Tissue plasminogen activator (tPA) has a well-known role in the coagulation pathway. tPA converts plasminogen to plasmin. Plasmin dissolves fibrin clots, thus limiting thrombus formation to the site of vascular injury.~In the extravascular compartment, tPA is a pivotal mediator of tissue formation and remodeling. Due to its proteolytic activity, tPA participates in processes as diverse as embryo adhesion, placental angiogenesis and vasculogenesis, and neuronal plasticity. Embryo adhesion and placentation, for example, depend on tPA-mediated activation of brain-derived neurotrophic factor, vascular endothelial growth factor and other growth factors, formation of hemidesmosomes, and degradation of extracellular matrix and basement membrane, either directly or by activating matrix metalloproteinases.~Assuming low tPA activity would impair both blood clot dissolution and placentation, the investigators postulated that patients with consecutive first-trimester abortions would have a high prevalence of severe dysmenorrhea, accompanied by the passage of large clots.~In 2011, the investigators assessed the prevalence of severe dysmenorrhea during early adolescence in two groups. The first one was made of women with ≥ 2 consecutive first-trimester abortions, and the other, of women with ≥ 2 living births, and no losses or preterm deliveries. Severe dysmenorrhea was defined as suprapubic menstrual cramp, intense enough to cause repeated absenteeism from school or fainting in the absence of analgesia. Early adolescents are unlikely to use contraceptives, or to have become pregnant, two situations that may reduce the pain. In this study, severe dysmenorrhea increased the chances of having consecutive first-trimester miscarriages by sevenfold (95% Confidence Interval: 3.4 to 14.1; p<0.001).~Since glucose and insulin stimulate release of a major tPA inhibitor by endothelial cells - plasminogen activator inhibitor (PAI)-1 - the investigators hypothesized that lifestyle interventions proven effective in maintaining glucose and insulin levels within the normal range would increase the take home baby rate in women undergoing assisted reproduction.~The protocol has already been tested at a Brazilian tertiary care center in women with unexplained consecutive first-trimester abortions, conceiving spontaneously. The objective of this study was to observe the impact of lifestyle interventions on the take home baby rate, and to observe if the intervention could reduce the prevalence of preeclampsia and neonatal hypoglycemia.~From 2011 to 2015, 480 patients aged 18 to 42 years with ≥ 2 consecutive first-trimester abortions documented by pathology or ultrasonography, were randomly assigned to protocol Walking and Diet (W+D) or to standard follow-up (controls). Women were enrolled independent of having had severe dysmenorrhea during adolescence. Patients assigned to protocol W+D were instructed to walk briskly for ≥ 40 minutes seven days a week. In addition, they were recommended to avoid high-carbohydrate meals such as snacks, candies, fiber-free juices, coconut water and sugar-sweetened beverages, and to eat two daily servings of meat, poultry, fish (e.g. 2 g/kg) or other protein-rich food, starting when they decided to get pregnant and continuing until delivery. Women with antiphospholipid antibodies, second- or third-trimester losses, multiple pregnancies, anatomical abnormalities that could increase the risk of first-trimester abortions, or any condition requiring a priori anticoagulation were excluded.
Embryo adhesion and placentation depend on tissue plasminogen activator (tPA)-mediated activation of brain-derived neurotrophic factor, vascular endothelial growth factor and other growth factors, formation of hemidesmosomes, and degradation of extracellular matrix and basement membrane, either directly or by activating matrix metalloproteinases.~Since glucose and insulin stimulate release of a major tPA inhibitor by endothelial cells - plasminogen activator inhibitor (PAI)-1 - the investigators hypothesized that lifestyle interventions proven effective in maintaining glucose and insulin levels within the normal range would increase the take home baby rate in women undergoing assisted reproduction.