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Biomedical subjects

L A Wolfe

Publications and source records attributed to L A Wolfe.

At least 19 recordsLinked to original sources

Plasma osmolality and the strong ion difference predict respiratory adaptations in pregnant and nonpregnant women.

This study tested the hypothesis that plasma osmolality and the strong ion difference ([SID]) predict PaCO2 during rest and during exercise in physically active pregnant (n = 22; gestational age 37.0 +/- 0.2 weeks) and nonpregnant (n = 17) women. Nonpregnant subjects were in varying stages of the menstrual cycle. Arterialized blood gases, hydrogen ion concentration, plasma osmolality, [SID], and circulating levels of progesterone were measured at rest and during upright cycling at work rates corresponding to 70 and 110% of the ventilatory threshold. Pooled data from the two groups at rest revealed significant correlations (P < 0.05) between PaCO2 with plasma osmolality, [SID], and progesterone. Progesterone was also significantly correlated with [SID] and osmolality. Also, changes in PaCO2 with exercise correlated significantly with changes in [SID]. The results support the hypothesis that plasma osmolality and [SID] are important factors in the modulation of respiratory sensitivity in healthy women. Also, the effects of progesterone on PaCO2 may be expressed, at least in part, through progesterone-induced changes in [SID] and osmolality.

Adult↗

Maximal exercise testing in late gestation: maternal responses.

OBJECTIVE: To study the effects of human pregnancy on metabolic and respiratory responses to maximal cycle ergometer testing and to test the hypothesis that the respiratory exchange ratio at maximal exercise and peak postexercise lactate concentration are lower in the pregnant compared with the nonpregnant state and that these effects are associated with lower excess postexercise oxygen consumption during pregnancy. METHODS: The pregnant (n = 14, mean gestational age 34.7 +/- 0.4 weeks) and nonpregnant control group (n = 14) included healthy, physically active women. Groups were matched for age, height, parity, prepregnant body mass and body mass index (BMI), and aerobic fitness. Breath-by-breath gas exchange was measured at rest, during exercise, and 15 minutes after exercise. The minimum sample size to detect a statistically significant result for a reasonable difference (0.25 L/min) in the ventilatory threshold was calculated to be ten subjects per group; thus, 14 was considered adequate. RESULTS: Maximal oxygen uptake, the ventilatory threshold, the point of respiratory compensation, and calculated work efficiency did not differ significantly between groups. However, the respiratory exchange ratio at maximal exercise, peak postexercise lactate, and excess postexercise oxygen consumption were significantly lower in the pregnant group. Peak lactate was significantly correlated with the respiratory exchange ratio and excess postexercise oxygen consumption. CONCLUSION: The capacity for weight-supported work is preserved in late gestation, and work efficiency is unchanged. However, carbohydrate utilization might be blunted at high levels of exertion. Blunted respiratory responses were attributed to reduced lactate production and/or dilution of lactate in an expanded blood volume.

Adult↗

Physicochemical analysis of phasic menstrual cycle effects on acid-base balance.

In accordance with Stewart's physicochemical approach, the three independent determinants of plasma hydrogen ion concentration ([H(+)]) were measured at rest and during exercise in the follicular (FP) and luteal phase (LP) of the human menstrual cycle. Healthy, physically active women with similar physical characteristics were tested during either the FP (n = 14) or LP (n = 14). Arterialized blood samples were obtained at rest and after 5 min of upright cycling at both 70 and 110% of the ventilatory threshold (T(Vent)). Measurements included plasma [H(+)], arterial carbon dioxide tension (Pa(CO(2))), total weak acid ([A(Tot)]) as reflected by total protein, and the strong-ion difference ([SID]). The transition from rest to exercise in both groups resulted in a significant increase in [H(+)] at 70% T(Vent) versus rest and at 110% T(Vent) versus both rest and 70% T(Vent). No significant between-group differences were observed for [H(+)] at rest or in response to exercise. At rest in the LP, [A(Tot)] and Pa(CO(2)) were significantly lower (acts to decrease [H(+)]) compared with the FP. This effect was offset by a reduction in [SID] (acts to increase [H(+)]). After the transition from rest to exercise, significantly lower [A(Tot)] during the LP was again observed. Although the [SID] and Pa(CO(2)) were not significantly different between groups, trends for changes in these two variables were similar to changes in the resting state. In conclusion, mechanisms regulating [H(+)] exhibit phase-related differences to ensure [H(+)] is relatively constant regardless of progesterone-mediated ventilatory changes during the LP.

