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Pregnancy-associated plasma protein-A (PAPP-A):Only 14 pages are availabe for public view
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Abstract
Pre-eclampsia is a pregnancy-related hypertensive disorder occurring usually after 20 weeks of gestation. If left untreated, it progresses to eclampsia. Worldwide, the incidence of preeclampsia ranges between 2% and 10% of pregnancies. The WHO estimates that the incidence of preeclampsia to be seven times higher in developing countries (2.8% of live births) than in developed countries (0.4%) (WHO 2015).
Although the etiology of preeclampsia is still unclear, its manifestations, including endothelial dysfunction, hypertension, and proteinuria, are thought to mediated by high circulating concentrations ofantiangiogenicproteins such as soluble fms-like tyrosine kinase-1 (sFLT-1), or soluble vascular endothelial growth factor receptor 1 (sVEGFR1)(Redman and Sargent, 2005).
Preeclampsia is associated with placental ischemia/hypoxia and secretion of soluble fms-like tyrosine kinase 1 and soluble endoglin into the maternal circulation. This causes widespread endothelial dysfunction that manifests clinically as hypertension and multisystem organ injury(Maynardetal., 2003; Nagamatsu etal., 2004 and Venkatesha et al., 2006). Recently, small molecule inhibitors of hypoxic inducible factor 1α have been found to reduce solublefms-like tyrosine kinase-1 and soluble endoglin secretion(Rana et al., 2014; Brownfootet al., 2015).
Metformin is safe in pregnancy and is also reported to inhibit hypoxic inducible factor 1α by reducing mitochondrial electron transport chain activity.It has been used during pregnancy in doses ranged from 500-2000 mg daily either accidentally during first trimester of pregnancy in (polycystic ovarian syndrome) PCO and diabetic women or in some trials for management of type II diabetes during pregnancy(Lautatzis et al., 2013).
Evidence of functional (in vitro) experiments using primary human tissuesto examine the effects of Metformin on (sFlt-1) and (sEng) secretion from placenta, endothelial cells, and placental villous explants from preterm preeclamptic patients suggest positive findings. They used succinate, mitochondrial complex II substrate, to examine whether the effects of Metformin on (sFlt-1) and (sEng) secretion were mediated through the mitochondria. Endothelial cells or whole maternal vessels were incubated with Metformin,and they concluded that Metformin reduced (sFlt-1) and (sEng) secretion from primary human tissues, possibly by inhibiting the mitochondrial electron transport chain, andreduced endothelial dysfunction, and induced angiogenesis, and has vasodilator effect. They concluded that Metformin has a potential to prevent or treat preeclampsia(Brownfootetal., 2016).
The available evidence is remainning an in-vitro experimental evidence of reduction of soluble Endoglin and soluble Fms-like Tyrosine kinase -1,biochemical markers of preeclampsia. Currently there is no available evidence of similar changes in humans. As long as metformin is a safe drug, the current study is the firstto test the hypothesis that metformin can reduce the serum level ofantiangiogenic factors (sFlt-1 and sEng) in preeclamptic patients, which could be of benefit in prevention & treatment of preeclampsia.FDA has listed Metformin as being category B medication. This means it is considered safe to be administrated during pregnancy.
Our study was conducted on forty preeclamptic patients before 37 weeks (mean gestational age 34 ± 2 weeks). Preeclampsia is defined according to ACOG guidelines as the presence of (1) systolic blood pressure (SBP) greater than or equal to 140 mmHg or a diastolic blood pressure (DBP) greater than or equal to 90 mmHg, on two occasions at least 4 hours apart in a previously normotensive patient, OR (2) an SBP greater than or equal to 160 mmHg or a DBP greater than or equal to 110 mmHg (in this case hypertension can be confirmed within minutes to facilities timely antihypertensive therapy).In addition to the blood pressure criteria, proteinuria greater than or equal to 300 mg/day in a 24-hr urine collection or a urine dipstick protein of 1+ or more is required to diagnose preeclampsia(ACOG guidelines 2013).
Patients with eclampsia and severe PET who are eligible for termination of pregnancy,diabetic patient receiving insulin therapy and any contraindication to metformin e.g. renal impairment (creatinine level >1.1 mg/dl) were excluded from the study.
Metformin tablets (500 mg three times daily)with meals was given from the time of admission till delivery or termination of pregnancy.
The Primary findings of the study was, after one week of metformin use, a significant reduction in serum endolgin and tyrosine kinase-1 with a mean difference -448.86±238.48, -397.72±125.52 respectively. In addition, the use of metformin in preeclamptic patients was associated with significant reductionof the blood pressure. Both systolic blood pressure decreased from147±12.4 to 131±10.6 mmHg and diastolic blood pressure decreased from92±7 to 85±8.2 mmHg one week after metformin use.
Other clinical outcomes in our studied women was generally good. There was no significant differencein the development of symptoms of severe PE (headache, epigastric pain, blurring of vision and decreased fetal movement) from before to after metformin treatment. Furthermore, there was no increase in the rate of urine dipstick results, 3 patients developed oligohydramnios and only one case had had non-reactive NST one week after metformin treatment. There were no statistically significant difference in the number of patients who had had abnormal (raised Doppler indices) from the time of study admission to after metformin treatment.
The maternal outcome of these forty patients was good, apart from five cases who developed severe preeclampsia. Interestingly, there was no reduction in serum endolgin and tyrosine kinase-1 in such cases in whom the mean difference were significantly higher than in the non-complicated cases (mean difference of serum sEng: 27.80±166.88 and-562.67±1600.41 and of sFlt-1: 233.20±431.3and -487.85±796.36 for severe preeclamsia and uncomplicated cases respectively.no other maternal complications in terms of Eclampsia, HELLP, DIC, Placental abruption and ICU admission. The neonatal outcome in the studied cases was fairly good with no event of stillbirth, neonatal death and a less than 8 five minute apgar score.