Tomi T. Kanninen

Oxidative stress in pathological pregnancies

Oxidative stress (OS) plays a role in pregnancy at risk of pre-eclampsia, diabetes and premature labour. We measured three markers of OS: total antioxidant capacity (TAC), thiolyte capacity and pro-oxidant capacity in 45 women: 15 normal pregnancies, 17 pathological pregnancies (pre-eclampsia and pregestational diabetes) and 13 delivered pre-term. Plasma TAC (μmol/ml) values in patients with pathological pregnancies (235.67 ± 70.08) (p1 = 0.0086) and pre-term labour (243.51 ± 50.52) (p2 = 0.0479) were significantly reduced as compared with the controls (306.78 ± 70.08). Thiolyte capacity (μmol/ml) in the pathological pregnancies (326.03 ± 78.24) (p3 = 0.0029) and in pre-term labour (335.94 ± 76.63) (p4 = 0.0084) groups were significantly reduced compared with the control group (417.48 ± 39.76) (p < 0.05). Pro-oxidant capacity (mg/100 ml) in the pathological pregnancies (94.11 ± 26.13) (p5 = 0.00034) and in pre-term labour (87.18 ± 20.28) (p6 = 0.00044) groups were significantly higher compared with the controls (60.27 ± 6.33). Elevated OS values were seen in pathological pregnancies. This supports the important role of OS in diseases in pregnancy, particularly pre-eclampsia, diabetes and pre-term birth.

The role of autophagy in reproduction from gametogenesis to parturition.

Autophagy is an intracellular process responsible for maintaining cellular homeostasis by the removal of cytoplasmic organelles, intracellular bacteria and viruses, and is a critical component of both the innate and acquired immune systems. A failure in physiological activation, assembly and function of the autophagic pathway has been implicated in a broad range of diseases including neurogenerative diseases, cardiopathy, infectious diseases, autoimmunity and cancer. Its involvement in reproduction, however, has not been extensively studied. Its activity is fundamental to many processes across the reproduction spectrum from development of the primordial follicle and spermatozoa to embryogenesis, placental development and maintaining uterine quiescence during pregnancy. Malfunctions in autophagy are associated with deleterious repercussions throughout reproduction. In this review we examine what is known about the involvement of autophagy in gamete formation, early post-fertilization embryogenesis, placental development and parturition, and propose promising areas for future research.

Altered autophagy induction by sera from pregnant women with pre-eclampsia: a case–control study

Mechanisms leading to pre‐eclampsia remain incompletely defined. Autophagy is a conserved process necessary for cell survival under adverse conditions. We hypothesised that sera from women with healthy pregnancies and women with pre‐eclampsia differed in autophagy induction.

HCV vertical transmission in pregnancy: New horizons in the era of DAAs

R outine prenatal hepatitis C virus (HCV) screening is not recommended in women lacking risk factors for infection. This is partially because of the absence of options in the management of maternal to neonatal transmission and the perceived low prevalence of HCV in pregnancy. Vertical transmission rates of HCV have been reported to be as high as 8%. Reducing maternal viremia may be beneficial given its role as a requirement for vertical transmission. Recent advances in HCV infection combination therapy have made high rates of sustained virological response and HCV-RNA clearance in nonpregnant adults achievable. Currently, there are no therapies to prevent HCV vertical transmission. However, certain direct-acting antiviral agents (DAAs) may have substantially more favorable profiles in pregnancy in comparison to past medications. Given that maternal viremia has been linked to vertical neonatal transmission, the use of DAAs may considerably lower HCV vertical transmission in pregnancy and warrant future studies. The prevalence of HCV infection in pregnancy has been estimated to be similar to the reported 0.5%-1.4% seropositivity in low-risk blood donors. Presently, routine prenatal HCV screening is not recommended by the American College of Obstetricians and Gynecologists and Centers for Disease Control and Prevention, except for women with significant risk factors for infection. This policy is the result of a lack of any available preor postnatal pharmacological, immunological, or interventional measures to decrease the risk of vertical transmission. HCV vertical transmission rates have been reported between 2% and 10% and HCV chronically infects an estimated 25,000-50,000 children with 750 new cases a year acquired through vertical transmission. Furthermore, though high rates of spontaneous resolution have been reported for children acquiring HCV infection at birth, many still become chronically infected. Current long-term outcome data on these chronically infected children is significantly limited given that HCV disease morbidity in general takes longer than two decades to develop. Clinicians frequently delay treatment for HCV until after pregnancy given limited experience with the use of interferon (IFN) in pregnancy and the absolute contraindication for ribavirin (RBV) use. Recent developments in HCV infection combination therapy have made persistent normalization of transaminase levels and HCV-RNA clearance in nonpregnant adults possible. Given that maternal viremia has been linked to vertical neonatal transmission, the use of DAAs for prevention of HCV transmission alone or in association with IFN warrants more-intense future study.

