Preterm birth prevention—Time to PROGRESS beyond progesterone

Norman, Jane E.; Bennett, Phillip R.

doi:10.1371/journal.pmed.1002391

Cited by 18 publications

(16 citation statements)

References 11 publications

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“…Primary prevention strategies (e.g., diet and exercise; nutritional supplements; nutritional education; screening for lower genital tract infections) and secondary prevention interventions (e.g., low dose aspirin and L-arginine for pre-eclampsia; treatment of bacterial vaginosis and candidiasis or periodontal disease; progesterone or cervical pessary for short cervix) have shown some efficacy with selected samples in controlled clinical trials [25]. However, population level reduction in preterm birth rates have not been achieved with widespread implementation of these interventions and there has been growing realization that clinical interventions focused on individuals alone are ineffective in addressing the ongoing preterm birth epidemic [26,27]. Moreover, the US preterm birth rate far exceeds that of other high income countries, and within the US, there are significant health disparities among demographic groups that are not adequately explained by the known clinical causes or access to available treatments, with women of color experiencing higher rates than white women and the highest rates occurring for non-Hispanic Black women [28,29].…”

Section: The Preterm Birth Epidemicmentioning

confidence: 99%

Research priorities of women at risk for preterm birth: findings and a call to action

Franck

McLemore

Williams

et al. 2020

BMC Pregnancy Childbirth

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Background: Traditional hierarchical approaches to research give privilege to small groups with decision-making power, without direct input from those with lived experience of illness who bear the burden of disease. A Research Justice framework values the expertise of patients and communities as well as their power in creating knowledge and in decisions about what research is conducted. Preterm birth has persisted at epidemic levels in the United States for decades and disproportionately affects women of color, especially Black women. Women of color have not been included in setting the agenda regarding preterm birth research. Methods: We used the Research Priorities of Affected Communities protocol to elicit and prioritize potential research questions and topics directly from women of color living in three communities that experience disproportionately high rates of preterm birth. Women participated in two focus group sessions, first describing their healthcare experiences and generating lists of uncertainties about their health and/or healthcare during pregnancy. Women then participated in consensus activities to achieve 'top-priority' research questions and topic lists. The priority research questions and topics produced by each group were examined within and across the three regions for similarities and differences.Results: Fifty-four women participated in seven groups (14 sessions) and generated 375 researchable questions, clustered within 22 topics and four overarching themes: Maternal Health and Care Before, During, and After Pregnancy; Newborn Health and Care of the Preterm Baby; Understanding Stress and Interventions to Prevent or Reduce Stress; and Interpersonal and Structural Health Inequities. The questions and topics represent a wide range of research domains, from basic science, translational, clinical, health and social care delivery to policy and economic research. There were many similarities and some unique differences in the questions, topics and priorities across the regions.Conclusions: These findings can be used to design and fund research addressing unanswered questions that matter most to women at high risk for preterm birth. Investigators and funders are strongly encouraged to incorporate women at the front lines of the preterm birth epidemic in research design and funding decisions, and more broadly, to advance methods to deepen healthcare research partnerships with affected communities.

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Section: The Preterm Birth Epidemicmentioning

confidence: 99%

Research priorities of women at risk for preterm birth: findings and a call to action

Franck

McLemore

Williams

et al. 2020

BMC Pregnancy Childbirth

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show abstract

“…In the cervix functional progesterone withdrawal is also associated with a local increase in proinflammatory mediators, matrix metalloproteinases and increased recruitment of immune cells that induces cervical remodeling that leads to PTB in human and animal models (Denison et al, 2000;Kuon et al, 2010;Kirby et al, 2016). While these findings suggest that progesterone supplementation maybe a useful therapeutic intervention for PTB prevention at least three large clinical trials have now demonstrated that vaginal progesterone does not significantly reduce preterm birth rates and in 2 of the studies, it did not reduce the rates of PPROM in subgroup analyses (O'Brien et al, 2007;Norman et al, 2016;Crowther et al, 2017;Norman and Bennett, 2017). The most recent PROLONG trial also demonstrated that another progestin 17αhydroxyprogesterone acetate did not significantly reduce recurrent spontaneous PTB (Blackwell et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…The most recent PROLONG trial also demonstrated that another progestin 17αhydroxyprogesterone acetate did not significantly reduce recurrent spontaneous PTB (Blackwell et al, 2020). This has prompted some researchers to opine that it is now time to examine alternative therapies to progesterone for PTB prevention (Norman and Bennett, 2017). However, given the multiple mechanisms that may lead to PTB, research now needs to be focused on identifying the patient populations that may derive benefit from progesterone therapy.…”

Section: Discussionmentioning

confidence: 99%

Progestins Inhibit Interleukin-1β-Induced Matrix Metalloproteinase 1 and Interleukin 8 Expression via the Glucocorticoid Receptor in Primary Human Amnion Mesenchymal Cells

