining 170 cases of postpartum hemorrhage had a normal bleeding score. Despite the high incidence of postpartum hemorrhage, the ability of the bleeding score to predict postpartum hemorrhage was poor: area under receiver operating curve 0.53 (95% CI 0.49-0.58) for postpartum hemorrhage (PPH) 1000mL.Conclusions: A history of significant postpartum hemorrhage was associated with an increased risk of subsequent postpartum hemorrhage. However, screening with a bleeding assessment tool did not help to discriminate women who will develop postpartum hemorrhage from women who will not. Show less
