Fetal response to maternal exercise in pregnancies with uteroplacental vascular insufficiency

American Journal of Obstetrics and Gynecology (2005) 193, 995–9

www.ajog.org

Fetal response to maternal exercise in pregnancies with uteroplacental insufficiency Vandana Chaddha, MD,a Michal J. Simchen, MD,a Lisa K. Hornberger, MD,c,e Victoria M. Allen, MD,a Shafagh Fallah, PhD,b Allan L. Coates, MD,d Anita Roberts,c Donna L. Wilkes,d Jane Schneiderman-Walker,d Edgar Jaeggi, MD,c John C. P. Kingdom, MDa Divisions of Maternal-Fetal Medicinea and Neonatology,b Mount Sinai Hospital, and Divisions of Pediatric Cardiologyc and Respirology,d Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Fetal Cardiovascular Program, University of California, San Francisco Children’s Hospital and Medical Center, San Francisco, CAe Received for publication February 28, 2005; revised May 27, 2005; accepted June 7, 2005

KEY WORDS Exercise IUGR Cardiac output Umbilical artery Perinatal outcome

Objective: The purpose of this study was to determine the fetal response to submaximal maternal exercise at 22 to 26 weeks in pregnancies with abnormal uterine artery Doppler. Study design: This was a prospective comparison of singleton pregnancies with uteroplacental vascular insufficiency (UPVI) (mean uterine pulsatility index [PI] values O1.45 [n = 12]) and those with normal uterine artery Doppler (n = 23). Maternal and fetal cardiovascular responses to 5 minutes of steady state cycling at 10% and at 15% of predicted work rate maximum were studied. Results: Umbilical artery Doppler deteriorated after exercise in patients with UPVI (pre PI 1.4 [0.35-2.14], post PI 1.64 [0.45-2.18]). Three (25%) had transient absent-end diastolic flow (AEDF) in umbilical artery, 2 of which developed early-onset intrauterine growth restriction (IUGR) with AEDF. Fetal cardiac output studies remained stable during the examinations. Conclusion: Submaximal steady state exercise had a transient deleterious effect in a subset of women with uteroplacental vascular insufficiency destined to develop early-onset IUGR. Ó 2005 Mosby, Inc. All rights reserved.

Intrauterine growth restriction (IUGR) is an important cause of perinatal mortality and neonatal morbidity, in particular when umbilical artery Doppler is Funding was provided by Physicians’ Services Incorporated (PSI), Ontario grant (no-00-42) to LH and JK. Presented at the Twenty-Fifth Annual Meeting of the Society for Maternal Fetal Medicine, February 7-12, 2005, Reno, Nev. Reprints not available from the authors. 0002-9378/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.06.035

abnormal before delivery.1 The more severe forms of IUGR, termed ‘‘early-onset’’ disease, are caused by a defect in the maternal spiral artery blood supply to the placenta and result in iatrogenic preterm delivery. The underlying pathology is termed uteroplacental vascular insufficiency (UPVI) and results in ischemic-thrombotic damage to the gas-exchanging chorionic villous tissue.2 A subset of pregnancies at risk of early-onset IUGR caused by abnormal placentation may be detected using

996 uterine artery Doppler at 20 to 22 weeks of gestation.3 Increased maternal-fetal surveillance, prophylactic steroids, and planned delivery in a tertiary center may improve perinatal prognosis, although drugs such as aspirin4 appear to have no benefit. Exercise in pregnancy may divert blood flow from the gravid uterus to the exercising limbs. However, 30 minutes of daily exercise is presumed safe in normal pregnancy,5,6 presumably because of a low-resistance uteroplacental circulation. Regular exercise in healthy women may prevent preeclampsia,7 although perhaps at the expense of birth weight.8 The safety of exercise in women with UPVI before the development of pregnancy complications is presently unknown and is the focus of this study.

Material and methods The study received Institutional Research Ethics Board approval at both sites (MSH REB # 01-0119-A) and was conducted between January 2002 and July 2004. Each woman gave written informed consent. Women were recruited from the high-risk pregnancy clinics at Mount Sinai Hospital, where uterine artery Doppler is used as a screening tool in women with medical and/or obstetric risk factors for placental insufficiency. Inclusion criteria were: singleton normotensive pregnancy, normal fetal growth, amniotic fluid and umbilical artery Doppler, abnormal uterine artery Doppler (mean pulsatility index [PI] O1.45 between 22-26 weeks of gestation), defined as a pregnancy with ‘‘uteroplacental vascular insufficiency.’’9 Maternal exclusion criteria were: smoking, active medical problems, vaginal bleeding, ruptured membranes, and placenta previa. Fetal exclusion criteria were: low amniotic fluid (maximum vertical depth of amniotic fluid !3 cm) or any structural or chromosomal abnormality, or abnormal umbilical artery Doppler.

