(1)Prevention of FGR &amp

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(1)Prevention of FGR & Its Sequele Prof. Seema Hakim MD(OBG), FICOG, FICMCH, ACME.

(2) This topic will cover  Some facts & terminology about FGR  Etiology & risk factors of FGR  Prevention of preventable causes of FGR  Uteroplacental insufficiency & FGR- Pathophysiology  Prevention of FGR due to placental insufficiency- Drug trials  Prevention of sequele of FGR-established strategies  Prevention of sequel of FGR-drugs under trial.

(3) FGR-Some Facts • FGR associated with 3-10% of all pregnancies • Perinatal mortality rate is 5-20 times higher for growth restricted fetuses. • 2nd leading contributor to the perinatal mortality rate. • 20% of all still births are FGR • Incidence of intrapartum asphyxia in cases of FGR has been reported to be 50%. • Early and proper identification and management lowers this perinatal mortality and morbidity..

(4) FGR & SGA Terminology  FGR-Fetuses with an estimated fetal weight less than 10th. Percentile for the gestational age.  SGA-New born whose birth weight is less than 10th percentile. for gestational age  Fetal Growth Restriction (FGR). fetus fails to reach its full. growth potential.  Small for Gestational Age (SGA) most reliable surrogate. marker for FGR.

(5) Etiology of FGR Maternal factors Constitutionally small Substance use and abuse (smoking, alcohol) Poor nutrition, severe anemia, eating disorder High altitude, social deprivation Maternal medical Infection illness • •Maternal illnesses Pregestational diabetes mellitus with vasculopathy, Hypertension, Renal disorders, Antiphospholipid Antibody syndrome, Autoimmune disease, Cyanotic heart disease. Placental and cord abnormalities Circumvallate placenta, placental tumours, marginal cord insertion Single umblical artery. Malaria, TORCH, syphills Multiple gestation Chromosomal abnormalities (Trisomy 13,18,21). Drugs and teratogens. Fetal malformation Congenital diaphragmatic hernia, congenital heart disease, omphalocele.

(6) Prevention of causes of FGR  Genetic counseling  Rubella vaccination  Correction of anemia  Nutritional supplementation  Correction of cyanotic heart disease  Avoid smoking.

(7) Prevention (contd…) • Improvement in nutritional status • Preconception counseling and care • Malaria antiprophylaxis • Cessation of smoking, alcohol and illicit drug use • Low dose aspirin.

(8) Prevention  Correction of anaemia, iron. supplementation  Care with use of medications  Immunization with rubella vaccine. in susceptible females  Protein/energy supplementation  Vitamin/mineral supplementation.

(9) Utero-placental insufficiency  Most important cause.. Abnormal/inadequate trophoblast invasion of spiral arteries. Incomplete remodeling of spiral arteries Persistence of high resistance and low flow circulation.

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(11) Oxidative stress. Reperfusion injury. Decreased placental perfusion  placental ischemia. Imbalance in angiogenic & antiangiogenic factors. Inefficient gaseous / nutrient exchange. Increased frequency of atherosis in placental bed.

(12)  Clinically , uteroplacental insufficiency presents as –  Fetal growth restriction  Pre-eclampsia  Placental abruption  Late pregnancy loss.

(13) Prevention of FGR due to Uteroplacental insufficiencyDrugs under trial . Aspirin. . Low molecular weight heparin. . Phosphodiesterase type 5 inhibitors. . Maternal VEGF gene therapy. . Nanoparticles & micro RNAs. . Proton pump inhibitors. . Melatonin. . Creatine. . N-acetylcysteine.

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(15) Aspirin  MECHANISM OF ACTION 1.. Irreversible inactivation of COX enzyme  suppression of prostaglandins and thromboxanes production  vasodilatation and inhibition of platelet aggregation.. 2.. Acetylation of endothelial nitric oxide synthase  nitric oxide release (vascular endothelium)  vasodilatation.. 3.. Increased activity of heme oxygenase-1 (endothelial cells)  catabolise heme  reduction in oxidative stress..

(16) Aspirin (contd…)  Modestly reduces SGA pregnancy in women at high risk.  Dose recommended – 100 to 150 mg.  Timing – evening dose.  Gestational age of commencement – at or before 16 weeks..

(17) Low molecular weight heparin [LMWH] Mechanism of action 1.. Anti coagulant  prevent placental thrombosis  prevent placental infarction.. 2.. Anti inflammatory. 3.. Complement inhibition. 4.. Pro angiogenic. Positively influence trophoblast development and invasion.

