Marie-Louise van der Hoorn

Changes in cytokine production and composition of peripheral blood leukocytes during pregnancy are not associated with a difference in the proliferative immune response to the fetus

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. Maternal peripheral blood mononuclear cells (PBMCs) were collected and stimulated with umbilical cord blood (UCB) of the mothers 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 mothers 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.

Differential immunoregulation in successful oocyte donation pregnancies compared with naturally conceived pregnancies

In oocyte donation (OD) pregnancies, there is a higher level of antigenic dissimilarity between mother and fetus compared with naturally conceived (NC) pregnancies. We hypothesize that a higher degree and/or a different type of immunoregulation is necessary to maintain an uncomplicated OD pregnancy. Different immunological aspects of successful OD pregnancies (n=28) were compared with those of NC pregnancies (n=51), and non-donor IVF (n=20) pregnancies. Maternal peripheral blood mononuclear cells (mPBMCs) were characterized by flow cytometry; the outcome correlated with the number of mother-child HLA mismatches. The fetus-specific alloreactivity of mPBMCs was measured in a mixed lymphocyte reaction. The percentages of CD4(+)CD25(bright) and CD4(+)CD25(dim) cells were higher in mPBMCs of OD and IVF pregnancies compared with NC pregnancies. The percentage of CD4(+)CD25(dim) cells in mPBMCs of OD pregnancies correlated positively with the number of HLA mismatches. Functional studies showed a lower proliferative response to umbilical cord blood by mPBMCs in OD pregnancies. In conclusion, we found a higher degree of peripheral immunoregulation in OD and IVF pregnancies compared with NC pregnancies. A higher number of HLA mismatches in successful OD pregnancies leads to increased percentages of activated T cells in peripheral blood, but not to a higher alloreactivity to the fetus. These studies show that immunoregulation in OD pregnancy is different from that in NC pregnancies. The antigenic dissimilarity in OD pregnancies may play a role in the pathophysiology of preeclampsia.

Dizygotic twin pregnancy after transfer of one embryo

OBJECTIVE To consider the risk of intercourse without contraception during infertility treatment. DESIGN Case report. SETTING Leiden University Medical Center. PATIENT(S) An infertile couple underwent IVF for tubal pathology. INTERVENTION(S) Transfer of one embryo during a natural cycle. MAIN OUTCOME MEASURE(S) Human leukocyte antigen typing, histochemical analysis of the fetal membranes, neonatal and maternal clinical outcomes. RESULT(S) A dizygotic twin pregnancy was confirmed after birth by human leukocyte antigen typing of both fetuses and mother and by histochemical analysis of the dividing fetal membranes. This suggests a pregnancy of concurrent IVF and spontaneous conception. Pregnancy was complicated by preeclampsia and intrauterine growth retardation of both fetuses. CONCLUSION(S) We state that couples should abstain from intercourse without contraception during infertility treatment to prevent multiple gestation and its related complications for mother and fetuses.

Uncomplicated oocyte donation pregnancies are associated with a higher incidence of human leukocyte antigen alloantibodies.

BACKGROUND Fetuses in pregnancies conceived after oocyte donation (OD) have a higher degree of antigeneic dissimilarity with the mother compared to semi-allogeneic fetuses after natural conception. We questioned whether this leads to higher level of HLA antibody formation in OD pregnancies. METHOD Uncomplicated pregnancies after OD were compared with pregnancies conceived either spontaneously or by IVF. We calculated the number of HLA- and epitope mismatches. Maternal sera were screened for HLA antibodies with ELISA; child HLA specific antibody production was determined using CDC and Luminex with single antigen beads for class I and II. RESULTS A significantly (p<0.0001) higher incidence of HLA antibody production was observed in women conceiving after OD (69%) compared to non-donor pregnancies (24-25%). The antibody formation was positively correlated with the number of fetomaternal antigen (Spearmans rho 0.95, p<0.0001) and epitope mismatches (Spearmans rho 0.91, p<0.0001). The number of HLA-DR mismatches between women and child was an independent risk factor for the production of HLA class I specific alloantibodies. CONCLUSION Women conceiving after OD have a higher risk of developing child-specific HLA antibodies; the higher the number of immunogenetic differences, the higher the chance these antibodies are formed. The high incidence of antibody production also strongly depends upon the number of HLA-DR mismatches. Despite the stronger antibody response, OD was associated with uncomplicated pregnancy in cases included in this study.

Towards standardized criteria for diagnosing chronic intervillositis of unknown etiology : A systematic review

Chronic intervillositis of unknown etiology (CIUE) is a poorly understood, relatively rare condition characterized histologically by the intervillous infiltration of mononuclear cells in the placenta. Clinically, CIUE is associated with poor pregnancy outcome (e.g., impaired fetal growth, preterm birth, fetal death) and high risk of recurrence in subsequent pregnancies. Because CIUE is not defined consistently, it is essential to clearly define this condition. We therefore review the published definitions of CIUE. In addition, we provide an overview of the reviewed histopathological and maternal characteristics, obstetric features, and pregnancy outcomes. Medical publication databases were searched for articles published through February 2017. Eighteen studies were included in our systematic review. The sole inclusion criterion used in all studies was the presence of intervillous infiltrates. Overall, CIUE was characterized by adverse pregnancy outcome. Miscarriage occurred in 24% of cases, with approximately half of these miscarriages defined as late. Impaired growth was commonly observed, 32.4% of pregnancies reached term, and the live birth rate was 54.9%. The high recurrence rate (25.1%) of the intervillous infiltrates in subsequent pregnancies underscores the clinical relevance of CIUE, the need for increased awareness among pathologists and clinicians, and the need for further research. Criteria for the diagnosis of CIUE are proposed and a Delphi study could be used to resolve any controversy regarding these criteria. Future studies should be designed to characterize the full clinical spectrum of CIUE.

Immunologic and Clinical Consequences of Oocyte Donation Pregnancies

Oocyte donation pregnancies are a result of in vitro fertilization of a donated oocyte by either a relative or more commonly an unrelated donor. In contrast to normal pregnancy, where the fetus is a semi-allograft expressing both maternal (self) and paternal (nonself) genes, in oocyte donation both fetal haplotypes are foreign to the gestational carrier. The placenta and fetal membranes are directly exposed to maternal tissue. Therefore, during an uncomplicated pregnancy, specific local immune adaptations are necessary at the fetal–maternal interface. It is possible that the genetic dissimilarity reflected by the number of human leukocyte antigen (HLA) mismatches results in an altered immunological reaction in oocyte donation pregnancies compared to naturally conceived pregnancies.