Doppler studies Uterine artery Doppler waveforms were assessed according to previously published methods to locate the proximal uterine artery.10 Umbilical artery waveforms were located from free loops of cord using color and pulsed Doppler. Pulsatility index (PI) values were recorded from a mean of 3 consecutive stable waveforms.

Exercise protocol Maternal exercise was performed by recumbent cycling (modified exercise cycle, Collins Pedalmate, Braintree, Mass) in a dedicated exercise laboratory at the Hospital for Sick Children.11 The staff performing the studies was not blinded as to whether the woman was a control subject or had UPVI. The 2 exercise levels, or work

Chaddha et al rates, were defined as level 1 (L1) being 10% of power output and level 2 (L2) as 15% of power output (submaximal exercise). These values (in watts) were calculated for each individual from their prepregnancy physical activity, maternal height, and weight. The exercises were done sequentially in the same session as baseline resting observations, L1, resting for 5 minutes, L2, resting for 5 minutes. Ultrasound parameters of umbilical artery blood flow and fetal cardiac output were obtained at baseline and during the 2 rest periods. Maternal cardio-respiratory responses were evaluated at the end of periods L1 and L2. During exercise, the subject breathed through a 1-way valve system from a dry gas meter and into a variable volume-mixing chamber as previously described.12 Mixed expired CO2 and O2 were measured, and VO2 (O2 consumption) and VCO2 (CO2 production) calculated by the nitrogen balance technique. Following a period of steady state exercise conditions, the subject performed a CO2 rebreathe maneuver to allow the measurement of mixed venous CO2 (PVCO2) from which cardiac output was calculated using the indirect Fick method.12,13

Fetal cardiovascular responses These studies were performed by an experienced fetal cardiac ultrasound technician (AR) or fetal cardiologist (LKH) using duplex ultrasound equipment (ATL 5000, Philips, Bothell, Wash). Ultrasound parameters studied were umbilical artery Doppler PI, aortic and pulmonary valve diameter in systole, velocity-time integral (VTI) of systolic flow spectra through pulmonary valve and aortic valve, left and right ventricular stroke volume (pr2 ! VTI), where r is the 0.5 of the diameter of the semilunar valve and cardiac output (stroke volume ! heart rate).14 All measurements were taped and analyzed off-line by the same investigator (VC). Values were calculated as mean values from 3 consecutive waveforms.

Clinical outcomes Pregnancy outcomes, including serial ultrasound examinations, were collected at delivery. Birth weight centiles were calculated,15 and hypertensive complications of pregnancy were categorized using American College of Obstetrics and Gynecologists (ACOG) criteria.16 Smallfor-gestational age (SGA) was defines as birth weight less than 10th centile. Early-onset IUGR was defined as birth before 32 weeks of an SGA infant with reduced amniotic fluid and AEDF in the umbilical arteries.1

Statistics The study sample size was prospectively calculated before commencement using data from a similar study involving IUGR pregnancies in the third trimester.17 To exclude an effect of exercise upon umbilical artery

Chaddha et al Doppler an alpha of 0.05 a power of 0.9, our study required a minimal sample size of 8 patients with UPBVI and 19 control subjects. Quantitative outcome variables that were measured serially were analyzed using 2-way repeated measures analysis of variance (ANOVA). Comparison of mean changes in maternal and fetal data between cases and controls was performed using Student t test. Multiple linear regression analysis was used to assess the contribution of clinical variables to the relationship between exercise and fetal and placental Doppler responses.

Results The study completed with recruitment of 12 subjects with UPVI and 23 controls. Comparison of baseline characteristics is shown in Table I. Comparison of delivery outcomes and pregnancy complications are shown in Table II. Subjects with UPVI delivered at an earlier gestation, with higher rates of IUGR and hypertension. Two women with UPVI (17%) developed earlyonset IUGR with AEDF in the umbilical arteries at the time of delivery. Only 2 of 12 women had uncomplicated outcomes in the UPVI group. Table III compares fetal heart rate and umbilical artery PI responses to the 2 levels of exercise. Mean umbilical artery PI increased in response to exercise in the UPVI group and decreased in the comparison group with normal uterine artery Doppler. Three of 12 UPVI subjects developed transient AEDF in the umbilical arteries after each level of exercise; 2 of these pregnancies subsequently developed early-onset IUGR with ARED in the umbilical arteries before delivery. Table IV compares fetal cardiac output parameters between the 2 groups. Baseline left ventricular stroke volume and output were lower in the UPVI group. Both parameters increased significantly over time (ANOVA, P = .048 for LV output) in each group. LV output correlated strongly with eventual birth weight in the controls (ANOVA, P = .0007) but this relationship was not observed in the UPVI group (ANOVA, P = .52). Baseline right stroke volume and output did not differ between the 2 groups and no significant differences were observed in either group following the 2 periods of exercise. Maternal cardiovascular responses to exercise showed no significant changes in either group: heart rate 107 (SD 12) beats/min in UPVI group versus 107 (SD 12) in control group and cardiac output 8.7 (SD 2.3) L/min in UPVI group versus 8.6 (SD 1.1) in control group.