(18) Low molecular weight heparin [LMWH] (contd…) . In vitro & in vivo studies suggest that LMWH may prevent FGR.. . But evidence from randomized controlled trials is inconsistent.. . Plasma levels of PlGF were elevated 1 and 3 hours after LMWH administration in women at high risk of preeclampsia, but its effect on uteroplacental circulation is less clear.. . No positive preventative effect of LMWH on prevention of FGR is demonstrated.. . Currently, LMWH therapy for the prevention of FGR should be limited to the research setting..

(19) Summary of progress of experimental treatments for fetal growth restriction (contd…) Experiment treatment. Method of administration. Potential mechanism of Current stage action of investigation. Phosphodiesterase type 5 inhibitors Sildenafil, tadalafil. Oral. Selective vascular smooth muscles relaxation and vasodilatation. Phase II/III Clinical trials. Maternal VEGF gene therapy. Injected into uterine arteries or applied to outside of vessels. Local vasodilatation and angiogenesis. Phase I/IIa clinical trial. VEGF, Vascular endothelial growth factor. Groom. Therapeutic interventions in fetal growth restriction. Am J Obstet Gynecol 2018..

(20) Summary of progress of experimental treatments for fetal growth restriction (contd…) Experiment treatment. Method of administration. Potential mechanism of action. Current stage of investigation. Nanoparticles. Intravenous injection. Uterine blood flow, placental function. Preclinical. MicroRNAs. Intravenous injection. Uterine blood flow, placental function. Preclinical. Statins. Oral. Antinflammatory, antioxidant and angiogenesis. phaseII/III clinical trials (for preeclampsia only). Groom. Therapeutic interventions in fetal growth restriction. Am J Obstet Gynecol 2018..

(21) Summary of progress of experimental treatments for fetal growth restriction (contd…) Experiment treatment. Method of administration. Potential mechanism of action. Current stage of investigation. Nitric oxide donors Oral. Selective vascular smooth muscles relaxation and vasodilatation. Phase II non randomized Clinical trials (for preeclampsia only). Hydrogen sulphide. Oral. Selective vascular smooth muscles relaxation and vasodilatation. phaseI/IIa clinical trial. Proton pump inhibitors Esomeprazole. Oral. Angiogenesis. Phase II /III Clinical trials (for preeclampsia only). Groom. Therapeutic interventions in fetal growth restriction. Am J Obstet Gynecol 2018..

(22) Summary of progress of experimental treatments for fetal growth restriction Experiment treatment. Method of Potential mechanism of administratio action n. Current stage of investigation. Melatonin. Oral. Antioxidants. Phase II Nonrandomized. Creatine. Oral. Cellular Energy homeostasis. Preclinical. N--acetylcysteine. Oral. Selective vascular smooth muscles relaxation and vasodilatation. Phase II randomized (for preeclampsia only). Groom. Therapeutic interventions in fetal growth restriction. Am J Obstet Gynecol 2018..

(23) Phosphodiesterase type 5 inhibitors  Sildenafil, tadalafil.  Mechanism of action  Block phosphodiesterase enzyme  prevent inactivation of cGMP. within vascular smooth muscle cells  potentiates the action of nitric oxide (NO)  vasodilatation.  Maternal. spiral arteries that have not undertaken complete. remodeling  intact muscular layer  so remain responsive to NO. (Hence, can be used in treatment of FGR)..

(24) Phosphodiesterase type 5 inhibitors (contd…)  Extensively researched in pre clinical and clinical studies.  Positive effects on maternal blood pressure evident, but no. difference in measures of fetal growth.  Limited human pregnancy studies are available.  Results from the international Sildenafil Therapy in Dismal. Prognosis Early-Onset Intrauterine Growth Restriction (STRIDER) Consortium of RCTs are awaited..

(25) Maternal VEGF Gene Therapy  Mechanism of action  Therapeutic angiogenesis.  Adenoviral (Ad) gene therapy vector used. . short term effect  VEGF expression in uterine arteries  increased endothelial NO synthase expression  vasodilatation.. . long term effect  vascular remodelling..

(26) Maternal VEGF Gene Therapy (contd..)  Interventional radiology can be used to deliver vector into the. uterine arteries.  To assess safety and efficacy of maternal uterine artery. Ad.VEGF gene therapy for severe early onset FGR, the EVERREST project-2013 (doEs Vascular endothelial growth factor gene therapy for seveRe Early-onset fetal growth reSTriction ) aims to carry a phase I/IIa clinical trial..