Acid-Base Equilibrium↗

Effects of human pregnancy on cardiac autonomic function above and below the ventilatory threshold.

This study examined the effects of human pregnancy on heart rate variability (HRV), spontaneous baroreflex (SBR) sensitivity, and plasma catecholamines at rest and during exercise. Subjects were 14 healthy, physically active pregnant women (PG; mean gestational age = 33.9 +/- 1.0 wk). Results were compared with an age-matched nonpregnant control group (NPG; n = 14) with similar characteristics. The electrocardiographic R-wave-R-wave interval and systolic blood pressure (via finger plethysmograph) were measured on a beat-to-beat basis at rest and during upright cycling at 60 and 110% of the ventilatory threshold (T(vent)). Parasympathetic nervous system (PNS) modulation (as reflected by HRV high-frequency/total power and SBR slope) was significantly reduced at rest in the PG vs. the NPG. During exercise, PNS modulation decreased significantly in both groups, but the magnitude of PNS withdrawal from rest to 110% T(vent) was smaller in the PG vs. NPG. Sympathetic nervous system (SNS) modulation (reflected by the low-frequency power-to-high-frequency power ratio) increased above resting values at 60 and 110% T(vent) in the NPG. SNS modulation at 110% T(vent) was significantly lower in the PG compared with the NPG. Plasma norepinephrine and epinephrine levels were also lower at 110% T(vent) in the PG. It was concluded that healthy pregnant women exhibit lower PNS modulation at rest and blunted SNS modulation during exercise above T(vent) in late gestation.

Adult↗

Maximal exercise testing in late gestation: fetal responses.

OBJECTIVE: To determine the fetal response to and safety of maximal maternal exercise in the third trimester. METHODS: Twenty-three active women with uncomplicated pregnancies (singleton gestations) underwent maximal exercise testing in late gestation using a progressive maximal cycle ergometer protocol. Fetal heart rate (FHR) responses were monitored and classified using National Institute of Child Health and Human Development guidelines. Statistical analyses involved use of the Student t test, repeated measures analysis of variance with Tukey-Kramer multiple comparisons posttest, and the chi(2) test. RESULTS: There was an increase in baseline FHR in the 20-minute posttest period compared with the 20-minute pretest period. There were significantly fewer accelerations in the second posttest 10-minute segment compared with the second pretest 10-minute segment. Variability was reduced in both posttest periods compared with the first 10-minute pretest period. Time to reactivity increased after testing. Mild tachycardia was noted in two tracings and bradycardia occurred in a fetus with previously undiagnosed growth restriction. There were no abnormal neonatal outcomes. CONCLUSION: Maximal exercise testing in late gestation led to minimal changes in FHR. Fetal bradycardiac responses were not seen in appropriate for gestational age fetuses, suggesting that brief maximal maternal exertion for research or diagnostic purposes is safe in this group.

Adult↗

Plasma acid-base regulation above and below ventilatory threshold in late gestation.

Stewart's physicochemical approach was used to study the effects of pregnancy on acid-base regulation in arterialized blood. Responses of 15 healthy pregnant women (PG; gestational age, 37.1 +/- 0.2 wk) were compared with those of 15 nonpregnant controls (CG) at rest and during cycling at 70 and 110% of the ventilatory threshold (T(vent)). Hydrogen ion concentration ([H(+)]) was lower in the PG vs. CG at rest and during exercise (P < 0.05 at rest and 70% T(vent)). Exercise-induced changes in [H(+)] were similar between groups. Lower resting [H(+)] values in the PG vs. CG resulted from lower values for arterialized PCO(2) (Pa(CO(2))) and total weak acid ([A](tot)), which were partly offset by a lower strong-ion difference ([SID]). Reductions in [A](tot) and [SID] at rest were primarily the result of reductions in albumin [Alb] and sodium [Na(+)], respectively. In the transition from rest to 70% T(vent), small increases in Pa(CO(2)) and [A](tot) contributed to moderate increases in [H(+)] in both groups, however [SID] increased in the PG and decreased in the CG (P < 0.05 between groups). In the transition from rest to 110% T(vent), decreases in [SID] made a significantly greater contribution to changes in [H(+)] in the CG vs. PG. Exercise-induced increases in [H(+)] are similar in the pregnant vs. nonpregnant state, but there is a reduced contribution of [SID] both above and below T(vent) during pregnancy.

