Perinatal Outcomes in Early and Late Gestational Diabetes Mellitus After Treatment From 24-28 Weeks' Gestation: A TOBOGM Secondary Analysis.

OBJECTIVE: In most gestational diabetes mellitus (GDM) studies, cohorts have included women combined into study populations without regard to whether hyperglycemia was present earlier in pregnancy. In this study we sought to compare perinatal outcomes between groups: women with early GDM (EGDM group: diagnosis before 20 weeks but no treatment until 24-28 weeks if GDM still present), with late GDM (LGDM group: present only at 24-28 weeks), and with normoglycemia at 24-28 weeks (control subjects). RESEARCH DESIGN AND METHODS: This is a secondary analysis of a randomized controlled treatment trial where we studied, among women with risk factors, early (<20 weeks' gestation) GDM defined according to World Health Organization 2013 criteria. Those receiving early treatment for GDM treatment were excluded. GDM was treated if present at 24-28 weeks. The primary outcome was a composite of birth before 37 weeks' gestation, birth weight ≥4,500 g, birth trauma, neonatal respiratory distress, phototherapy, stillbirth/neonatal death, and shoulder dystocia. Comparisons included adjustment for age, ethnicity, BMI, site, smoking, primigravity, and education. RESULTS: Women with EGDM (n = 254) and LGDM (n = 467) had shorter pregnancy duration than control subjects (n = 2,339). BMI was lowest with LGDM. The composite was increased with EGDM (odds ratio [OR] 1.59, 95% CI 1.18-2.12)) but not LGDM (OR 1.19, 95% CI 0.94-1.50). Induction of labor was higher in both GDM groups. In comparisons with control subjects there were higher birth centile, higher preterm birth rate, and higher rate of neonatal jaundice for the EGDM group (but not the LGDM group). The greatest need for insulin and/or metformin was with EGDM. CONCLUSIONS: Adverse perinatal outcomes were increased with EGDM despite treatment from 24-28 weeks' gestation, suggesting the need to initiate treatment early, and more aggressively, to reduce the effects of exposure to the more severe maternal hyperglycemia from early pregnancy.

Effect of asthma management with exhaled nitric oxide versus usual care on perinatal outcomes.

INTRODUCTION: Asthma exacerbations in pregnancy are associated with adverse perinatal outcomes. We aimed to determine whether fractional exhaled nitric oxide (F ENO)-based asthma management improves perinatal outcomes compared to usual care. METHODS: The Breathing for Life Trial was a multicentre, parallel-group, randomised controlled trial conducted in six hospital antenatal clinics, which compared asthma management guided by F ENO (adjustment of asthma treatment according to exhaled nitric oxide and symptoms each 6-12 weeks) to usual care (no treatment adjustment as part of the trial). The primary outcome was a composite of adverse perinatal events (preterm birth, small for gestational age (SGA), perinatal mortality or neonatal hospitalisation) assessed using hospital records. Secondary outcomes included maternal asthma exacerbations. Concealed random allocation, stratified by study site and self-reported smoking status was used, with blinded outcome assessment and statistical analysis (intention to treat). RESULTS: Pregnant women with current asthma were recruited; 599 to the control group (608 infants) and 601 to the intervention (615 infants). There were no significant group differences for the primary composite perinatal outcome (152 (25.6%) out of 594 control, 177 (29.4%) out of 603 intervention; OR 1.21, 95% CI 0.94-1.56; p=0.15), preterm birth (OR 1.14, 95% CI 0.78-1.68), SGA (OR 1.06, 95% CI 0.78-1.68), perinatal mortality (OR 3.62, 95% CI 0.80-16.5), neonatal hospitalisation (OR 1.24, 95% CI 0.89-1.72) or maternal asthma exacerbations requiring hospital admission or emergency department presentation (OR 1.19, 95% CI 0.69-2.05). CONCLUSION: F ENO-guided asthma pharmacotherapy delivered by a nurse or midwife in the antenatal clinic setting did not improve perinatal outcomes.