Comment Physicians and other health-care providers are frequently asked questions by their pregnant patients

997 Table I Comparison of baseline demographic characteristics between groups with uteroplacental vascular insufficiency (UPVI) and normal controls

Age (y) GA (wk) Height (cm) Prepregnancy weight (kg) Current weight (kg) WR-L1 (w) WR-L2 (w)

UPVI cases (n = 12) Mean (SD)

Controls (n = 23) Mean (SD)

P value (t test)

29.6 25 167.5 57.9

34.4 25 166.5 58.6

.81 .93 .11 .42

(3.2) (1.6) (6) (12.4)

68.2 (12.2) 25 (2.2) 35 (6)

(6.38) (1.9) (8.3231) (9.9)

67.7 (12) 25 (3.5) 35 (6.6)

.6 .74 .96

GA, Gestational age; WR, work rate (watts); L1, 1st level–10%predicted capacity; L2, 2nd level–15%predicted capacity.

Table II Comparison of pregnancy outcomes between groups with uteroplacental vascular insufficiency (UPVI) and normal controls

GA at delivery (wk) Birth weight (kg) SGA Gestational hypertension PET HELLP NRNST AEDF

UPVI cases (n = 12) Mean (SD)

Controls (n = 23) Mean (SD)

33 (3.7) 1.7 (1) 5 2

40 (1.4) 3.2 (0.4) 0 0

6 1 2 2

0 0 0 0

P value Chi-square (t test) .0014 .0014 .0024 .11 ! 0.0001 .34 .11 .11

PET, Preeclamptic toxemia; HELLP, hemolytic anemia, elevated liver enzymes and low platelets; AEDF, absent end-diastolic flow in the umbilical arteries; NRNST, nonreassuring non-stress test.

regarding the safety of exercise in pregnancy. This is especially pertinent in clinically high-risk women based on medial or obstetric risk factors. Most studies of exercise in pregnancy have focused on outcomes in clinically low-risk women such that moderate regular exercise is encouraged by ACOG.5 By contrast, few studies have involved women with clinical complications in the third trimester.17,18 Hackett et al19 demonstrated a deleterious effect of maternal exercise upon the uteroplacental circulation in hypertensive or SGA fetuses in the third trimester. More recently, Ertan et al18 studied uterine, umbilical, and fetal Doppler responses to exercise in 10 SGA fetuses and 33 controls. Baseline uterine artery Doppler studies were normal in both groups and no differences in umbilical parameters, although fetal cerebral vasodilatation was seen more pronounced in the IUGR group after exercise.

998

Chaddha et al

Table III Comparison of fetal heart rate and umbilical artery pulsatility index between groups with uteroplacental vascular insufficiency and normal controls after level 1 (L1) and level 2 (L2) exercise periods

FHR (bpm)-rest FHR (bpm)-L1 FHR (bpm)-L2 UA – PI rest UA – PI L1 UA – PI L2

UPVI cases (n = 12) Mean (SD)

Controls (n = 23) Mean (SD)

P value Unpaired t test

148.1 146.1 148.8 1.5 1.5 1.6

144.7 143 143.2 1.3 1.2 1.3

.89 .2 .1 .06 .03 .03

(6.6) (6.5) (9.9) (0.3) (0.4) (0.4)

(6.0) (6.7) (6.6) (0.20) (0.3) (0.2)

FHR, Fetal heart rate; bpm, beats per minute; PI, pulsatility index; UPVI, uteroplacental vascular insufficiency; UA, umbilical artery.