Microorganisms in the Female Genital Tract during Pregnancy: Tolerance versus Pathogenesis

Microorganisms in the pregnant female genital tract are not always associated with pathology. The factors that influence the maternal response to microorganisms remain ill defined. We review the state of knowledge of microbe–host interactions in gestational tissues and highlight mechanisms that promote tolerance or pathogenesis. Tolerance to microorganisms is promoted during pregnancy by several mechanisms including upregulation of anti‐inflammatory mediators, induction of endotoxin tolerance, and possibly by regulation of autophagy. Conversely, an altered vaginal microbiota or a pre‐existing viral presence may result in induction of excessive inflammation and preterm labor. Although infections play a prevalent role in preterm birth, microbes are present in gestational tissues of women with healthy outcomes and may provide beneficial functions. The complex interactions between different microbial species and the maternal immune system during gestation remain incompletely elucidated.

Interaction between the inducible 70-kDa heat shock protein and autophagy: effects on fertility and pregnancy

A consequence of hsp70 (HSPA1A) induction is the inhibition of autophagy. Evidence of autophagy involvement in all aspects of the reproductive process is reviewed, and possible consequences of hsp70 induction at each developmental stage are postulated. It is proposed that aberrant external or internal stimuli that result in high levels of hsp70 production interfere with normal autophagy-related functions and lead to a decrease in the number of functional ova and spermatozoa, impaired pre- and post-implantation embryo development, and increased susceptibility to premature labor and delivery. The purpose of this review is to increase understanding of hsp70-autophagy interactions during reproduction. Interventions to modulate this interaction will lead to development of novel protocols to improve fertility and pregnancy outcome.

Potential effects of chocolate on human pregnancy: a randomized controlled trial

Objective: This trial was undertaken to evaluate the effects of high-cocoa-content chocolate supplementation in pregnancy on several haematochemical and clinical parameters. The study had as reference population the pregnant women requesting an obstetric control at Outpatient Clinic of Obstetrics and Gynaecology of the S. Maria della Misericordia University Hospital, Perugia, Italy. Candidates who participated in this study were all Caucasian women aged 18–40 years, who had a single gestation pregnancy between 11th + 0 and 13th + 0 week gestational age. Methods: We conducted a single-center randomized controlled trial. The pregnant women selected were randomized into Group A, which received daily doses of 30 g of chocolate (70% cocoa), and Group B, which was free to increase their diet with other foods. Results: Ninety women were randomized. Significant difference was found between the two groups for diastolic blood pressure (p = 0.05), systolic (p < 0.0001) and levels of liver enzymes, with values lower in Group A than in Group B. Total cholesterol levels and weight gain in Group A did not increase more than in Group B. Conclusions: A modest daily intake of high-cocoa-content chocolate contributes to reduce blood pressure, glycemic and liver pattern during pregnancy without affecting the weight gain.

Unique variation in genetic selection among Black North American women and its potential influence on pregnancy outcome.

