Objective
We sought to investigate the effect of body mass index (BMI) on in vitro response to tocolytics.
Study Design
Myometrial biopsies were obtained at the time of scheduled cesarean deliveries from term nonlaboring women with BMI ≤29.9 (26.3 ± 1.3; n = 7), 30-34.9 (31.8 ± 1.2; n = 16), and ≥35 (39.5 ± 4.9; n = 9). Tissue strips were suspended in organ chambers for isometric tension recording. The effects of cumulative doses (10 −10 to 10 −5 mol/L) of nifedipine or indomethacin on spontaneous uterine contractility were determined. Areas under the contraction curve were compared using 1-way analysis of variance with Tukey post hoc test.
Results
Myometrial response to tocolytics did not differ between the BMI groups. Nifedipine, but not indomethacin, significantly inhibited myometrial contractility independent of BMI.
Conclusion
BMI does not affect uterine response to tocolytics in isolated uterine tissue from term nonlaboring women.
Over the past 2 decades the prevalence of obesity (body mass index [BMI] ≥30 kg/m 2 ) has doubled while that of morbid obesity (or class III obesity, BMI >40 kg/m 2 ) has quadrupled. In the United States, obese women represented 33.2% of the female adult population in 2003 through 2004. Reproductive health is one area where the burden of the obesity epidemic is strongly felt, as 22.4% of women delivering in 2001 through 2004 conceived while obese and another 23% were overweight (BMI 25-29.9).
Obese women and their fetuses are at higher risk of antepartum and peripartum complications including birth defects, fetal death, macrosomia, shoulder dystocia, preeclampsia, and gestational diabetes, as well as postoperative complications such as wound disruption and venous thromboembolism. Moreover, prospective cohort studies have demonstrated that obesity is associated with a reduction in spontaneous labor, an increase in postdates induction, labor arrest, and cesarean delivery. It has been shown that the higher incidence of medical and obstetric complications accounts for many of the preterm births (PTBs) in the obese population; on the contrary, the association between maternal obesity and spontaneous preterm labor (PTL) or PTB with preterm premature rupture of membranes remains controversial.
Based on these data, we chose myometrial samples from term pregnancies to investigate the in vitro effect of maternal BMI on spontaneous uterine contractility and uterine response to tocolytics. The answer to such questions would enable clinicians to better tailor the treatment of spontaneous PTL in the obese population.
Materials and Methods
The study was approved by the institutional review board of the University of Texas Medical Branch. Patients undergoing scheduled low transverse cesarean delivery at term (37-42 weeks’ gestation) were approached for consent. Patients with >3 contractions per hour, rupture of membranes, placenta previa, and uterine abnormalities affecting contractility (eg, leiomyomas) were excluded.
At the time of cesarean delivery, biopsies from the upper edge of the transverse incision in the lower uterine segment were obtained from term nonlaboring women. They were then placed in Hanks balanced salt solution (Gibco BRL Products, Rockville, MD) and prepared into 9 × 2 × 2 mm strips.
Tissue organ chamber
Myometrial strips were mounted vertically in 10-mL organ chambers containing Krebs-Henseleit solution and prepared for isometric tension recording using stainless steel hooks and surgical silk sutures. One end of the strip was attached to a fixed support at the bottom of the chamber, while the other end was connected to an isometric force transducer. The temperature in the organ bath was maintained at 37°C and the solution was continuously bubbled with 5% carbon dioxide in air (pH ∼7.4). Strips were equilibrated at the passive tension of 1 g in Krebs solution. Isometric tension was measured with Harvard isometric force transducers (Harvard Apparatus, South Natick, MA) connected to a computer. The data were acquired and analyzed using Windaq data acquisition (Dataq Instruments Inc, Akron, OH). The specimens were equilibrated for 1-2 hours until the contractions generated from passive tension application stabilized; the bath solution was changed every 30 minutes. Tissues with poor spontaneous contractile activity were discarded with the assumption that they represented scar tissue or that the tissue was not viable at the time of the experiment. Cumulative concentrations of nifedipine (10 −10 to 10 −5 mol/L) or indomethacin (10 −10 to 10 −5 mol/L) were then added.
