Immune Changes in Infants of Preeclampsia Mothers: A Systematic Review of Literature

Abstract Preeclampsia (PE) is a prevalent disease especially in developing countries. PE influences maternal immune cells and cytokines, with prevailing of proinflammatory cytokines and reduction of regulatory cells. It has a short- and long-term impact on newborn mortalities and morbidities. The aim of this study is to provide an overview of previous literature discussing the effect of PE on infant immunity to help design future research. A comprehensive search was done on three databases including PubMed, Medline, and EMBASE with mesh and text terms. We could identify 851 titles published from 2000 to the time of search. Twenty-four studies met the inclusion criteria, and they were included in the quality assessment. Twenty-four studies were identified, covering the impact of PE on various neonatal immune cells and cytokines. PE is associated with a decrease in the number of several immune cells in newborns, particularly neutrophils, with enhancing cytotoxic effect of both neutrophils and natural killer (NK) cells. Treg cells were considerably reduced with increase of cytotoxic T cells CD8+ and memory cells CD45RO+ in both CD4+ and CD8 + . Proinflammatory cytokines like IL6, IL8, and TNF were raised in severe PE. PE is linked to a decrease in regulatory immune cells and an increase in the immune cells' cytotoxic capability, as well as the prevalence of proinflammatory cytokines in newborns. These changes were observed in cord blood and peripheral blood samples; however, future research should investigate the long-term effect of PE on neonatal immunity.


Introduction
Preeclampsia is a highly prevalent pregnancy-specific disorder as it affects 2 to 8% of all pregnancies worldwide.The rate of preeclampsia is increasing from the 1980s and it is more common in extreme maternal ages and primigravida.Preeclampsia causes different maternal and neonatal morbidities and mortalities. 1The infants who were born from preeclampsia pregnancy have increased risk of neonatal complications including preterm birth, intrauterine growth restriction (IUGR), neonatal sepsis, feed intolerance, poor growth and bronchopulmonary dysplasia (BPD), as well as higher risk of cerebral palsy, abnormal neurodevelopmental outcomes, cardiovascular disease, stroke, and mental disorders during childhood and adulthood. 2,3reeclampsia is diagnosed according to new International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria 2014 as a new onset of high blood pressure !140/90 in two occasions, 4 hours apart in previous normotensive mother after 20 weeks of gestation and one or more of the following: (1) evidence of proteinuria in urine !0.3 mg/mol on protein/creatinine ratio; !þ 2 in urine dipstick or !300 mg/d in 24-hour urine sample; (2) acute kidney with creatinine !90 µmol/L, acute hepatic dysfunction with transaminases !40 IU/L with or without upper right hypochondria pain or epigastric pain, or signs of neurological or hematological complications; (3) signs of uteroplacental dysfunction such as fetal growth restriction, abnormal uterine artery Doppler, or still birth.Preeclampsia is classified to early onset and late onset with delivery of less than 34 þ0 and !34 þ0 weeks' gestation consecutively.Moreover, preeclampsia could be classified to preterm preeclampsia and term preeclampsia with delivery at less than 37 þ0 and !37 þ0 consecutively. 4 During normal pregnancy, the maternal immune system undergoes some modification to tolerate the foreign fetal tissue and provide host defense against infection at the same time.The cytotoxic immune responses are decreased (natural killer [NK] cells, effector cells, and phagocytosis) and regulatory immune elements are increased (regulatory T cells [Treg cells] and NK regulatory cells).These changes help avoid abortion and still birth. 5During preeclampsia, the T helper cells shift toward Th1, which leads to enhanced secretion of IL12 and IL18 and diminished secretion of IL10.This leads to decreased anti-inflammatory response, which increases apoptosis and decreases trophoblast cell invasion. 6reeclampsia is a major cause of IUGR and still birth.It increases the risk of BPD and necrotizing enterocolitis (NEC) in neonates.In a large retrospective cohort study, preeclampsia was associated with higher rate of neonatal sepsis. 7reeclampsia causes changes in neonatal immunity, especially in the first few days after birth such as decrease in Treg cells, increase in NK cells, and decrease in neutrophilic count and function. 8These immune changes could increase the risk of sepsis, BPD, and NEC in neonates. 9n our study, we collected evidence from the past 20 years to highlight the effect of preeclampsia on the immune function of newborns.As far as we know, this is the first qualitative systematic review on the effect of preeclampsia on neonatal immunity.