Factors Associated with Nonadherence to Inhaled Corticosteroids for Asthma During Pregnancy.

BACKGROUND: Nonadherence is common among pregnant women prescribed inhaled corticosteroids (ICS) for asthma and may have serious consequences for mother and baby. Factors associated with ICS nonadherence have not been determined in this population. OBJECTIVES: To determine factors associated with {1} nonadherence to ICS in early-mid pregnancy (cross-sectional) and {2} persistent nonadherence to ICS during pregnancy (longitudinal). METHODS: Data used come from 3 prospective studies (2004-2019) involving women with asthma recruited by 23 weeks' gestation (N = 1614). Demographics, asthma history, and current symptoms were assessed, and spirometry was performed at baseline and throughout pregnancy. Women self-reported current medication use and number of ICS doses missed in the past week. Nonadherence was defined as ≥20% of prescribed dosages missed in the past week (baseline) and on at least 2 occasions during follow-up (persistent). Factors associated with ICS nonadherence were examined using backward stepwise logistic regression. RESULTS: Of 610 (38%) women prescribed ICS at baseline, 236 (39%) were classified as nonadherent. Of 612 (38%) women prescribed ICS during at least 2 follow-up visits, 149 (24%) were classified as persistent nonadherent. Factors associated with nonadherence at baseline were current or ex-smoking, non-Caucasian/non-Indigenous ethnicity, adult diagnosis of asthma, and lower lung function. Factors associated with persistent nonadherence to ICS were lower maternal age, higher parity, and no prescribed ICS at baseline. CONCLUSION: Young multiparous non-Caucasian/non-Indigenous mothers are at increased risk of being nonadherent to ICS during pregnancy. Strategies to improve ICS nonadherence should address maternal smoking and target women who (re-)initiate ICS use in pregnancy.

The Association of Falling Insulin Requirements With Maternal Biomarkers and Placental Dysfunction: A Prospective Study of Women With Preexisting Diabetes in Pregnancy.

OBJECTIVE: To investigate the association of falling insulin requirements (FIR) among women with preexisting diabetes with adverse obstetric outcomes and maternal biomarkers longitudinally in pregnancy. RESEARCH DESIGN AND METHODS: A multicenter prospective cohort study of 158 women (41 with type 1 diabetes and 117 with type 2 diabetes) was conducted. Women with FIR of ≥15% from the peak total daily dose after 20 weeks' gestation were considered case subjects (n = 32). The primary outcome was a composite of clinical markers of placental dysfunction (preeclampsia, small for gestational age [≤5th centile], stillbirth, premature delivery [<30 weeks], and placental abruption). Maternal circulating angiogenic markers (placental growth factor [PlGF] and soluble fms-like tyrosine kinase 1 [sFlt-1]), placental hormones (human placental lactogen, progesterone, and tumor necrosis factor-α), HbA1c, and creatinine were studied serially during pregnancy. RESULTS: FIR ≥15% were associated with an increased risk of the composite primary outcome (odds ratio [OR] 4.38 [95% CI 1.9-10.3]; P < 0.001), preeclampsia (OR 6.76 [95% CI 2.7-16.7]; P < 0.001), and was more common among women with type 1 diabetes (36.6 vs. 14.5%; P = 0.002). Creatinine was modestly elevated among women with FIR ≥15%; however, there was no difference in HbA1c. The ratio of sFlt-1 to PlGF was significantly higher among women with FIR at 25, 30, and 36 weeks, with differences maintained in the subgroup that developed preeclampsia. There was no difference in placental hormones between the groups. CONCLUSIONS: This is the first prospective study to associate FIR with altered expression of placental antiangiogenic factors and preeclampsia. FIR are an important clinical sign, among women with preexisting diabetes, that should alert the clinician to investigate underlying placental dysfunction.

Altered Fetal Head Growth in Preeclampsia: A Retrospective Cohort Proof-Of-Concept Study.