Acid-Base Equilibrium↗

Physical conditioning effects on fetal heart rate responses to graded maternal exercise.

PURPOSE: This study examined the effects of advancing gestational age and maternal aerobic conditioning (stationary cycling) on fetal heart rate (FHR) responses to strenuous non-steady-state maternal exercise. METHODS: Subjects chose to participate in either an exercise group (EG) or control group (CG). Fourteen healthy, previously sedentary pregnant women participated in the exercise group, and six pregnant controls remained sedentary. Stationary cycling (heart rate target: 145 beats x min(-1)) was performed 3 d x wk(-1) by the exercised group. Exercise duration was increased from 14 to 25 min x session(-1) during the second trimester and was maintained at 25 min x session(-1) throughout the third trimester. FHR was monitored before, during, and after a progressive submaximal cycle ergometer test (peak heart rate = 170 beats x min(-1)) performed at approximately 27 and 37 wk gestation. RESULTS: Mean FHR increased significantly (P < 0.05) during exercise, followed by a modest suppression and then a delayed rise during the recovery period at both observation times. Fetal bradycardia was not observed in any of the exercise tests. Effects of advancing gestational age included a lower FHR baseline both at rest and in response to maternal exercise and a lower incidence of exercise-induced tachycardia. Maternal physical conditioning did not significantly alter FHR response to maternal exercise. CONCLUSION: Our results support the hypothesis that FHR responses to strenuous exercise are altered by advancing gestational age and a brief progressive exercise test terminated at a maternal heart rate of 170 beats x min(-1) does not induce fetal distress during a healthy pregnancy.

Adult↗

Fetal responses to maternal strength conditioning exercises in late gestation.

Cardiovascular responses to strength conditioning exercises were examined in 12 healthy pregnant women and their unborn fetuses during the third trimester. A group of 12 healthy nonpregnant women of similar ages, parity, body height, and pre-pregnant body mass was also studied. Maternal heart rate and blood pressure and fetal heart rate (FHR) responses were measured in both the supine (30 degrees tilt) and seated postures during handgrip (HG), single-leg extension (SL), and double-leg extension (DL) exercise. Subjects performed 3 sets of 10 reps at 50, 70, and 90% of their 10-repetition maximum (10-RM) for each exercise in both postures. Pregnant subjects exhibited higher heart rates but similar blood pressure responses to control subjects under all experimental conditions. Significant increases were observed for the frequency of FHR accelerations (0.10 to 0.27/min) from rest to DL in the sitting posture at 90% RM. Moderate fetal bradycardia was observed occasionally in the tilted supine posture at rest and both during (SL, DL) and following (HG, SL, DL) exercise, suggesting that this posture should be avoided in late gestation. The results support the safety of moderate strength conditioning exercises in healthy pregnancy.

Adult↗

Effects of pregnancy and chronic exercise on maternal cardiac structure and function.

This study examined the interactive effects of pregnancy and aerobic conditioning on maternal cardiac structure and function. Effects of closely monitored cycle ergometer conditioning were studied during the second (TM2) and third trimesters (TM3) in 22 previously sedentary pregnant women (exercised group, EG) and a nonexercising pregnant control group with similar characteristics (CG, n = 19). Subjects were studied in the resting state by two-dimensional echocardiography and during cycle ergometer exercise at three steady-state power outputs at the start of TM2 (ENTRY), at the end of TM2 and TM3 (postconditioning), and 3-4 months postpartum (NPR, nonpregnant reference, CG only). Aerobic conditioning did not increase left ventricular dimensions beyond those attributable to pregnancy itself. In addition, in contrast with previous studies of nonpregnant women, physical conditioning during pregnancy did not reduce heart rate (HR) in the resting state. During exercise, the slope of the HR versus oxygen uptake (VO2) regression decreased significantly between preconditioning and the end of TM3 in the EG, suggesting that training-induced reductions in HR become more evident with increasing exercise intensity. Also, significant reductions in oxygen pulse (VO2/HR) were observed at all three work rates in the CG, but not in the EG. These findings support the hypothesis that the cardiovascular effects of aerobic conditioning are obscured by more powerful effects of pregnancy in the resting state but become "unmasked" during strenuous exercise.