(27) Nanotechnology and other Uteroplacental Targeting Strategies  Mechanism of action . Tumor homing peptide sequences CGKRK and iRGD bind selectively to human placental surface.. . Cargoes of proteins can be delivered specifically to placenta, by coating nanoparticles with these sequences..

(28) Nanotechnology and other Uteroplacental Targeting Strategies (contd…)  Particles delivered -. Proteins like Insulin like growth factor (IGF-2).. -. NO donor (SE175) encapsulated into targeted liposomes.. -. Mito-targeted antioxidant Mito Q.. - Micro RNA treatment – miR-145 & miR675 (negative regulators of placental growth).

(29) Potential Drug Therapies . Focus on treatment of pre eclampsia rather than FGR.. Statins . Lipid lowering medication .. . Anti inflammatory. . Anti oxidant. . Angiogenic properties. . Reduces level of sFlt-1 and maternal hypertension.. . Increases VEGF and fetal weight.. In animal models.

(30) Potential Drug Therapies (contd…) Nitric oxide donor Isosorbide dinitrate . Relaxes vascular smooth muscle cells vasodilatation.. . Reduces maternal blood pressure.. . Lowers resistance in umbilical artery and uterine artery Doppler waveforms.. . No RCTs have assessed long term therapy or effect on pregnancy outcome. Short term therapy.

(31) Potential Drug Therapies (contd…) Hydrogen sulphide  Acts on smooth muscle cell ATP sensitive potassium channels.  vasodilatation.  Angiogenic effects (mediated by VEGF and VEGF receptor 2).  Further work needed to investigate its therapeutic potential..

(32) Repurposing drugs – Proton pump inhibitors Esomeprazole  In vitro studies – decrease sFlt-1 and soluble endoglin and. improve markers of endothelial dysfunction.  Pre eclampsia Intervention with Esomeprazole (PIE) – The. RCT will assess esomeprazole to treat early onset pre eclampsia, but does not include fetal growth..

(33) Prevention of sequelae of FGR  Iatrogenic preterm birth (when risk of hypoxia, acidosis and. intrauterine death is high and fetus is viable).  Timely antenatal administration of.  corticosteroids (fetal lung maturation) magnesium sulphate (neuroprotection)  Careful consideration of mode of delivery..

(34) Prevention of sequelae of FGR(contd…)  FGR is associated with long term neurodevelopmental and. cardiac impairment (oxidative stress).  Interventions are now being developed to ameliorate this. antenatal insult.  Melatonin  Creatine  N-acetylcysteine.

(35) Melatonin  Endogenous lipid soluble hormone.  Produced by pineal gland  Antioxidant effect  Direct: scavenging reactive oxygen species.  Indirect:. increased expression of antioxidant (glutathione peroxidase and glutathione reductase)..  Cardioprotective  Neuroprotective. enzyme.

(36) Melatonin (contd…)  Safety study in 6 women with early onset FGR 4 mg x BD  Found no fetal or maternal safety concerns.  Results showed  Higher levels of melatonin in cord blood.  Lower levels of malondialdehyde in placenta (marker of. oxidative stress).  Efficacy study results are awaited..

(37) Creatine  Naturally produced amino acid derivative.  Facilitate recycling of ATP.  Essential for cellular energy production.  Maternal administration crosses placenta  prolong cellular energy. homeostasis during hypoxia  Protects from hypoxic injury to brain, kidney and skeletal muscle.. (spiny mouse model).  No RCT of maternal dietary creatine supplementation in humans have. been undertaken.

(38) N-acetylcysteine  Scavenges reactive oxygen species.  Forms the antioxidant glutathione.  Increases bioavailability of nitric oxide.  A RCT found that oral N-acetylcysteine did not stabilize the process. of established severe pre eclampsia or improve neonatal outcome.  Further studies are needed to investigate whether N-acetylcysteine. prevent FGR..

(39) Take home message. .

(40)  A 100-150 mg evening dose of aspirin commenced prior to 16. weeks gestation  modest risk reduction of FGR in women at risk.  No proven treatment of FGR.  Only intervention that can be offered  iatrogenic preterm birth (. corticosteroids, magnesium sulphate)  Several potential new therapies are on the horizon.  Wait for the results of RCTs specific to FGR..

(41) Thank You!.

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