Low-dose aspirin therapy in IVF and ICSI patients

Abstract The first aim of this randomized, placebo-controlled and double-blind study was to investigate whether low-dose aspirin therapy, started prior to controlled ovarian hyperstimulation, improves ovarian stimulation response, uterine haemodynamics and clinical pregnancy rates in unselected patients who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). The second aim was to examine if the maternal serum placental proteome is different in IVF/ICSI pregnancies compared with spontaneous pregnancies, and whether low-dose aspirin modifies maternal serum placental protein expression and uteroplacental haemodynamics during the first half of pregnancy. Finally, the effect of low-dose aspirin therapy on the incidence of hypertensive pregnancy complications among women who became pregnant after IVF/ICSI was investigated. Low-dose aspirin therapy did not increase the number of oocytes retrieved, the total number of embryos or number of top-quality embryos, endometrial thickness or uterine haemodynamics on the day of embryo transfer (ET) or clinical pregnancy rates compared with placebo-treated IVF/ICSI women. On the day of ET, low-dose aspirin did not affect UtA vascular impedance, but the incidence of non-optimal uterine artery haemodynamics (UtA PI≥3.0) was statistically significantly lower (p<0.05) in the aspirin group compared with the placebo group. In the placebo-treated IVF/ICSI patients, maternal serum proteome analysis showed altered protein expression compared with women with spontaneous pregnancies. Between aspirin- and placebo-treated IVF/ICSI patients, proteome analysis showed a unique and distinct pattern of differentially expressed proteins including extra-cellular matrix, complement and transport proteins. At 6 weeks’ gestation, arcuate artery PI and at 18 weeks’ gestation, UtA PI values were lower (p<0.05) in the aspirin group than in the placebo group. In conclusion, low-dose aspirin therapy, when started concomitantly with controlled ovarian hyperstimulation, did not improve ovarian responsiveness, uterine receptivity, pregnancy outcome in unselected IVF/ICSI women or affect UtA vascular impedance on the day of ET. Low-dose aspirin modified the early placentation process and reduced uteroplacental vascular impedance in mid-pregnancy, but did not decrease the incidence of hypertensive pregnancy complications.Tiivistelmä Keinoalkuisten hedelmöityshoitojen seurauksena keskimäärin reilu kolmannes naisista tulee raskaaksi hoitokertaa kohti. Näissä raskauksissa äidin seerumista määritettyjen istukkaperäisten merkkiaineiden pitoisuuksissa on eroavaisuuksia verrattuna spontaanisti raskaaksi tulleiden naisten seerumipitoisuuksiin ensimmäisen ja toisen raskauskolmanneksen aikana. Pre-eklampsian eli raskausmyrkytyksen riski on myös lisääntynyt. Syyksi arvellaan istukan verisuonipuuston poikkeavaa kehitystä. Pre-eklampsiaan liitetään intravaskulaarisen prostasykliinin ja tromboksaanin epätasapaino, joka johtaa verihiutaleiden aggregaation lisääntymiseen ja verisuonten supistumiseen. Matala-annoksinen asetyylisalisyylihappo (ASA) vähentää tromboksaanituotantoa ja korjaa tromboksaani- ja prostasykliinituotannon epätasapainoa, mutta sen ei ole todettu merkittävästi vähentävän näiden raskauskomplikaatioiden esiintyvyyttä edes riskiryhmillä, kun lääkitys on aloitettu toisen raskauskolmanneksen aikana. Tämän satunnaistetun ja plasebo-kontrolloidun kaksoissokkotutkimuksen tavoitteena oli tutkia keinoalkuisia hedelmöityshoitoja saavilla naisilla matala-annoksisen ASA-hoidon (100 mg/vrk) merkitystä munasarjojen stimulaatiovasteeseen, alkion kiinnittymiseen, istukan muodostumiseen ja kehittymiseen sekä lääkehoidon vaikutusta kohdun, istukan ja sikiön verenkiertoon, kun lääkitys aloitettiin munasarjojen stimulaatiohoidon alkaessa. Lisätavoitteena oli selvittää, onko lapsettomuushoitoja saavien naisten raskauksissa todettavissa spesifinen istukkaproteomiikkalöydös (istukan tuottamat valkuaisaineet) verrattuna spontaanisti raskaaksi tulleisiin naisiin ja voidaanko siihen vaikuttaa matala-annoksisella ASA-hoidolla. Toisena lisätavoitteena oli selvittää matala-annoksisen ASA-hoidon vaikutus pre-eklampsian esiintyvyyteen loppuraskaudessa. Matala-annoksinen asetyylisalisyylihappo (ASA) ei paranna keinoalkuisten hedelmöityshoitojen hoitotuloksia eikä vaikuta kohdun verenkiertoon tai kohdun limakalvon paksuuteen ultraäänellä arvioituna alkion siirtopäivänä. Matala-annoksista ASA-hoitoa käyttäneiden potilaiden ryhmässä todettiin kuitenkin merkitsevästi vähemmän naisia, joilla oli huonoa hoitotulosta keinoalkuisissa hedelmöityshoidoissa ennakoiva korkea molemminpuolinen kohtuvaltimoiden verenvirtausvastus alkion siirtopäivänä verrattuna plasebo-ryhmään. Raskaaksi tulleilla naisilla, jotka käyttivät matala-annoksista ASA-hoitoa, todettiin kohdun verenvirtausvastus matalammaksi alku- ja keskiraskaudessa verrattuna plasebo-ryhmän naisiin. Istukkaproteomiikkatutkimusten mukaan varhaisistukan proteiinituotanto on erilainen keinoalkuisissa raskauksissa verrattuna spontaanisti alkaneisiin raskauksiin ja siihen voidaan vaikuttaa matala-annoksisella ASA-hoidolla. Pre-eklampsian ja sikiön kasvunhidastuman esiintyvyydessä ei ryhmien välillä todettu eroa. Matala-annoksinen ASA-hoito aloitettuna ennen raskautta munasarjojen stimulaatiohoidon alkaessa ei paranna munasarjojen vastetta lapsettomuushoidoissa käytettäville hormonihoidoille, raskauslukuja eikä kohdun verenkiertoa alkion siirtopäivänä. Hoidon todettiin kuitenkin vaikuttavan varhaisistukan kehittymiseen sekä parantavan kohdun verenkierto alku- ja keskiraskaudessa viitaten istukan verisuonipuuston parempaan kehittymiseen. Matala-annoksinen ASA-hoito ei vähentänyt istukkaperäisten raskauskomplikaatioiden esiintymistä