Inclusion and Exclusion Criteria
The search was restricted to full text articles on human subjects, written in English, and published in or after 2000.We included articles that focus on the effect of maternal preeclampsia on newborn immunity in cord and peripheral blood during neonatal period.We excluded nonhuman studies, case report, in vitro cell line test studies, narrative review, and systematic review.We excluded studies that focus only on maternal immunity.The references of the selected studies were also checked to determine if any were applicable for our search.Two authors independently screened the titles and abstracts of all citations and selected the potential related studies.Full texts were independently reviewed by the two authors, and data were extracted independently by them.Any disagreement between the investigators was resolved by discussion.The following data were extracted from each article: name of the first author, publication year, type of study, number of participants, gestational age, source of blood sample, immune marker, method of assessment, main results, and p-value.These characteristics are summarized in ►Table 1.

Quality Assessment of Selected Studies
Two authors assessed the quality of the selected studies utilizing the criteria of quality evaluation checklist developed by Rahimzadeh et al. 11 The quality assessment tool was based on 19 criteria, which consisted of four key areas: proper baseline for studies, appropriate population selection, adequate study design, and appropriate outcome reporting.The possible score ranged from 0 to 40.According to this score, the quality of the included studies was categorized into three rankings: rank A (score: 70-100%), rank B (score: 40-69%), and rank C (score: <40%).If the two authors disagreed on more than two grades, a third person was asked to recheck the article.The checklist for quality evaluation is illustrated in ►Table 2. The numbers define the score of the study.

Results
As shown in ►Fig. 1, the total number of articles from the three databases were 851 after removal of duplication.Seventy-one potential studies were retrieved based on the title and abstract.After a thorough analysis of the full texts, 51 were excluded.Four studies were added after examining the references of the selected articles.Some review articles published, but none of them focused on the immune changes in infants.Finally, 24 articles were included in this review.The main results of each article are summarized in ►Table 3.
Most of the studies were case control designs, while two were prospective cohorts and one was cross-sectional.Five   Were the participant randomized into groups? 2 0 3. Case and control definition: Were the characteristics of the preeclampsia clearly defined? 2 0 Was the stage of the disease assigned? 2 0 Was the source of the cells mentioned? 2 0 Was the gestational age of the participants mentioned? 2 0 Were other disorders or medication considered? 2 0 Were the characteristics of the control group the same as the case group? 4 0 4. Study design: Was the exposure clearly defined? 2 0 Was the time frame of the study mentioned? 2 0 Were the methods of Treg measuring valid? 2 0 Did the study incorporate blinding? 2 0 Were the potential confounding factors considered in the design? 2 0 Was the statistical analysis appropriate to the design? 2 0 5. Results: Were the results adjusted for confounding factors? 2 0 Were the main findings of the study clearly described? 2 0 Did the study provide estimates of the random variability in the data for the main outcomes? 2 0 Had actual probability values been reported?2 0 Immune Changes in Infants of Preeclampsia Mothers Saleh et al. e5 Table 3 The main results of each study

Study Main result
Ødegård et al 29 • No difference between IL6 level in the PE and control groups • IL6 was lower in early PE and severe PE compared with controls, with p < 0.001 for both • Decrease IL6 level was more statistically significant with lower birth weight ratio Tosun et al 28 In cord blood: 28, and CD4/CD8 were lower in the PET group than in the control group , and CD25 on (CD19þ and CD8 þ ) was higher in the PE group than in the control group

and CD25 on CD3þ in both groups