Adult↗

Physical conditioning attenuates respiratory responses to steady-state exercise in late gestation.

PURPOSE: To study the ventilatory effects of closely monitored cycle ergometer conditioning (HR target, 145-150 beats x min(-1); 25 min/session; three sessions per week) during the second and third pregnancy trimesters (TMs) in healthy human pregnancy. METHODS: Subjects were 27 previously sedentary pregnant women (exercised group, EG). A sedentary control group (CG, N = 20) was also studied. Subjects were tested at rest and during upright cycle ergometry at three steady-state power outputs (approximately 20, 45, and 65 W) at the start of the second TM (ENTRY), at the end of the second and third TMs (post-training), and 3 months postpartum (PP, nonpregnant control). RESULTS: Significant reductions in exercise HR were observed in the EG at each exercise level, confirming achievement of an aerobic conditioning effect. In both groups the ventilatory equivalent for oxygen (VE/O2) was significantly higher at all work rates during pregnancy compared with that during PP. This effect was caused by significantly higher exercise tidal volumes (VT) at each work rate in both groups during pregnancy versus PP. Respiratory sensitivity as reflected by the ventilatory equivalent for carbon dioxide (E/VECO2) and calculated arterial carbon dioxide tension (PaCO2) was significantly increased at all three work rates in late gestation versus PP and increased slightly with advancing gestational age in both groups. The main effects of physical conditioning were attenuation of increases in VE/VO2 observed at all exercise levels between the end of TM2 and TM3 and reductions in respiratory perception of effort (RPEr) between ENTRY and the end of TM3. Attenuation of increases in VE/VO2 during TM3 in the EG was attributed to the combined effects of enhanced fat versus carbohydrate utilization (resulting in reduced CO2 output and drive to ventilate) and attenuation of pregnancy-induced increases in dead space ventilation in late gestation. CONCLUSION: The study results support the hypothesis that physical conditioning reduces both ventilatory demand and respiratory perception of effort in late gestation.

Adult↗

Acid-base regulation and control of ventilation in human pregnancy.

The purposes of this review were twofold: to apply modern physicochemical principles to explain changes in acid-base regulation and the control of ventilation in human pregnancy; and to demonstrate the value of pregnancy as a model for the study of endocrine effects on physiological control systems. Application of P.A. Stewart's approach (P.A. Stewart. Can. J. Physiol. Pharmacol. 61: 1444-1461, 1983) shows that lower values of plasma hydrogen ion concentration ([H+]) observed at rest and in association with exercise in pregnancy are the result of lower values for carbon dioxide tension (Pco2) and total weak acid ([A(tot)]). This effect is partly offset by a lower strong ion difference ([SID]). The ability to predict plasma [H+] at rest and following strenuous exercise in pregnancy (J.G. Kemp, F.A. Greer, and L.A. Wolfe. J. Appl. Physiol. 83: 644-651, 1997) supports the validity of Stewart's approach. Jennings and associates (D.B. Jennings. Can. J. Physiol. Pharmacol. 72: 1499-1512, 1994) have further demonstrated in animal models the involvement of plasma osmolality and circulating levels of angiotensin II (ANG II) and arginine vasopressin (AVP) in the chemical control of ventilation. We hypothesize that pregnancy-induced increases in respiratory sensitivity to carbon dioxide are the combined result of reduced plasma osmolality, reduced cerebrospinal fluid [SID], and augmented circulating levels of progesterone, ANG II, and AVP.

Acid-Base Equilibrium↗

Reliability of noninvasive methods to measure cardiac autonomic function.

Cardiac autonomic modulation was examined in 10 healthy subjects (mean age = 27.8 +/- 1.7) at rest (paced breathing at 12 and 16 breaths/min) and during a submaximal cycle ergometer exercise test. Heart rate variability (HRV) spectral parameters and spontaneous baroreflex (SBR) function variables showed no significant differences between mean values for any of the testing conditions. Spectral parameters and SBR function did not differ significantly between the resting conditions. Significant reliability coefficients (r = 0.59-0.73) were observed for all spectral parameters except low frequency power (r = 0.22) during 12 breaths/min, with moderately lower values during 16 breaths/min (r = 0.10-0.75) and exercise (r = 0.20-0.89). Significant reliability coefficients were observed for baroreflex sensitivity at 12 (r = 0.83) and 16 (r = 0.92) breaths/min. It was concluded that at rest, HRV spectral and SBR analyses are reliable methods for studying cardiac autonomic balance.