Fetal cardiovascular hemodynamics in type 1 diabetic pregnancies at near‐term gestation

Abstract Introduction: Poor glycemic control in maternal type 1 diabetes mellitus during pregnancy can affect fetal cardiac and placental function. However, studies concerning fetal central hemodynamics have revealed conflicting results. We hypothesized that in pregnancies complicated by maternal type 1 diabetes, fetal cardiovascular and placental hemodynamics are comparable to the control fetuses at near‐term gestation. In addition, we investigated the relation between newborn serum biomarkers of cardiac function and fetal cardiovascular and placental hemodynamics. Furthermore, we studied whether maternal diabetes is associated with placental inflammation. Material and methods: In this prospective case‐control study, fetal central and peripheral hemodynamics were assessed by ultrasonography in 33 women with type 1 diabetes and in 67 controls with singleton pregnancies between 34+2 and 40+2 gestational weeks. Newborn umbilical cord serum was collected to analyze cardiac natriuretic peptides (atrial and B‐type natriuretic peptides) and troponin T concentrations. Placental tissue samples were obtained for cytokine analyses. Results: Fetal ventricular wall thicknesses were greater and weight‐adjusted stroke volumes and cardiac outputs were lower in the type 1 diabetes group than in the control group. Pulsatility in the aortic isthmus and inferior vena cava blood flow velocity waveforms was greater in the type 1 diabetes group fetuses than in the controls. A positive correlation was found between branch pulmonary artery and aortic isthmus pulsatility index values. Umbilical artery pulsatility indices were comparable between the groups. Umbilical cord serum natriuretic peptide and troponin T concentrations were elevated in the type 1 diabetes fetuses. These cardiac biomarkers correlated significantly with cardiovascular hemodynamics. Placental cytokine levels were not different between the groups. Conclusions: In maternal type 1 diabetes pregnancies, fetal cardiovascular hemodynamics is impaired. Maternal type 1 diabetes does not seem to alter placental vascular impedance or induce placental inflammation