Na lei et al 2016 42 • Content of CD3 cells, IgG, IgA, IgM, C3, and C4 was lower in the preeclampsia group than in controls • IgG and CD4 lower in GH than control Sava et al 23 • CD4þ T lymphocyte and CD4 þ HLA-DRþ T cells are lower in the PET group on day 3 (p ¼ 0.0159 and 0.034, respectively) • CD4 þ CD45ROþ memory T cells is higher in the PET group on day 7 (p ¼ 0.0308) • CD4/CD8 cell ratio lower in the PET group on days 0, 1, and 3 (p ¼ 0.0062, 0.0252, and 0.0043, respectively) • CD8 þ CXCR3þ was lower in the PET group on days 1 and 7 (p ¼ 0.0009 and 0.0163, respectively) • CD8 þ CD69þ T cells was lower in the PET group on days 0 and 1 (p ¼ 0.0109 and 0.0015, respectively) • CD8 þ HLA-DRþ T cells was lower on days 0, 3, and 7 (p ¼ 0.0084, 0.0308, and 0.0019, respectively) • mDCs (myeloid dendritic cells) was lower in the PET group on days 1 and 3 (p ¼ 0.0011 and 0.0538, respectively) • Cytokines levels were higher in the PET group on days 1, 3, and 7 and lower on day 0 • Cortisol level was lower in PET on day 1 and 7 (p ¼ 0.037 and 0.047, respectively) Laskowska et al 30 • All the studies included infants born to mothers with normal blood pressure during pregnancy as a control.The selected studies included participants with different gestational ages.Full-term babies were defined as gestational age greater than 37 weeks and preterm babies as less than 37 weeks of gestation.According to the mean and median gestational age of the participants, 12 of these studies recruited fullterm babies born to preeclampsia mothers.Twelve studies compared preterm babies born to mothers with preeclampsia and compared them with preterm controls; however, three of these studies recruited full-term controls.Gestational age as a confounder was reported in all studies and it was matched between the study and control groups in only nine studies.Most of the research articles analyzed cord blood samples to detect the immunological changes in infants with preeclampsia, while four studies looked at these changes in neonate peripheral blood samples collected at different times after birth.In most trials, the preeclampsia group was not classified.Only two studies distinguished between preeclampsia with and without IUGR, whereas two studies characterized it as mild or severe.Only two studies recruited infants from pregnancy-induced hypertension, besides normotensive control.According to the quality ranking, 19 of the studies was ranked B, 5 as A, and none as C. The included studies compared different aspects of immunological function in cord blood and peripheral blood samples from babies of preeclampsia mothers and normotensive controls.Six studies investigated the surface markers on different immune cells and 12 articles focused on the plasm level of different cytokines and interleukins.Furthermore, six studies focused on both the surface markers of the immune cells and plasma cytokines.NK cells, lymphocytes, monocytes, and neutrophils were studied in these articles.Four studies showed the changes in NK cells' surface markers, and three articles reported mainly Treg cells changes.Four studies investigated monocytes, and four articles demonstrated the difference in neutrophils.Tumor necrosis factor-α (TNF-α), interleukin-6 (IL6), and IL8 were the most cytokines and interleukins investigated in preeclampsia.TNF-α and IL-6 were investigated by five studies each, while IL-8 was reported in four articles.
3][14][15][16][17] Kuntz et al detected a reduction in Fasl surface expression on neutrophils in cord blood. 14However, Mellembakken et al found an increase in the CD15s, CD11a, Cd31, Cd49d/Cd25, and CD54 expression on neutrophils in cord blood of the preeclampsia group. 18During the first week of life, Turunen et al reported an increase in CD11b expression on neutrophils in the peripheral blood of preterm infants with severe respiratory distress syndrome (RDS) on mechanical ventilation born to preeclampsia mothers. 12aini et al noticed an increase in the surface adhesion markers CD18, CD11a, CD11b, and CD11c in cord blood samples and discovered that these markers were significantly higher in severe preeclampsia than in mild cases. 19n comparison to normotensive controls, the overall number of monocytes was lower in cord blood samples of preeclampsia. 13Turunen et al observed increased level of CD11b on neutrophils in the peripheral blood samples of preterm baby with RDS on mechanical ventilation who were born to preeclampsia mothers compared with infants of matched gestational age and condition delivered to normotensive mothers.Additionally, Mellembakken et al found an increase in CD11c and CD54 in cord blood samples of preterm infants with severe preeclampsia, whereas the control group consisted of full-term infants born to mothers with normal pregnancy. 12,18However, Sohlberg et al revealed no statistically significant difference between the two groups in the percentage of CD3-CD14þ monocytes or any of the surface expression markers CD11c, CD80, CD86, CD163, and HLA-DR in cord blood samples, despite categorizing preeclampsia as mild or severe.The same result was found by Loewendorf et al. 20,21 Bujold et al showed a higher number of (CD3-/CD56 þ CD16 þ ) NK cells in cord blood samples from infants of preeclampsia mothers with a lower gestational age than controls. 