We hypothesize that variations in the frequency of genetic polymorphisms, reflecting ancestral differences in living conditions and exposure to microorganisms, increase susceptibility to adverse pregnancy outcome among present day Black North American women. Striking differences were observed in the frequency of genetic variants between Black and White or Hispanic women in 5 genes (IL1RN, MBL2, PPARA, ATG16L1, CIAS1) associated with inflammation and anti-microbial immunity. The CIAS1 and IL1RN polymorphisms were associated with altered interleukin-1β serum levels; the MBL2 polymorphism resulted in a decreased serum mannose-binding lectin concentration. Gene polymorphisms associated with an alteration in innate immunity were most frequent in Black women. This may reflect an evolutionary selection in response to an ancient environment containing a high multitude of microorganisms, and may increase susceptibility of Black women to infection-associated preterm birth in the current North American environment.

Inhibition of Autophagy by Sera From Pregnant Women

Autophagy is a process that maintains homeostasis by eliminating senescent or damaged intracellular organelles and proteins. Its role in pregnancy has been scarcely studied. We compared the influence of sera from pregnant and nonpregnant women on autophagy induction. Peripheral blood mononuclear cells (PBMCs) were incubated with sera from 35 pregnant or nonpregnant women in the presence or absence of the autophagy inducer, rapamycin. After 48 hours, the cells were assayed for p62, a cytoplasmic protein essential for autophagy induction. Its concentration in the cytoplasm is inversely proportional to the level of autophagy induction. Sera were tested for immune mediators by enzyme-linked immunosorbent assay. Median (range) p62 concentrations were 6.7 ng/mL (1.1-22.7) for PBMCs incubated with pregnancy sera versus 2.5 ng/mL (0.8-7.7) for nonpregnant sera (P < .0001). In the presence of rapamycin, median p62 levels were 1.3 ng/mL (<0.1-4.9) with pregnancy sera, when compared to 0.6 ng/mL (<0.1-3.3) with control sera (P = .0191). Among the pregnant patients, the p62 level was inversely proportional to the results of a 50-g glucose challenge test (r = −.5630, P = .0005). Sera from pregnant women had elevated levels of insulin-like growth factor 1 (IGF-1), interleukin 13 (IL-13), and transforming growth factor β1 (TGF-β1). Autophagy during pregnancy may be inhibited by IGF-1, IL-13, and/or TGF-β1 and may influence insulin resistance.

Induction of the 70 kDa heat shock protein stress response inhibits autophagy: possible consequences for pregnancy outcome

Abstract Aim: The induction of heat shock protein synthesis and activation of autophagy are intracellular processes stimulated under adverse conditions. We evaluated the relationship between intracellular concentrations of the inducible 70 kDa heat shock protein (hsp70) and autophagy induction in human peripheral blood mononuclear cells (PBMCs) following exposure to sera from pregnant and non-pregnant women. Methods: Autophagy was induced in PBMCs by incubation for 48 h with sera from 42 pregnant women at mid-gestation and 45 non-pregnant women. Intracellular concentrations of hsp70 and p62 were measured by ELISA. p62 is a cytoplasmic protein that is consumed during autophagy induction. Its concentration in the cytoplasm is inversely proportional to the extent of autophagy induction (high p62 = low autophagy). Results: The p62 concentration was highly correlated with the hsp70 level utilizing sera from both pregnant (Spearman r = 0.4731, p = 0.0015) and non-pregnant (Spearman r = 0.6214, p < 0.0001) women. Median p62 (7.4 ng/ml versus 2.7 ng/ml, p < 0.0001) and hsp70 (7.0 ng/ml versus 3.5 ng/ml, p = 0.0022) levels were higher when PBMCS were incubated with sera from pregnant women. Conclusion: The extent of autophagy in PBMCs is inversely proportional to the intracellular hsp70 concentration and sera from pregnant women induces hsp70 and inhibits autophagy to a greater extent than does sera from non-pregnant women. A stress response that induces hsp70 has the potential to interfere with autophagy-related events.