Peripheral chemoreflex activation and cardiac function during hypoxemia in near-term fetal sheep without placental compromise

Abstract A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheralvasoconstriction and redistribution of bloodflow to protect the brain, myocardium, and adrenal glands. By using a chronicallyinstrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship betweenperipheral chemoreflex activation induced by hypoxemia and central hemodynamics. A total of 17 Åland landrace sheep fetusesat 115–128/145 gestational days were instrumented. Carotid artery was catheterized in 10 fetuses and descending aorta in 7fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascu-lar hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane anesthesia. Comparable data to baselinewere collected 10 min (acute hypoxemia) and 60 min (prolonged hypoxemia) after maternal hypo-oxygenation to saturation levelof 70%–80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower and lactate levels were higher inthe descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aortaincreased, whereas in the carotid artery, MAP decreased. In addition, right pulmonary artery pulsatility index values increased,and the diastolic component in the aortic isthmus bloodflow velocity waveform became more retrograde, thus decreasing theaortic isthmus antegrade/retrograde bloodflow (AoI Net Flow) ratio. Both fetal ventricular cardiac outputs were maintained evenduring prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hy-poxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed left ventricular cardiac output (LVCO)or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure

Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe

Abstract: Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non-pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5-2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118-127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 lg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 lg/kg/hr were applied to antebrachium, and ewes were then given a 2 lg/kg intravenous bolus followed by an intra-operative 2.5 lg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra-and post-operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep. Opioids are commonly used to treat pain during labour and caesarean section, and also for pregnant women for surgical procedures and other severe pain conditions. Fentanyl, a synthetic opiate derivative, has a rapid onset and short half-life In animal studies, intravenous and transdermal fentanyl pharmacokinetics has been studied in several species, including llamas, non-pregnant sheep and horses The fentanyl dosing regimen for pregnant sheep undergoing major abdominal surgery was designed based on the reported information on fentanyl pharmacokinetics in non-pregnant sheep. The primary aim of the current study was to determine fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during abdominal surgery and, thus, to gain confidence on the adequacy of pain treatment. The dosing regimen with target plasma fentanyl concentration of 0.5-2 ng/ml was calculated a priori based on the pharmacokinetics reported in non-pregnant sheep and nominal dose rate of transdermal patches. Subsequent drug concentration measurements and further pharmacokinetic modelling were conducted to evaluate the analgesia protocol during and after the surgery. Materials and Methods A priori exposure and dose prediction. A two-compartment model and pharmacokinetic parameters in non-pregnant sheep reported b

Foramen ovale blood flow and cardiac function after main pulmonary artery occlusion in fetal sheep

Abstract The foramen ovale (FO) accounts for the majority of fetal left ventricular (LV) output. Increased right ventricular afterload can cause a redistribution of combined cardiac output between the ventricles. To understand the capability of the FO to increase its volume blood flow and thus LV output, we mechanically occluded the main pulmonary artery in seven chronically instrumented near‐term sheep fetuses. We hypothesized that FO volume blood flow and LV output would increase during main pulmonary artery occlusion. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the main pulmonary artery and 15 min after occlusion was released. Fetal ascending aorta and central venous pressures and blood gas values were monitored. Main pulmonary artery occlusion initially increased fetal heart rate (P < 0.05) from [mean (SD)] 158 (7) to 188 (23) beats min⁻¹ and LV cardiac output (P < 0.0001) from 629 (198) to 776 (283) ml min⁻¹. Combined cardiac output fell (P < 0.0001) from 1524 (341) to 720 (273) ml min⁻¹. During main pulmonary artery occlusion, FO volume blood flow increased (P < 0.001) from 507 (181) to 776 (283) ml min⁻¹. This increase was related to fetal tachycardia, because LV stroke volume did not change. Fetal ascending aortic blood pressure remained stable. Central venous pressure was higher (P < 0.05) during the occlusion than after it was released. During the occlusion, fetal pH decreased and PCO₂ increased. Left ventricular systolic dysfunction developed while LV diastolic function was preserved. Right ventricular systolic and diastolic function deteriorated after the occlusion. In conclusion, the FO has a limited capacity to increase its volume blood flow at near‐term gestation