Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

Functional vascular changes of the kidney during pregnancy in animals: a systematic review and meta-analysis.

Renal vascular responses to pregnancy have frequently been studied, by investigating renal vascular resistance (RVR), renal flow, glomerular filtration rate (GFR), and renal artery responses to stimuli. Nonetheless, several questions remain: 1. Which vasodilator pathways are activated and to what extent do they affect RVR, renal flow and GFR across species, strains and gestational ages, 2. Are these changes dependent on renal artery adaptation, 3. At which cellular level does pregnancy affect the involved pathways? In an attempt to answer the questions raised, we performed a systematic review and meta-analysis on animal data. We included 37 studies (116 responses). At mid-gestation, RVR and GFR change to a similar degree across species and strains, accompanied by variable change in renal flow. At least in rats, changes depend on NO activation. At late gestation, changes in RVR, renal flow and GFR vary between species and strains. In rats, these changes are effectuated by sympathetic stimulation. Overall, renal artery responsiveness to stimuli is unaffected by pregnancy, except for Sprague Dawley rats in which pregnancy enhances renal artery vascular compliance and reduces renal artery myogenic reactivity. Our meta-analysis shows that: 1. Pregnancy changes RVR, renal flow and GFR dependent on NO-activation and sympathetic de-activation, but adjustments are different among species, strains and gestational ages; 2. These changes do not depend on adaptation of renal artery responsiveness; 3. It remains unknown at which cellular level pregnancy affects the pathways. Our meta-analysis suggests that renal changes during pregnancy in animals are qualitatively similar, even in comparison to humans, but quantitatively different.

30(+) years of exercise in pregnancy.

In 1980 I came to Loma Linda to study maternal exercise, with Dr. Longo as my mentor. For millennia strenuous exercise was considered harmful for the fetus. Early studies reinforced that idea, by showing that exercise reduced uterine blood flow and fetal PO2 by up to 40 and 29 %, respectively. But utero-placental reserve is ~50 %. So why was fetal PO2 so much reduced during exercise?Methods proved to be important. It took chronically instrumented animals accustomed to the laboratory environment, experiments standardized to fitness of the individual (%VO2max), measurement of total uterine blood flow, and blood gas values corrected for body temperature. The results were simple and hold till this day. Uterine blood flow decreases linearly with maternal heart rate increase, which depends on exercise intensity and duration. Maximal reduction in uterine blood flow is ~20 % and uterine O2-uptake remains unaltered because blood flow reduction is compensated by increases in hematocrit and uterine O2-extraction. Fetal body temperature increases with that of the mother by ~2 °C at maximal exercise and fetal blood gas values are little affected by exhaustive maternal exercise, if properly corrected for temperature. So I left Loma Linda knowing that pregnant sheep can exercise to exhaustion without harm to the fetus, thanks to effective compensatory mechanisms.After returning to Erasmus University Rotterdam further studies in humans showed that physical fitness is unaffected by pregnancy, weight-gain affects performance, and strenuous exercise in healthy pregnant women does not harm the fetus. Thus, the millennia-old perspective has changed.

Adaptive changes of mesenteric arteries in pregnancy: a meta-analysis.

The vascular response to pregnancy has been frequently studied in mesenteric artery models by investigating endothelial cell (EC)- and smooth muscle cell (SMC)-dependent responses to mechanical (flow-mediated vasodilation, myogenic reactivity, and vascular compliance) and pharmacological stimuli (G protein-coupled receptor responses: Gq(EC), Gs(SMC), Gq(SMC)). It is unclear to what extent these pathways contribute to normal pregnancy-induced vasodilation across species, strains, and/or gestational age and at which receptor level pregnancy affects the pathways. We performed a meta-analysis on responses to mechanical and pharmacological stimuli associated with pregnancy-induced vasodilation of mesenteric arteries and included 55 (188 responses) out of 398 studies. Most included studies (84%) were performed in Wistar and Sprague-Dawley rats (SDRs) and compared late gestation versus nonpregnant controls (80%). Pregnancy promotes flow-mediated vasodilation in all investigated species. Only in SDRs, pregnancy additionally stimulates both vasodilator Gq(EC) sensitivity (EC(50) reduced by -0.76 [-0.92, -0.60] log[M]) and Gs(SMC) sensitivity (EC(50) reduced by -0.51 [-0.82, -0.20] log[M]), depresses vasopressor Gq(SMC) sensitivity (EC(50) increase in SDRs by 0.23 [0.16, 0.31] log[M]), and enhances arterial compliance. We conclude that 1) pregnancy facilitates flow-mediated vasodilation at term among all investigated species, and the contribution of additional vascular responses is species and strain specific, and 2) late pregnancy mediates vasodilation through changes at the receptor level for the substances tested. The initial steps of vasodilation in early pregnancy remain to be elucidated.