2020

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Preterm premature rupture of membranes is a leading cause of preterm births. Cytokine induced matrix metalloproteinase1 and interleukin 8 production from amnion mesenchymal cells may contribute to fetal membrane weakening and rupture. Progestins inhibit inflammation induced fetal membrane weakening but their effect on the inflammatory response of amnion mesenchymal cells is unknown. This study was designed to determine the role of progesterone receptor membrane component 1 and the glucocorticoid receptor in mediating the effects of progestins on interleukin-1β induced matrix metalloproteinase 1 and interleukin-8 expression in human amnion mesenchymal cells. Primary amnion mesenchymal cells harvested from human fetal membranes were passaged once and treated with vehicle, progesterone or medroxyprogesterone acetate at 10 −6 M for 1 h followed by stimulation with interleukin-1β at 1 ng/ml for 24 h. Medroxyprogesterone acetate but not progesterone inhibited interleukin-1β-induced interlukin-8 and matrix metalloproteinase 1 mRNA expression. In subsequent dose response studies, medroxyprogesterone acetate, but not progesterone, at doses of 10 −6-10 −8 M inhibited interleukin-1β induced interleukin-8 and matrix metalloproteinase 1 mRNA expression. We further demonstrated that inhibition of glucocorticoid receptor expression, but not progesterone receptor membrane component 1 knockdown with small interfering RNA transfection, resulted in a reversal in medroxyprogesterone acetate's (10 −7 M) inhibition of interleukin-1β-induced matrix metalloproteinase 1 mRNA expression and interleukin-8 mRNA expression and protein expression. Our findings demonstrate that medroxyprogesterone acetate exerts its anti-inflammatory effect primarily through the glucocorticoid receptor in human amnion mesenchymal cells. Modulation of glucocorticoid receptor signaling pathways maybe a useful therapeutic strategy for preventing inflammation induced fetal membrane weakening leading to preterm premature rupture of membranes.

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“…Supplemental progesterone decreases both the number of episodes of uterine contractions and the incidence of PTB in women at high risk for PTB [7]. However, progesterone prophylaxis is not a magic treatment as it was found to reduce the risk of PTB by just 20% despite proper dose and the absolute PTB rate would be reduced by only 0.01%, because most PTB are not recurrences and prophylaxis has limited efficacy [8]. Moreover, there is limited information available regarding long-term infant and childhood outcomes.…”

Section: Introductionmentioning

confidence: 99%

Oral Micronized or Parenteral Progesterone versus Health Education in the Prevention of Preterm Birth: A Single Blinded Randomized Controlled Trial

Darwish¹,

Ismail²,

Mohammad³

et al. 2019

OJOG

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Objective: The primary aim of this study was to evaluate the possible prophylactic role of progesterone in women with a history of spontaneous preterm birth (PTB) while the secondary aim was to compare oral or intramuscular progesterone versus health education in such cases. Methods: A randomized, single blinded interventional randomized controlled trial was conducted. It comprised 90 cases with a history of PTB who were divided into 3 equal groups who received oral micronized progestogen capsule 200 mg daily (group A), parenteral 17 α-hydroxyprogesterone caproate 250 mg weekly IM injections (group B) or received health education including rest (group C) starting from 20 weeks till the end of 34 weeks of gestation. Results: This study included eligible 90 pregnant women at high risk of PTB who continued follow-up. For socio-demographic characteristics, there were no significant differences between the groups in respect to age, residence, education level, occupation, gravidity, parity and number of living children apart from significant difference between group A and C regarding mean patients' age. Mode and place of delivery did not differ between the groups while gestational age at time of delivery was significantly better on using injectable than oral progesterone. Neonatal birth weight was significantly higher in group B if compared separately to groups A and C and was still significantly higher in group A if compared with group C. NICU admission rate was higher in group C if compared to group B or to the combined group A and B. Compliance was significantly higher in group B if compared to both group A and C and was significantly higher in the intervention group A and B if compared to group C. Conclusions: Progesterone supplementation has a significant role in prevention of PTB if compared with just health education.

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Preterm birth prevention—Time to PROGRESS beyond progesterone

Abstract: In a Perspective, Jane Norman and Phillip Bennett argue that it is time to explore alternatives to progesterone for preventing preterm birth.

Cited by 18 publications

References 11 publications

Research priorities of women at risk for preterm birth: findings and a call to action

Research priorities of women at risk for preterm birth: findings and a call to action

Progestins Inhibit Interleukin-1β-Induced Matrix Metalloproteinase 1 and Interleukin 8 Expression via the Glucocorticoid Receptor in Primary Human Amnion Mesenchymal Cells

Oral Micronized or Parenteral Progesterone versus Health Education in the Prevention of Preterm Birth: A Single Blinded Randomized Controlled Trial

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