OBJECTIVE Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model. STUDY DESIGN A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace. RESULTS Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an “inflammatory pulse” that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth. CONCLUSION Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.

The uterus is subject to stretch throughout pregnancy, which, in the presence of progesterone, is a potent stimulus for uterine growth. However, in the absence of progesterone or when stretch is excessive, as in multiple pregnancy, it may provoke the onset of labour. We have investigated the effect of stretch on prostaglandin synthesis in primary human uterine myocytes [non-pregnant (NP), pregnant not in labour (NL) and pregnant in labour (L)]. The cells were grown on flexible bottom culture plates and subjected to 1 or 6 h static stretch. Expression of type 2 cyclooxygenase (COX-2) mRNA was similar in samples obtained from NP and L groups and both were significantly greater than those found in the NL group. Stretch of cells from all groups resulted in increased COX-2 mRNA expression. In further studies carried out on cells taken from the NL group, 6 h of stretch resulted in increased COX-2 protein levels and, in the media, increases in prostaglandin (PG) I(2) metabolite and PGE(2) concentrations and a reduction in the concentration of PGF(2)alpha metabolites. After stretch, EMSA studies showed increased activator protein-1 (AP-1) nuclear protein DNA binding activity but not of nuclear factor kappaB. These data demonstrate that stretch of human myocytes results in increased COX-2 activity and suggest that this may occur through activation of the AP-1 system.

Stretch of the uterus plays a role in parturition. Uterine stretch also leads to stretch of the fetal membranes, including the amnion, an important source of prostaglandin E2 (PGE2). We tested the hypothesis that stretch of the amnion leads to increased cyclooxygenase (COX)-2 expression and PGE2 synthesis and investigated the mechanisms involved. We obtained amnion from women undergoing term elective cesarean section and isolated amnion epithelial cells. These cells were subjected to 11% static stretch. Stretch increased COX-2 expression and PGE2 production. EMSA studies showed that stretch increased both activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) DNA binding at 1 and 6 h. In contrast, IL-1beta increased both AP-1 and NF-kappaB DNA binding at 1 h only. Chromatin immunoprecipitation studies confirmed that stretch increased binding of NF-kappaB to the COX-2 promoter in vivo. Stretch had no effect on inhibitory-kappaBalpha (IkappaBalpha) levels at the early time points but caused a decrease at 4 h. IL-1beta stimulation decreased IkappaBalpha levels after 30 min. MG132, a proteasome inhibitor, inhibited only the second stretch-induced increase in NF-kappaB binding. This suggests that stretch initially activates NF-kappaB via a nonclassical pathway, which does not involve the inhibitory-kappa kinase-induced degradation of IkappaBalpha. The second peak of NF-kappaB activation may be mediated by the classical mechanism. Stretch of the amnion may contribute to increased expression of COX-2- and other AP-1- and NF-kappaB-regulated genes with the onset of labor in the human.

ObjectivesInformation to guide counselling and management for pregnancy in women with Marfan syndrome (MFS) is limited. We therefore conducted a UK multicentre study.MethodsRetrospective observational study of women with MFS delivering between January 1998 and March 2018 in 12 UK centres reporting data on maternal and neonatal outcomes.ResultsIn total, there were 258 pregnancies in 151 women with MFS (19 women had prior aortic root replacements), including 226 pregnancies ≥24 weeks (two sets of twins), 20 miscarriages and 12 pregnancy terminations. Excluding miscarriages and terminations, there were 221 live births in 139 women. Only 50% of women received preconception counselling. There were no deaths, but five women experienced aortic dissection (1.9%; one type A and four type B—one had a type B dissection at 12 weeks and subsequent termination of pregnancy). Five women required cardiac surgery postpartum. No predictors for aortic dissection could be identified. The babies of the 131 (65.8%) women taking beta-blockers were on average 316 g lighter (p<0.001). Caesarean section rates were high (50%), particularly in women with dilated aortic roots. In 55 women, echocardiographic aortic imaging was available prepregnancy and postpregnancy; there was a small but significant average increase in AoR size of 0.84 mm (Median follow-up 2.3 months)ConclusionThere were no maternal deaths, and the aortic dissection rate was 1.9% (mainly type B). There with no identifiable factors associated with aortic dissection in our cohort. Preconception counselling rates were low and need improvement. Aortic size measurements increased marginally following pregnancy.