Impaired vascular responses to relaxin in diet-induced overweight female rats.

Relaxin mediates renal and mesenteric vascular adaptations to pregnancy by increasing endothelium-dependent vasodilation and compliance and decreasing myogenic reactivity. Diet-induced overweight and obesity are associated with impaired endothelial dysfunction and vascular remodeling leading to a reduction in arterial diameter. In this study, we tested the hypothesis that local vascular responses to relaxin are impaired in diet-induced overweight female rats on a high-fat cafeteria-style diet for 9 wk. Rats were chronically infused with either relaxin or placebo for 5 days, and vascular responses were measured in isolated mesenteric arteries and the perfused kidney. Diet-induced overweight significantly increased sensitivity to phenylephrine (by 17%) and vessel wall thickness, and reduced renal perfusion flow (RPFF; by 16%), but did not affect flow-mediated vasodilation, myogenic reactivity, and vascular compliance. In the normal weight rats, relaxin treatment significantly enhanced flow-mediated vasodilation (2.67-fold), decreased myogenic reactivity, and reduced sensitivity to phenylephrine (by 28%), but had no effect on compliance or RPFF. NO blockade by l-NAME diminished most relaxin-mediated effects. In diet-induced overweight rats, the vasodilator effects of relaxin were markedly reduced for flow-mediated vasodilation, sensitivity to phenylephrine, and myogenic response compared with the normal diet rats, mostly persistent under l-NAME. Our data demonstrate that some of the vasodilator responses to in vivo relaxin administration are impaired in isolated mesenteric arteries and the perfused kidney in diet-induced overweight female rats. This does not result from a decrease in Rxfp1 (relaxin family peptide receptor) expression but is likely to result from downstream disruption to endothelial-dependent mechanisms in diet-induced overweight animals.

Contribution of different local vascular responses to mid-gestational vasodilation.

OBJECTIVE: At-term pregnancy-induced vasodilation is the resultant of endothelium-dependent vasodilation, decreased myogenic reactivity, increased compliance, and reduced sensitivity to vasoconstrictor agents. We hypothesized that these vascular changes are already present at mid-gestation. STUDY DESIGN: In 20 mid-pregnant and 20 nonpregnant Wistar Hannover rats, we measured vascular responses of isolated mesenteric arteries and kidney. RESULTS: In the pregnant rats compared with the nonpregnant rats, mesenteric flow-mediated vasodilation and renal perfusion flow increased 1.52-fold (from 47±5 to 31±4 µL/min) and 1.13-fold (from 12.8±0.1 to 14.4±0.1 mL/min), respectively. Nitric oxide inhibition reduced mesenteric flow-mediated vasodilation to a similar extent in the pregnant and nonpregnant rats; it completely blocked the pregnancy-induced increase in renal perfusion flow. Pregnancy did not change mesenteric artery sensitivity to phenylephrine, myogenic reactivity, nor vascular compliance. CONCLUSION: At mid-gestation, alterations in rat mesenteric vascular tone depend primarily on flow-mediated endothelium-dependent changes and not on changes in α-adrenergic vasoconstrictor sensitivity, myogenic reactivity, or vascular compliance.

Aging attenuates the vasodilator response to relaxin.