22Furthermore, Sohlberg et al found a higher expression of surface activation marker NKP30 and lower expression of NKG2D in cord blood sample and it was significantly different in mild form compared with controls.In contrast, there were no changes in the expression of these activation markers when normal cord blood mononuclear cells (CBMCs) were incubated in cord blood serum from women with control, mild, and severe preeclampsia. 20Loewendorf et al reported a reduced ratio of nonactive NK cells (CD56 high CD16-) to active NK cells (CD56 low CD16-) in cord blood samples from full-term infants with preeclampsia compared with infants with comparable gestational age without preeclampsia. 21otal CD4þ cells and CD4 þ/CD8þ ratio was reported to be decreased in cord blood and postnatal blood of term and preterm infants with preeclampsia.Memory cells CD4 þ CD45ROþ and CD8 þ CD45ROþ were elevated in the cord blood and peripheral newborn samples of preterm and term infants with preeclampsia. 13,21,23,24Sava et al revealed lower levels of CD4 þ HLA-DRþ and CD8 þ HLA-DRþ in cord blood and postnatal peripheral blood of preterm infants with preeclampsia. 23Treg cells in cord blood were identified by Vargas-Rojas et al as CD4þ CD127 low FoxP3 þ , and they were considerably diminished in full-term infants with preeclampsia.El- and CD4 þ CD25 low to identify Treg cells.Their data demonstrated a significant decrease in the level of CD4 þ CD25 high FoxP3þ and CD4 þ FoxP3þ as well as an increase in CD4 þ CD25 low FoxP3þ in cord blood of full-term infants with preeclampsia.In addition, CD4 þ CD25 high FopP3þ and CD4 þ FoxP3þ were negatively correlated with preeclampsia severity, whereas CD4 þ CD25 low FopP3þ was positively correlated with preeclampsia severity.Loewendorf et al examined CD4 þ FoxP3þ to detect Treg cells and they found that it was lower in the preeclampsia group.However, when they subdivided FoxP3 into high and low, they noticed a reduction of CD4 þ Foxp3 low and no changes in CD4 þ Foxp3 high in infants with preeclampsia. 21,25,26everal researches have addressed the changes in cytokines levels in fetomaternal interface and peripheral blood of preeclampsia infants.Twelve articles explore these alternations, with the majority using cord blood and only one using postnatal peripheral blood.IL6, IL8, TNF-α were the most reported cytokines.Three studies 13,15,27 revealed no difference in the IL6 level in cord blood.However, Tosun et al observed a rise in the IL6 level in postnatal peripheral blood of preterm infants born of preeclampsia mothers. 28Additionally, Ødegård et al found a decrease in the level of IL6 in cord blood that had a positive correlation with birth weight; however, they measured the IL6 level using colorimetric assay of hybridoma cell line B13.29 clone 9 growth. 29Three studies reported an increase in the IL8 levels in preeclampsia, while Faulhaber et al found a decrease and Cakir et al found no difference in the IL8 levels between the two groups.Mellembakken et al identified a higher level of GROα in cord blood samples from preterm infants with preeclampsia than from full-term healthy controls. 15,17,18,28,30In four research 13,29,31,32 there were a higher level of IL6 in preeclampsia group, however in only one study 15 there was no changes.Besides higher level of TNF-α in cord blood, Xia et al 31 reported higher level of TLR4 protein expression in cord blood and Guillemette et al 32 revealed high level of TNF-α in maternal blood in the second trimester.In cord blood of infants with preeclampsia, Vargas-Rojas et al reported a decreased level of intracellular IL4 but no difference on the levels of intracellular INFγ and IL17. 25The CXC12 levels increased, while CXCL9 and CXC10 levels decreased, according to Darakhshan et al. 33 Sava et al found an increase in Th1 cytokines, particularly monocyte chemotactic protein 1 (MCP1), and IL4 in peripheral blood of infants with preeclampsia compared with normotensive control. 23

Discussion
Preeclampsia is one of the common complications of pregnancy, and it is associated with adverse health outcome in infants and mothers.Preeclampsia is associated with immune changes in both mothers and babies.The objective of this study is to collect evidence regarding the effect of preeclampsia on newborn immunity in cord blood and postnatal peripheral blood.We collected 24 articles that were published from 2000 till the time of the search that investigated different aspects of immune cells and cytokines.Most of the studies were focused on immune changes in cord blood cells, with only a few studies looking at immune changes in postnatal peripheral blood.More research is needed to determine whether long-term immunological changes in infants exist and its long-term consequences.