We focused our study upon women with uteroplacental vascular insufficiency in the second trimester, before the development of any clinical complications. We based our sample size calculation upon the observations of the Japanese group Nabeshima et al.17 In this study, graded walking was employed to assess the effect of exercise upon fetal umbilical artery Doppler in 7 pregnancies with IUGR. Umbilical artery Doppler waveforms post-exercise did not show a significant change in these women compared with those obtained from 17 controls. The extent of UPVI was unknown because uterine artery Doppler studies were not reported. Most pregnancies complicated by IUGR or preeclampsia sufficient to result in delivery before 32 weeks of gestation have distinctly abnormal uterine artery Doppler, and concomitant ischemic-thrombotic placental pathology.2 If evidence-based recommendations are to be given to women with potentially high-risk pregnancies regarding the safety of exercise, these need to be based upon data obtained before the development of the disease of interest (IUGR or preeclampsia resulting in preterm delivery). We selected potentially high-risk women using a strict definition of abnormal uterine artery Doppler based upon previously published cohort data.9 Outcomes at delivery confirmed the high-risk nature of our subjects. Our study was limited by being unable to blind the exercise staff as to whether the subjects were controls or had been recruited from our high-risk pregnancy clinic with a finding of abnormal uterine artery Doppler. This limitation was addressed partially by offline data analysis of taped Doppler information. Our study confirms hemodynamic stability in the maternal and fetal compartments of healthy women exercising at 10% to 15% of predicted workload in the second trimester. Analysis of our data in women with abnormal uterine artery Doppler showed a significant deterioration in umbilical artery Doppler in response to a level of exercise that few women would regard as challenging; 3 fetuses (25%) exhibited transient AEDF after each exercise period, 2 of which

Table IV Comparison of fetal cardiac circulation parameters after L1 and L2 between groups with uteroplacental vascular insufficiency (UPVI) and normal controls UPVI cases (n = 12) Mean (SD) LV stroke volume rest LV stroke volume L1 LV stroke volume L2 LV output rest LV output L1 LV output L2 RV stroke volume rest* RV stroke volume L1* RV stroke volume L2* RV output rest RV output L1 RV output L2

Controls (n = 23) Mean (SD)

P value Unpaired t test

2.5 (0.6)

3 (0.7)

.03

2.8 (0.6)

3.3 (1.3)

.13

3.3 (1)

.34

443 492 476 2.5

.03 .08 .59 .49

3 (0.8) 361 406.7 449.8 2.7

(91) (92) (124) (0.8)

(113) (189) (154) (0.8)

2.8 (0.6)

2.8 (0.9)

2.7 (0.7)

2.8 (1)

.73

372 (122.8) 407 (117.4) 404 (147.2)

.59 .85 .81

393.9 (108.4) 413.6 (93.5) 392.9 (116.5)

1

* Units, milliliters, all other units milliliters per minute.

subsequently developed early-onset IUGR with AEDF in the umbilical arteries, requiring elective preterm delivery in the fetal interest. These findings were associated with stable fetal right ventricular stroke volume and cardiac output during exercise, implying that impaired fetoplacental perfusion was not caused by impaired ejection of the right ventricle via the ductus arteriosus. An alternative explanation is that exercise is capable of diverting maternal blood flow away from the highresistance uteroplacental circulation in the UPVI group to the exercising lower limbs. Reduced intraplacental oxygenation may therefore cause hypoxia-induced vasoconstriction in placental stem arteries, leading to a transient increase in feto-placental vascular resistance.20 Middle cerebral artery Doppler may be used to noninvasively assess fetal oxygenation21 but was not included in this study. Rather we chose to serially assess left ventricular output because the brain is the major organ perfused by the left ventricle during fetal life. The observed increase in left ventricular stroke volume in response to exercise is consistent with the known increase in cerebral blood flow that occurs in response to mild hypoxia.22 Thus, we conclude from our data that exercise at 10% to 15% of power output in women with UPVI may result in a transient reduction in umbilical artery blood flow because of feto-placental vasoconstriction, and that the systemic transient hypoxia results in increased left ventricular output in order to preserve fetal cerebral oxygenation.

Chaddha et al Our data have 3 clinically-relevant implications. First, those women in whom UPVI is detected in the second trimester, presumably as a result of previous high-risk factors, should be cautioned regarding the potential safety of continuing with daily moderate exercise. Further research into the safety of exercise from the fetal perspective is necessary in women with impaired uteroplacental blood flow. Second, umbilical artery Doppler response to exercise may be a prognostic test of perinatal outcome in women with UPVI and, thus, deserves further evaluation, alongside maternal serum screening data and placental morphology.2 Third, our data suggest that bed rest, more accurately described as home-rest off work, should be evaluated as a potentially therapeutic tool to improve outcomes in clinically high-risk women with UPVI.

Acknowledgment We would like to thank Dr Jeffrey Smallhorn, Department of Pediatric Cardiology, Hospital for Sick Children, Toronto, for his input into the original conception of the study.

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