Relaxin, an insulin-like growth factor peptide, increases endothelium-dependent vasodilation and vascular compliance and decreases myogenic reactivity. These vascular effects significantly contribute to the physiological circulatory adaptations in pregnancy, particularly in the mesentery and kidney. Aging predisposes to vascular maladaptation and gestational hypertensive disease. We hypothesized that mild aging reduces the vascular responses to relaxin. In 20 young (10-12 wk) and 20 middle-aged (40-46 wk) female Wistar Hannover rats, vascular responses to chronic exposure of relaxin vs. placebo (5 days) were quantified in isolated mesenteric arteries and kidney. Vascular responses were evaluated using pressure-perfusion myograph, wire myograph, and an isolated perfused rat kidney model. Rxfp1 (relaxin family peptide) gene expression was determined by quantitative polymerase chain reaction. In young rats, relaxin stimulated nitric oxide (NO)-dependent flow-mediated vasodilation (2.67-fold, from 48 ± 9 to 18 ± 4 µl/min), reduced myogenic reactivity (from -1 ± 2 to 7 ± 3 µm/10 mmHg), and decreased mesenteric sensitivity to (28%, from 1.39 ± 0.08 to 1.78 ± 0.10 µM) but did not change compliance and renal perfusion flow (RPFF). In aged rats, relaxin did not affect any of the analyzed mesenteric or renal parameters. In aged compared with young placebo-treated rats, all mesenteric characteristics were comparable, while RPFF was lower (17%, from 6.9 ± 0.2 to 5.7 ± 0.1 ml·min⁻¹·100 g⁻¹) even though NO availability was comparable. Rxfp1 expression was not different among young and aged rats. Our findings suggest that moderate aging involves normal endothelial function but blunts the physiological endothelium-dependent and -independent vasodilator response to relaxin.

Effect of childbirth on the course of Crohn's disease; results from a retrospective cohort study in the Netherlands.

BACKGROUND: Pregnant women with Crohn's disease needs proper counselling about the effect of pregnancy and childbirth on their disease. However, Literature about the effect of childbirth on Crohn's disease is limited. This study examined the effect of childbirth on the course of Crohn's disease and especially perianal Crohn's disease. METHODS: This is a retrospective cohort study which was performed in a tertiary level referral hospital in the Netherlands. From the IBD database, female patients aged 18-80 years in 2004 were selected. Data analysis took place in the years 2005 and 2006. Eventually, 114 women with at least one pregnancy after the diagnosis of Crohn's disease were eligible for the study. Differences between groups were analyzed using Wilcoxon Mann Whitney tests and Chi-square analysis with 2 × 2 or 2 × 3 contingency tables. Two-tailed values were used and p values < 0.05 were considered statistically significant. RESULTS: 21/114 women (18%) had active luminal disease prior to pregnancy, with significantly more pregnancy related complications compared to women with inactive luminal disease (Odds ratio 2.8; 95% CI 1.0 - 7.4). Caesarean section rate was relatively high (37/114, 32%), especially in patients with perianal disease prior to pregnancy compared to women without perianal disease (Odds ratio 4.6; 95% CI 1.8 - 11.4). Disease progression after childbirth was more frequent in patients with active luminal disease prior to pregnancy compared to inactive luminal disease (Odds ratio 9.7; 95% CI 2.1 - 44.3). Progression of perianal disease seems less frequent after vaginal delivery compared with caesarean section, in both women with prior perianal disease (18% vs. 31%, NS) and without prior perianal disease (5% vs 14%, NS). There were no more fistula-related complications after childbirth in women with an episiotomy or second degree tear. CONCLUSION: A relatively high rate of caesarean sections was observed in women with Crohn's disease, especially in women with perianal disease prior to pregnancy. A protective effect of caesarean section on progression of perianal disease was not observed. However, this must be interpreted carefully due to confounder effect by indication for caesarean section.

Cardiac diastolic dysfunction and metabolic syndrome in young women after placental syndrome.

OBJECTIVE: To estimate whether women with a recent history of a placental syndrome and concomitant metabolic syndrome have reduced cardiac diastolic function. METHODS: In this cohort study, women with a history of a placental syndrome were included. We assessed body mass index, blood pressure, fasting serum lipids, glucose and insulin levels, and 24-hour urinary protein and albumin output after an interval of at least 6 months postpartum. Cardiac diastolic function was assessed by echocardiography. RESULTS: Metabolic syndrome was found in 22% of the women evaluated. Diastolic dysfunction was seen in 24% of the women with the metabolic syndrome compared with 6.3% in those without (odds ratio 4.77, 95% confidence interval 2.18-10.41; adjusted odds ratio 6.09, 95% confidence interval 2.64-14.04). Univariable analysis showed that all the constituents of the metabolic syndrome related to diastolic dysfunction. CONCLUSION: In women with a history of placental syndrome complicating pregnancy, the presence of metabolic syndrome increases the risk of cardiac diastolic dysfunction fourfold. LEVEL OF EVIDENCE: II.