Data analysis
The area under the curve defining myometrial contractions (integral activity) over a 30-minute period was used as a measure of contractility. Baseline activity was defined as the integral activity over the 30 minutes following stabilization of spontaneous myometrial contractions. The effects of nifedipine and indomethacin were expressed as percentage of the baseline activity, dividing the integral activity calculated after adding each dose of tocolytic agent by the baseline myometrial contractility. Temporal controls were exposed to the solvent dimethyl sulfoxide and used to normalize for the effects of time-dependent decay in contractility. Dose-response curves were then generated for indomethacin and nifedipine, and for each, the area under the curve was calculated using GraphPad Prism, version 3.00 for Windows (GraphPad Software, San Diego, CA). Recording of myometrial contractility started 1-30 minutes after measurement of baseline activity. Continuous variables were analyzed with 1-way analysis of variance followed by Tukey post hoc test; if normality test failed, Kruskal-Wallis analysis of variance on ranks was performed. Mean ± SEM was utilized to describe normally distributed continuous variables, otherwise median and interquartile ranges were provided. Categorical data were compared using Fisher’s exact test (significance: P < .05).
Drugs and solutions
Nifedipine and indomethacin were purchased from Sigma (St Louis, MO). Nifedipine was dissolved in dimethyl sulfoxide, indomethacin in 99% ethanol. Solutions were aliquoted and kept at −20°C until use. The final concentration of ethanol in the organ chamber solution (1.3 * 10 −4 mol/L) was 130 times inferior to a plasma concentration that could possibly account for a tocolytic effect.
Results
Table 1 describes the characteristics of the 32 term nonlaboring women enrolled in the study. Obstetric and demographic characteristics did not differ significantly among the 3 BMI groups. After discarding the samples with poor contractile activity, 89 strips were included in the data analysis.
| Characteristic | BMI ≤29.9 (n = 7) | BMI 30-34.9 (n = 16) | BMI ≥35 (n = 9) | P |
|---|---|---|---|---|
| BMI, kg/m 2 | 26.3 ± 1.3 | 31.8 ± 1.2 | 39.5 ± 4.9 | |
| Age, y | 29.3 ± 5 | 29.1 ± 5.1 | 30.1 ± 5.2 | .9 a |
| Gravidity | 3.6 ± 1.3 | 4.1 ± 1.7 | 3.8 ± 1.2 | .7 a |
| Parity, n (range) | 2 (1–3) | 2 (1.25–3) | 1 (1–3.5) | .5 b |
| Gestational age, wk | 39.3 ± 1 | 39.2 ± 0.6 | 39 ± 0.8 | .6 a |
| PCD, n (range) | 1 (1–2) | 1.5 (1–3) | 1 (0–1.5) | .1 b |
| Ethnicity | ||||
| Hispanic | 6 (85.7) | 15 (93.8) | 8 (88.9) | |
| Caucasian | 0 (0) | 0 (0) | 1 (11.1) | |
| African American | 1 (14.3) | 1 (6.2) | 0 (0) | P A = P B = 1 c |
| Indication for primary cesarean section | ||||
| Malpresentation | 1 (100) | 1 (100) | 2 (50) | |
| Maternal request | 0 (0) | 0 (0) | 2 (50) | P A = P B = .9 c |
| Indication for first cesarean section in women with PCD | ||||
| Failure/arrest of dilatation/descent | 2 (33.3) | 4 (26.7) | 2 (40) | |
| Other | 3 (50) | 7 (46.6) | 3 (60) | |
| Not known | 1 (66.7) | 4 (26.7) | 0 (0) | P A = .5, P B = .3 c |
a Continuous variables were analyzed with 1-way analysis of variance followed by Tukey post hoc test;
b If normality test failed, Kruskal-Wallis analysis of variance on ranks was performed;
c Categorical data are presented as n (%) and analyzed using Fisher’s exact test.
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