Adult↗

Toward antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1 and novel in vivo stable prodrugs of methotrexate.

Antibody-directed enzyme prodrug therapy (ADEPT) has the potential of greatly enhancing antitumor selectivity of cancer therapy by synthesizing chemotherapeutic agents selectively at tumor sites. This therapy is based upon targeting a prodrug-activating enzyme to a tumor by attaching the enzyme to a tumor-selective antibody and dosing the enzyme-antibody conjugate systemically. After the enzyme-antibody conjugate is localized to the tumor, the prodrug is then also dosed systemically, and the previously targeted enzyme converts it to the active drug selectively at the tumor. Unfortunately, most enzymes capable of this specific, tumor site generation of drugs are foreign to the human body and as such are expected to raise an immune response when injected, which will limit their repeated administration. We reasoned that with the power of crystallography, molecular modeling and site-directed mutagenesis, this problem could be addressed through the development of a human enzyme that is capable of catalyzing a reaction that is otherwise not carried out in the human body. This would then allow use of prodrugs that are otherwise stable in vivo but that are substrates for a tumor-targeted mutant human enzyme. We report here the first test of this concept using the human enzyme carboxypeptidase A1 (hCPA1) and prodrugs of methotrexate (MTX). Based upon a computer model of the human enzyme built from the well known crystal structure of bovine carboxypeptidase A, we have designed and synthesized novel bulky phenylalanine- and tyrosine-based prodrugs of MTX that are metabolically stable in vivo and are not substrates for wild type human carboxypeptidases A. Two of these analogs are MTX-alpha-3-cyclobutylphenylalanine and MTX-alpha-3-cyclopentyltyrosine. Also based upon the computer model, we have designed and produced a mutant of human carboxypeptidase A1, changed at position 268 from the wild type threonine to a glycine (hCPA1-T268G). This novel enzyme is capable of using the in vivo stable prodrugs, which are not substrates for the wild type hCPA1, as efficiently as the wild type hCPA1 uses its best substrates (i.e. MTX-alpha-phenylalanine). Thus, the kcat/Km value for the wild type hCPA1 with MTX-alpha-phenylalanine is 0.44 microM-1 s-1, and kcat/Km values for hCPA1-T268G with MTX-alpha-3-cyclobutylphenylalanine and MTX-alpha-3-cyclopentyltyrosine are 1.8 and 0.16 microM-1 s-1, respectively. The cytotoxic efficiency of hCPA1-268G was tested in an in vitro ADEPT model. For this experiment, hCPA1-T268G was chemically conjugated to ING-1, an antibody that binds to the tumor antigen Ep-Cam, or to Campath-1H, an antibody that binds to the T and B cell antigen CDw52. These conjugates were then incubated with HT-29 human colon adenocarcinoma cells (which express Ep-Cam but not the Campath 1H antigen) followed by incubation of the cells with the in vivo stable prodrugs. The results showed that the targeted ING-1:hCPA1-T268G conjugate produced excellent activation of the MTX prodrugs to kill HT-29 cells as efficiently as MTX itself. By contrast, the enzyme-Campath 1H conjugate was without effect. These data strongly support the feasibility of ADEPT using a mutated human enzyme with a single amino acid change.

Animals↗

Acid-base regulation after maximal exercise testing in late gestation.