Cytokines are produced by a variety of immune cells, particularly Th1 and Th2.Th1 secretes proinflammatory cytokines such interferon-γ (IFNγ), IL2, and TNF-β, which boost cell-mediated immunity and phagocytic-dependent inflammation.Anti-inflammatory cytokines such as IL4, IL5, IL10, and IL13 are secreted by Th2.In normal pregnancy, both are in balance, with a predisposition for Th2 to tolerate fetal tissue.There is cytokine imbalance in preeclampsia, with a decrease in proinflammatory Th2 and an increase in inflammatory cytokines Th1 and Th17, leading to an increase in apoptosis of trophoblast cells, which impacts placenta invasion and contributes to the development of preeclampsia. 34lthough many studies found no changes in cytokine levels in infants born to preeclampsia mothers, infants with severe preeclampsia with IUGR had significantly higher level of proinflammatory cytokines such IL6, IL8, and TNF-α in cord blood and infant peripheral blood.Researchers also reported a decrease in anti-inflammatory Th2 cytokines such as IL4, CXCL9, and CXC10.Preeclampsia can lead to a cytokine imbalance, which can affect fetal and neonatal outcomes, particularly in preterm infants with IUGR who were born with severe preeclampsia.
Preeclampsia could alter the fetal innate and adaptive immune cells.Monocytes are one of innate immune cells that can be differentiated to macrophages and dendritic cells, which aid in the defense against infection and inflammation. 35Studies revealed an increase on the monocyte markers CD15s, CD11c, and CD54 in the cord blood and CD11b in postnatal peripheral blood samples from infants born preterm from severe preeclampsia pregnancy.They used CD14 and CD49 as markers to identify monocyte. 12,18owever, in other research, there was no difference on monocyte receptors on the cord blood of full-term babies born from mild to severe preeclampsia pregnancy in comparison to normotensive control.They used CD14CD16 to identify monocytes that are more specific than the previous markers. 20Preeclampsia may impact monocytic function in preterm babies with severe preeclampsia, but this effect must be proven in a well-designed study involving both preterm and full-term participants with varying degree of preeclampsia and using most recent markers to identify monocytes.
NK cells are cytotoxic T lymphocytes that play a key role in innate immunity. 36The percentage of NK cells (CD16 þ CD56 þ ) and effector subtype (CD56 low CD16 þ ) was increased in fetal cord blood samples from preeclampsia mothers, and this could be due to preeclampsia and uteroplacental insufficiency, causing long-term perinatal stress. 21,22,24Sohlberg et al reported an increase in NKP30 and a decrease in NKG2D markers on NK cells in fetal cord blood of preeclampsia mothers.However, there was no difference between the two groups when normal CBMCs were incubated in fetal cord blood serum from preeclampsia and control.This suggests that alternations in NK cell markers are inherent rather than induced by cytokine activation in the serum, potentially leading to long-term abnormalities in NK cells in preeclampsia babies. 20Howev-er, further research is needed to test this theory.Dendritic cells are also one of the innate immunity cells.Preeclampsia causes decrease on the level of CD11c þ mDC on the peripheral blood of these infants. 23eutrophils are the most common type of immune cells.Proteases and active oxygen species are released by activated neutrophils, which can induce vascular endothelium injury and influence vascular tone. 37Neonatal neutropenia may raise the risk of sepsis and its associated mortalities, particularly in preterm newborns even after recovery from neutropenia. 38,394][15] There was an increase in surface markers CD11b on neutrophils in peripheral blood samples of preterm infants with RDS born from severe preeclampsia pregnancies. 12Surface integrin CD11b was also increased, besides CD18, CD11a, and CD11c, in cord blood samples from full-term infants with mild and severe preeclampsia. 19Although the number of participants in these studies is low, the results still revealed neutrophil activation in fetomaternal interface and early neonatal life.CD49d/CD29, CD31, and CD15s were also raised in cord blood samples, but there was mismatch across study groups in terms of gestational age and weight, with the preeclampsia group having lower gestation and weight. 18The activation of neutrophils in fetomaternal interface in preeclampsia might be the result of prenatal exposure to chronic stress and inflammation related to preeclampsia.Moreover, the activated neutrophils may trigger a viscous loop of cell activation, which may contribute to a variety of complications in infants born from preeclampsia pregnancies.