Clinical aspects of cervical insufficiency.

Fetal loss is a painful experience. A history of second or early third trimester fetal loss, after painless dilatation of the cervix, prolapse or rupture of the membranes, and expulsion of a live fetus despite minimal uterine activity, is characteristic for cervical insufficiency. In such cases the risk of recurrence is high, and a policy of prophylactic cerclage may be safer than one of serial cervical length measurements followed by cerclage, tocolysis and bed rest in case of cervical shortening or dilatation. In low risk cases, however, prophylactic cerclage is not useful. There is a need for more basic knowledge of cervical ripening, objective assessment of cervical visco-elastic properties, and randomized controlled trials of technical aspects of cervical cerclage (e.g. suturing technique).

Outcome after transabdominal cervicoisthmic cerclage.

OBJECTIVE: To estimate benefits and risks of transabdominal cervicoisthmic cerclage in women with cervical insufficiency in whom transvaginal cerclage is considered surgically unfeasible. METHODS: This was an observational cohort study with historical controls of 101 pregnancies after transabdominal cervicoisthmic cerclage in 101 women with a classic history of cervical insufficiency and severe cervical defects precluding transvaginal cerclage. RESULTS: Median gestational age at elective transabdominal cerclage (n = 95) was 14 (range 12-16) weeks and at emergency cerclage (n = 6) was 18 (range 17-22) weeks. Perioperative complications were blood loss 500 mL or more (n = 3) and rupture of membranes (n = 2). Patients were delivered by cesarean. Before cerclage 76% (95% confidence interval [CI] 70.2-81.1%) of births occurred before 32 weeks of gestation; total neonatal survival was 27.5% (95% CI 22.5-33.8%). After transabdominal cervicoisthmic cerclage 7% (95% CI 2.9-13.9%) of births took place before 32 weeks of gestation, and total neonatal survival was 93.5% (95% CI 85.5-96.6%). CONCLUSION: In women with a classic history of cervical insufficiency and a traumatized cervix that precludes transvaginal cerclage, transabdominal cervicoisthmic cerclage is associated with successful outcome in the absence of procedure-related major complications. LEVEL OF EVIDENCE: II-2.

The prognostic value of asymmetric laxity of the sacroiliac joints in pregnancy-related pelvic pain.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To determine the prognostic value of asymmetric laxity of the sacroiliac joints during pregnancy on pregnancy-related pelvic pain postpartum. SUMMARY OF BACKGROUND DATA: In a previous study, we observed a significant relation between asymmetric laxity of the sacroiliac joints and moderate to severe pregnancy-related pelvic pain during pregnancy. METHODS: A group of 123 women were prospectively questioned and examined, and sacroiliac joint laxity was measured by means of Doppler imaging of vibrations at 36 weeks' gestation and at 8 weeks' postpartum. A left to right difference in sacroiliac joint laxity >or=3 threshold units was considered to indicate asymmetric laxity of the sacroiliac joints. RESULTS: In subjects with moderate to severe pregnancy-related pelvic pain during pregnancy, sacroiliac joint asymmetric laxity was predictive of moderate to severe pregnancy-related pelvic pain persisting into the postpartum period in 77% of the subjects. The sensitivity, specificity, and positive predictive value of sacroiliac joint asymmetric laxity during pregnancy for pregnancy-related pelvic pain persisting postpartum were 65%, 83%, and 77%, respectively. Subjects with moderate to severe pregnancy-related pelvic pain and asymmetric laxity of the sacroiliac joints during pregnancy have a threefold higher risk of moderate to severe pregnancy-related pelvic pain postpartum than subjects with symmetric laxity. CONCLUSION: These data indicate that in women with moderate to severe complaints of pelvic pain during pregnancy, sacroiliac joint asymmetric laxity measured during pregnancy is predictive of the persistence of moderate to severe pregnancy-related pelvic pain into the postpartum period.