This study employed Stewart's physicochemical approach to quantify the effects of pregnancy and strenuous exercise on the independent determinants of plasma H+ concentration ([H+]). Subjects were nine physically active pregnant women [mean gestational age = 33 +/- 1 (SE) wk] and 14 age-matched nonpregnant controls. Venous blood samples and respiratory data were obtained at rest and during 15 min of recovery from a maximal cycle ergometer test that involved 20 W/min increases in work rate to exhaustion. Mean values for [H+], PCO2, and total protein increased, whereas those for bicarbonate concentration ([HCO-3]) and the strong ion difference ([SID]) decreased in the transition from rest to maximal exercise within both groups. At rest and throughout postexercise recovery, the pregnant group exhibited significantly lower mean values for PCO2, [HCO-3], and total protein, whereas [SID] was significantly lower at rest and early recovery from exercise. [H+] was also lower at all sampling times in the pregnant group, but this effect was significant only at rest. Our results support the hypothesis that reduced PCO2 and weak acid concentration are important mechanisms to regulate plasma [H+] and to maintain a less acidic plasma environment at rest and after exercise in late gestation compared with the nonpregnant state. These effects are established in the resting state and appear to be maintained after maximal exertion.

Acid-Base Equilibrium↗

Potentiation of radiation therapy by vinorelbine (Navelbine) in non-small cell lung cancer.

Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France), a semisynthetic vinca alkaloid that is a potent inhibitor of mitotic microtubule polymerization, was recently approved for the treatment of non-small cell lung cancer. Radiotherapy also has been widely used to treat this malignancy. Since other antitumor agents that act on microtubules, such as paclitaxel and estramustine, have been shown to act as radiosensitizers, we studied the ability of vinorelbine to potentiate radiation. The in vitro activity of this combination was evaluated in the human lung carcinoma cell lines NCI-H460 and A549. when NCI-H460 cells were exposed to vinorelbine for 24 hours and then irradiated (1 to 6 Gy) the drug potentiated radiation in a dose-dependent manner, with the ratio of fractional survival (radiation) to fractional survival (drug plus radiation) ranging from 1.7:1 at 1 Gy to 5.5:1 at 6 Gy. When the treatment sequence was reversed (ie, radiation was followed by drug exposure), similar survival ratios were obtained at concentrations of vinorelbine that were five to 10 times lower. In this cell line radiation produced a block in the G2/M phase of the cell cycle, with the maximum block (60% to 70%) occurring 10 hours after treatment. The greatest potentiation was seen when irradiated cells were exposed to vinorelbine after they had plateaued in the G2/M phase of the cycle. Vinorelbine given early after irradiation, when only 10% to 30% of the cells were in G2/M, produced survival ratios similar to those of controls treated with radiation alone. In A549 cells radiation induced a G1 block. In this case, vinorelbine was unable to potentiate the effects of radiation. These studies show that vinorelbine can potentiate the antitumor effects of radiation and that the potentiation is cell cycle-dependent, with the maximal effect being obtained when the cells are in the G2 phase.

Carcinoma↗

Exercise, posture, and back pain during pregnancy.

One of the expected benefits of exercise programmes for pregnant women is to reduce or prevent back pain by improving posture. The aim of this project was to evaluate the effect of fitness classes for pregnant women on posture and back pain. In this article, postural aspects are reported. Sixty five pregnant volunteers were included in the study, of whom 27 were enrolled in exercise classes designed according to Canadian guidelines and 38 acted as sedentary controls. Posture was assessed every 4 weeks during pregnancy and 4 months postpartum by measuring curvatures of the lumbar and thoracic spines in a standard relaxed standing position from lateral photographs. Laxity of knee ligaments was also monitored using a clinical arthrometer. Weight gain could explain part of lordosis increase during pregnancy but the effect was not very strong. No effect of exercise on posture was detected. RELEVANCE: This study showed that fitness classes for pregnant women designed according to Canadian guidelines had no detectable effect on posture during pregnancy.

Journal Article↗

Exercise, posture, and back pain during pregnancy.

In this article the effect of exercise on pregnancy-related back pain is reported. Sixty five pregnant volunteers were included in the study, of whom 27 were enrolled in exercise classes designed according to Canadian guidelines, and 38 acted as sedentary controls. Back pain and functional limitations were assessed every 4 weeks during pregnancy and 4 months postpartum by questionnaires. No significant differences in back pain or functional limitations reported by the two groups were found. The biomechanical factors measured in this study, weight, back posture, and laxity, were unable to explain most of the variation in pain reported. RELEVANCE: This study showed that fitness classes for pregnant women designed according to Canadian guidelines had no detectable effect on back pain during pregnancy. If prevention of pregnancy-related back pain is sought through exercise, design of fitness programmes for pregnant women should be reconsidered.

Journal Article↗