Even though different studies have employed distinct markers to identify Treg cells, they have been significantly reduced in cord blood samples of infants with preeclampsia in all included research. 21,25,26This indicates the disruption of Treg cell function because of preeclampsia.In normal pregnancy, Treg cells play a negative regulatory role on various immune cells, enhancing immunological tolerance to paternal-fetal antigens.The number of CD4 Treg cells in cord blood is increased in normal pregnancy in comparison to miscarriage. 40It also plays a protective role against heart fibrosis and coronary arteriole endothelial dysfunction in hypertension in mice. 41T lymphocyte CD4þ level and CD4 þ/ CD8þ ratio were both low in cord and peripheral blood samples from infants with different gestational age and degrees of preeclampsia. 21,23,24Memory cells in newborns are expected to be low because they have few opportunities to be activated; however, CD4 þ CD45ROþ and CD8CD45ROþ cells were found in higher numbers in cord 24 and peripheral blood samples 23 from these infants with preeclampsia, indicating a long-standing immune activation during fetal life as a result of chronic inflammation, hypoxia, and stress caused by preeclampsia.HLA-DRþ is expressed on antigen presenting cells and it is antigenspecific T cell activation.CD4 þ HLA-DRþ and CD8 þ HLA-DRþ were reduced in peripheral blood of infants with severe preeclampsia. 23Preeclampsia is linked to a decrease in Treg cells and an increase in memory cells in fetomaternal interface and even in newborn blood samples in a few studies.
This may help us to understand the effect of preeclampsia on short-and long-term implications of pregnancy.
We were unable to conduct a quantitative analysis on the selected studies due to the large variation in participants and outcomes.Participants were from different gestational age groups, and each study focused on different aspects of immune function.Instead, we present an overview of the impact of preeclampsia on several neonatal immune processes.
Preeclampsia has influenced neonatal immunity in cord blood samples and peripheral blood, but the long-term immunological effects have not been studied yet.Preeclampsia is associated with neutropenia and reduction in other immune cell lines, but with enhancing cytotoxic effect of various immune cells, particularly neutrophils, T cell CD8 þ , and NK cells.Treg cells were also lower in mother blood, cord blood, and neonatal peripheral blood.Preeclampsia contributes to perinatal and neonatal mortalities, as well as morbidities such as IUGR, BPD, NEC, and sepsis.Immune dysfunction may be one of the factors contributing to these disorders.More research is needed to determine the impact of these immunological changes on neonatal outcomes such as sepsis, BPD, and NEC, as well as how long they last.

Fig. 1
Fig. 1 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart of study selection.

Table 1
Basic characteristics of the studies on preeclampsia and normotensive controls

Table 2
Criteria of quality evaluation of selected studies • IL6 was higher in the PE group than in control: 114.57(43.57-712.89),and 23.72 (7.48-422.62),respectively.• IL6 was higher in severe PE than in mild PE: 118.31 (76.81-546.35)and 72.89 (49.75-155.45),respectively • IL6 was higher in PE with IUGR than PE without IUGR: 133.8 (76.81-546.35)and 81.47 (43.57-155.45),respectively • IL8 was higher in the PE group than in normal: 254.58 (140.73-670.7)and 135.02 (135.02-940.69),respectively • IL8 was higher in severe PE than in mild PE: 331.97 (147.96-670.7)and 130.85 (70.67-199.03),respectively • IL8 was higher in PE with IUGR than in PE without IUGR: 353.49(170.58-670.7)and 144.34 (30.85-693.31),respectively • TNF-α was higher in the PE group than in controls: 15.95 (5.66-19.78)and 9.18 (4.06-18.27),respectively Vargas-Rojas et al 25 Lower level of leucocyte, neutrophil, eosinophil, lymphocyte, and monocyte in the PE group than in the control group • Similar level of IL6 and TNF-α in both groups • CRP was higher