BACKGROUND: Preeclampsia is associated with fetal growth restriction and low birth weights. Neurotrophins, which mediate neuronal growth and development, are also increased in the placenta and cord blood in preeclampsia. Hence, the aim of this study was to determine whether fetal head growth is altered in preeclampsia, adjusting for growth restriction and other confounding variables. METHODS: This research included a retrospective cohort study, looking at fetal head circumference at birth, plus a case-control study examining fetal head circumference at mid-gestation. The head circumference at birth analysis consisted of 14,607 pregnancies (preeclampsia = 382, control = 14,225), delivered between July 2006 and June 2012 at Nepean Hospital, Australia. Head circumference at birth, in addition to other maternal and fetal variables, was sourced from the Nepean Obstetric Database. The head circumference at mid-gestation study consisted of 756 pregnancies (preeclampsia = 248, control = 508), delivered within the same data collection period at Nepean Hospital. Head circumference at mid-gestation was retrieved from an earlier ultrasound scan. Exclusion criteria included >1 fetus, illegal drug use, alcohol consumption, and chronic or gestational hypertension. Generalized linear models were used to analyze fetal head circumference in preeclampsia versus controls, adjusting for confounding variables. RESULTS: Head circumference increased at a greater rate in preeclampsia versus controls, adjusted for gestation, fetal gender, birth weight and length, smoking, maternal BMI, and growth restriction. At mid-gestation, there was no difference in head circumference between preeclampsia and controls. CONCLUSION: For the first time, this research has suggested increased fetal head growth in preeclampsia, adjusted for confounders. This finding may be explained by altered fetal exposure to neurotrophins in preeclampsia. The long-term neurodevelopmental consequences of preeclampsia remain unclear.

Expansion of CD4(+) HLA-G(+) T Cell in human pregnancy is impaired in pre-eclampsia.

PROBLEM: The role of CD4(+) HLA-G(+) T cells in healthy pregnancy and pre-eclampsia is unclear. METHOD OF STUDY: CD4(+) HLA-G(+) T cells were analysed from peripheral blood and decidual samples from healthy pregnant and pre-eclamptic women. In vitro T-cell induction, trogocytosis and suppression assays were performed. RESULTS: In peripheral blood, CD4(+) HLA-G(+) T cells were significantly higher in pregnant women (mean ± S.E.M.: 7.98 ± 1.10%), compared with non-pregnant controls (mean ± S.E.M.: 1.78 ± 0.30%) and pre-eclamptic women (mean ± S.E.M.: 3.69 ± 0.51%). The presence of CD4(+) HLA-G(+) T cells is even more prominent in the decidua, suggestive of local induction and accumulation. Decidual CD14(+) DC-SIGN(+) antigen-presenting cells (APCs) enhance the HLA-G expression of cocultured CD4(+) naïve T cells in vitro. IL-10 augments expression of HLA-G, ILT4 and DC-SIGN in monocyte-derived DCs (MoDCs), endowing them with a phenotype analogous to decidual CD14(+) DC-SIGN(+) APCs of healthy pregnancy. Furthermore, naïve T cells acquire HLA-G from these IL-10-treated MoDCs via the process of trogocytosis. CONCLUSIONS: Our data indicate that in addition to Foxp3(+) Treg cells, CD4(+) T cells acquire HLA-G from decidual DCs and may play an important role in immune tolerance induction in pregnancy, a process which is impaired in pre-eclampsia.

Fetal-maternal alignment of regulatory T cells correlates with IL-10 and Bcl-2 upregulation in pregnancy.