Inflammatory bowel disease (IBD) poses complex issues in pregnancy, but with high-quality care excellent pregnancy outcomes are achievable. In this article, we review the current evidence and recommendations for pregnant women with IBD and aim to provide guidance for clinicians involved in their care. Many women with IBD have poor knowledge about pregnancy-related issues and a substantial minority remains voluntarily childless. Active IBD is associated with an increased risk of preterm birth, low for gestation weight and fetal loss. With the exception of methotrexate and tofacitinib the risk of a flare outweighs the risk of IBD medication and maintenance of remission from IBD should be the main of care. Most women with IBD will experience a normal pregnancy and can have a vaginal delivery. Active perianal Crohn’s disease is an absolute and ileal pouch surgery a relative indication for a caesarean section. Breast feeding is beneficial to the infant and the risk from most IBD medications is negligible.

BackgroundPregnant women with inflammatory bowel disease (IBD) are at increased risk of adverse pregnancy outcomes. Comprehensive guidelines on medical management have been published; yet, there is limited guidance on service set-up and minimum standards of care for pregnant women with IBD.AimTo develop a position statement on service set-up and minimum standards of care in the UK.MethodsA working group consisting of 16 gastroenterologists, obstetricians, obstetric physician, IBD specialist nurses and midwives was assembled. Initial draft statements were produced and a modified Delphi process with two rounds of voting applied. Statements were modified according to voters’ feedback after each round. Statements with ≥80% agreement were accepted.ResultsAll 15 statements met criteria for inclusion. To facilitate optimal care, regular and effective communication between IBD and obstetric teams is required. There should be nominated link clinicians for IBD in obstetric units and for pregnancy in IBD units. Preconception counselling should be available for all women with IBD. All pregnant women should be advised on the safety of IBD medication during pregnancy and breast feeding, the optimal mode of delivery, the management of biologics (where applicable) and safety of childhood vaccinations. Regular audit of pregnancy outcomes and documentation of advice given is recommended.ConclusionPosition statements have been developed that advise on the importance of joined-up multidisciplinary care, proactive decision-making with clear documentation and communication to the woman and other healthcare practitioners.

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Premature activation of the inflammatory processes that mediate human parturition leads to preterm birth, a major clinical problem associated with neonatal morbidity and mortality. Histone deacetylase inhibitors (HDACi) are currently in clinical trials for the treatment of inflammatory disorders. Recent evidence suggests that there may be a therapeutic use for HDACi in the management of preterm birth, with administration of HDACi to pregnant mice shown to delay delivery. Because NF-B is a key orchestrator of the inflammatory response and plays a pivotal role in parturition, it is important to understand how administration of HDACi might affect NF-B activity in human uterine tissues. We show here that the effects of HDACi on nuclear factor-B (NF-B) in human myometrial cells are time-dependent. Short-term exposure to HDACi enhanced interleukin (IL)-1␤-induced NF-B activity as a result of potentiating IB kinase (IKK)␤ activity, thereby leading to persistent turnover of IB␣/ proteins and prolonging NF-B phosphorylation, nuclear localization, and DNA binding. Conversely, longterm HDACi treatments resulted in repression of NF-B DNA binding. Nevertheless, both short-and long-term HDACi treatments inhibited the expression of four labor-associated proinflammatory genes (COX-2, IL-8, IL-6, and RANTES), and this was associated with repression of the proinflammatory transcription factor c-Jun. Together, our data indicate that HDACi exert anti-inflammatory effects in human myometrium and may thus be useful in achieving a myometrial gene expression profile that favors uterine quiescence. However, coadministration of an IKK␤ inhibitor may be both necessary and sufficient to circumvent potential induction of labor-associated pathways that could result from HDACi-induced augmentation of NF-B activity.During parturition, myometrium undergoes a transition from a state of quiescence to one of contractility, resulting in delivery of the neonate. Although the molecular mechanisms that underpin this transition are poorly understood, it is widely accepted that parturition is an inflammatory process, involving the up-regulation of multiple proinflammatory genes (Romero et al., 2006). Premature activation of uterine proinflammatory pathways can lead to preterm birth, a major clinical problem that occurs in 5 to 10% of pregnancies and is associated with 70 to 75% of neonatal morbidity/ mortality (Wen et al., 2004).Histone acetylation plays a major role in gene transcription, enabling the partial unraveling of local chromatin structure that is required to make the DNA accessible for binding by transcription factors and the basal transcription machinery (Li et al., 2004). Acetylation is reversible and reflects a dynamic balance between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Aberrant recruitment of HDACs to promoters and/or overexpression of HDACs are observed in cancer cells, and This work was supported by Tommy's Campaign. Article, publication date, and citation information can be foun...