in the PET group than in control group Kuntz et al 14 • Neutrophil was lower in neonate from PE women than in the control group (3,490 AE 2,993 and 7,534 AE 2,642, respectively, p < 0.02) • Serum sFas showed no difference in both groups in cord blood • Serum sFasl was higher in PE than in controls in cord blood sample, p < 0.01 • Surface expression of Fasl in neutrophil was lower in PET than in controls in cord blood, but there was no difference in expression on lymphocytes • No difference in surface of Fas in both lymphocyte and neutrophil in both groups • Intracellular INF-gamma (Th1) and IL17 (Th17) showed no difference between the groups • Intracellular IL4 (Th4) was significantly decreased in the preeclampsia group in compared with normal (16.25 AE 6.61 and 21.07 AE 6.45, respectively, p ¼ 0.015) • Foxp3 (Treg cells) was significantly decreased in the preeclampsia group in compared with normal (17.48AE 6.76 and 25.93 AE 6.34, respectively, p ¼ 0.0001) Cakir et al 15 • No statistical difference between groups in the level of cytokines • Neutrophil count in the PE group was lower than normotensive control: 2,559/mm 3 (669-5,940) and 3,300 (1,000-8,190), respectively • Number of babies with neutropenia was higher in the PE group than in controls: 6 (18%) and 4 (5%), respectively Darakhashan et al 33 In cord blood the cytokines shown: • CXCL 9 level was lower in the PE group than in normotensive controls (125 AE 14.•The PE group showed babies with neutropenia more than the normotensive group: 13 (23.6%)and 5 (7.8%), respectively, p ¼ 0.032 • Lower level of IL8 in the PE group than in the control group: 26.54 (3.6-87.2) and 157.1 (86.4-261.3),respectively, p < 0.0001 • No statistically significant difference in the GRO-α level in the PE and control groups: 185.5 (63.9-309.7)and 229.5 (116.6-321.3),respectively
sCD40L was higher in the PET group and PET with IUGR group in comparison to control (2.633 AE 1.984, 2.703 AE 1.996, and 1.112 AE 0.436 ng/mL, respectively) for PET and PET with IUGR, p ¼ 0.001 and 0.02, respectively Journal of Child Science Vol. 14 No. 1/2024 © 2024.The Author(s).Immune Changes in Infants of Preeclampsia Mothers Saleh et al. e7 studies were performed in the United States, three in each Turkey and Poland, and two in each Norway and China.The remaining researches were conducted in Finland, Sweden, Hungary, Iran, Mexico, Kuwait, Egypt, Brazil, and Portugal.

Table 3 (
Continued) Ratio between effector NK cell (CD56loCD16 þ ) to regulatory NK cell (CD56hiCd16 þ ) is significant lower in the PET group.•CD4 þ/CD8þ ratio was significant lower in the PET group.• CD4 was significant lower in the PET group (67 AE 5.8 to 73 AE 4.34) and CD8 was nonsignificantly higher in the PET group (24.28 AE 8.1% to 73 AE 4.34%) • Treg cells (CD4 þ FOXP3 þ ) was significant lower in the PET group.CD16þ monocytes were higher in PE, but Cd11b expression was lower • Intracellular expression of IFNγ and TNF in NK cells was higher in PE group.• Stimulation of intracellular cytokines production from CD3-CD56þ NK cells and CD14þ monocyte was not affected by preeclampsia Bujold et al 22 • The PE group had higher level of NK cells (CD3-Cd56 þ 16 þ ) than control (17.9 AE 9% and 12 AE 6.2%, respectively) • Preterm PE had higher level of NK cells than preterm control (16.3 AE 9.4% and 12.1 AE 6.2%, respectively) • Full-term PE had a higher level of NK cells than full-term control (20 AE 7% and 11.9 AE 7.2%, respectively) Saini et al 19 • Higher expression of CD18 in the PE group than in controls (432 AE 236.3 and 230 AE 97.9, respectively) • Higher expression of CD11a in the PE group than in controls (552 AE 272.4 and 326.9 AE 268.6, respectively) • Higher expression of CD18 in the PE group than in controls (937.2AE 521.9 and 576.6 AE 352.9, respectively) • Higher expression of CD18 in the PE group than in controls (228.5 AE 130.3 and 133 AE 77.1, respectively) Abbreviations: IL, interleukin; INF, interferon; IUGR, intrauterine growth retardation; PE, preeclampsia; Th, T helper; TNF, tumour necrotic factor.