Transplacental immune regulation refers to the concept that during pregnancy, significant cross-talk occurs between the maternal and fetal immune system with potential long-term effects for both the mother and child. In this study, we made the surprising observation that there is a strong correlation of peripheral blood regulatory T (Treg) cells between the mother and the fetus. In contrast, there is no significant Treg cell correlation between paternal fetal dyads (pairs), suggesting that the specific context of pregnancy, rather than the genetic parental similarity to the fetus, is responsible for this correlation. Gene microarray analysis of Treg cells identified a typical IL-10-dependent signature in maternal and fetal Treg cells. In addition, a direct correlation of serum IL-10 protein levels between maternal fetal dyads was observed. Furthermore, we show that maternal serum IL-10 levels correlate with serum estradiol and estriol, implicating hormonal involvement in this alignment. Interestingly, we show that Treg cells possess higher expression of IL-10 receptor α and that Treg cell IL-10 receptor α expression directly correlates with their Bcl-2 expression. Indeed, in vitro data in both humans and mice demonstrate that IL-10 upregulates Bcl-2 specifically in Treg cells but not non-Treg cells. Our results provide evidence for transplacental regulation of cellular immunity and suggest that IL-10 may influence Treg cell homeostasis through its effect on Treg cell Bcl-2 expression. These novel findings have important implications on immune tolerance in pregnancy and beyond in areas of autoimmunity, allergy, and transplantation.

Impaired fetal thymic growth precedes clinical preeclampsia: a case-control study.

In preeclampsia the maternal adaptive immune system undergoes specific changes, which are different from the physiological processes associated with healthy pregnancy. Whether preeclampsia also affects the fetal immune system is difficult to investigate, due to limited access to the fetus. We hypothesized that if preeclampsia affects the fetal adaptive immune system this might be associated with early changes in thymic growth. In this case-control study, 53 preeclamptic and 120 healthy control pregnancies were matched for maternal age, gestational age and smoking. Fetal thymus diameter was measured as the greatest width perpendicular to a line connecting sternum and spine based on ultrasound images taken at 17-21 weeks gestation. Independent of fetal and maternal anthropometric measures, thymuses were found to be smaller in preeclamptic pregnancies than healthy controls (16.2 mm versus 18.3 mm, respectively, mean difference=2.1 mm, 95% CI: 0.8-3.3, p<0.001), and the odds of developing preeclampsia was estimated to be 0.72 (95% CI: 0.60-0.86, p<0.001) lower for each 1 mm increase in thymus diameter. There was no correlation between the onset of preeclampsia and fetal thymus size. This is the first study to suggest that fetal thymus growth is reduced before the clinical onset of preeclampsia and precedes any described fetal anomalies or maternal immunological changes associated with preeclampsia. We propose that the fetal adaptive immune system is either passively affected by maternal processes preceding clinical preeclampsia or is actively involved in initiating preeclampsia in later pregnancy.

Therapeutic potential of stem cells in perinatal medicine.

Increasing evidence suggests that stem cells have tremendous potential to facilitate repair of damaged tissue and to exert protective influences that limit the extent of damage. Their inherent capacity to respond to signals generated by damaged tissue, migrate to these regions and either replace dead tissue or deliver protection by secretion of specific growth hormones and protective factors, suggests that they might have unrivalled therapeutic potential in perinatal medicine. A further potential of stem cells is their use in gene repair strategies for genetic disorders; an application which is exceedingly interesting from a perinatal perspective. Because of the relatively small size of infants and their capacity for future growth, stem cell therapy could be more successful in newborns than in older children or adults. In practical terms, the placenta, with its large reservoir of fetal blood, offers the ideal source of autologous stem cells. This affords the opportunity for stem cells to be collected and used, either directly ex vivo or after in vitro modulation, both for disorders in the neonatal period and for those arising later in life. The organs most affected from tissue damage in the neonatal period are the brain and the lung. So far, the most promising application of stem cells might be in the treatment of neurological injury. In this review we discuss recent research findings with adult stem cell therapy and their potential use in perinatal medicine. Furthermore, specific animal models suitable to explore the patho-physiological mechanisms of stem cell transplantation after neurological injury will be discussed. This review gives an overview of basic science findings and their possible role for clinical application with regards to the therapeutic potential of stem cells in perinatal medicine. Medline was searched for journal selection in peer-reviewed journals with high impact scores, which were relevant to this topic. All articles were in English and the search was not limited by publication year. However, the oldest publication was dated 1988 (reference 1).