Professional Documents
Culture Documents
www.AJOG .org
had ultrasounds. Mean age was 25.5 5.5 years with a body mass
index of 28.0 7.3 kg/m2. Sixty-seven percent were white/Caucasian, 27% black/African American, and 6% Hispanic/Latina. Mean
delivery gestational age was 38.5 2.9 weeks, with 23% delivering
by cesarean and 59% achieving uncomplicated spontaneous VD.
Cite this article as: Oliphant SS, Nygaard IE, Zong W, et al. Maternal adaptations in preparation for parturition predict uncomplicated spontaneous delivery outcome. Am J
Obstet Gynecol 2014;211:xx-xx.
From the Division of Urogynecology, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR (Dr Oliphant);
Division of Urogynecology, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT (Dr Nygaard); and Divisions
of Ultrasonography (Dr Canavan) and Urogynecology and Reconstructive Pelvic Surgery (Dr Moalli), Department of Obstetrics, Gynecology, and
Reproductive Sciences, and Magee-Womens Research Institute and Foundation (Drs Zong and Moalli), Department of Obstetrics, Gynecology, and
Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Received March 20, 2014; revised June 5, 2014; accepted June 9, 2014.
This study was supported by an unrestricted grant from the Jewish Healthcare Foundation, Pittsburgh, PA.
The authors report no conict of interest.
Presented in oral format at the 34th Annual Scientic Meeting of the American Urogynecologic Society, Las Vegas, NV, Oct. 16-19, 2013.
Reprints not available from the authors.
0002-9378/$36.00 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.06.021
1.e1
Research
www.AJOG.org
M ATERIALS
AND
M ETHODS
Clinical data
During study visits in the rst and third
trimesters, study investigators or trained
pelvic oor research nurses performed
pelvic examinations to measure vaginal
support using the POP-Q examination
as described by Bump et al.20 The parent
study collected extensive demographic,
health, and obstetric data for each subject. Our analysis included the baseline
demographics and delivery variables
collected via medical record and parent
study chart abstraction.
Elastase activity assay
At the rst- and third-trimester visits, we
collected vaginal uid swabs from the
posterior and lateral fornices to obtain
vaginal epithelial cells. After collection,
vaginal uid swabs were processed, the
supernatant collected, and the protein
concentration determined using the BioRad Protein Assay (Bio-Rad Laboratories, Hercules, CA). Halt proteinase
inhibitor cocktail (Thermo Fisher Scientic, Pittsburgh, PA) was added to
each sample to preserve proteinase activity. An EnzChek elastase assay kit (Life
Technologies, Grand Island, NY) was
used to test each sample. This kit contains proprietary DQ elastin labeled with
BODIPY FL dye in which the uorescence has been quenched in the undigested form. When digested by elastase
or other proteases that exhibit elastaselike activity, highly uorescent particles
are yielded. This uorescence is proportional to the amount of elastase
activity in the sample and measured at an
excitation wavelength of 485 nm and an
emission wavelength of 530 nm using a
Molecular Devices SpectroMax M2
(Sunnyvale, CA).
Data were analyzed using a
4-parameter regression curve (Masterplex ReaderFit; Miraibio, San Francisco,
CA) of puried elastase from pig
pancreas and expressed as units per
milliliter total elastase, in which 1 unit
is dened as the amount of enzyme
necessary to solubilize 1 mg of elastin in
20 minutes at pH 8.8 and 37 C. Values
are then normalized to protein concentration to yield a nal elastase activity
value expressed as units of elastase per
milligram of protein. We chose to use
this noninvasive method to reect the
levels of elastase in the vagina because we
previously have found that the levels of
active matrix metalloproteinases in
vaginal swabs are highly correlated with
those in full-thickness vaginal biopsies
(obtained from the vaginal apex) in both
humans (Spearmans rho 0.92, P <
.001) and rhesus macaque monkeys
(Spearmans rho 0.92, P .05) (data
not shown and P. Moalli, personal
communication).
Transperineal ultrasonography
A subset of consecutive women at one
site also underwent ultrasound measures
of the levator hiatus in the rst and
third trimesters using transperineal
3-dimensional (3-D) technique ultrasound at rest and with maximal strain
(Valsalva) as described by Dietz.21
Transperineal ultrasound was performed
by a single unblinded examiner using a
Philips IU22 (Philips, Andover, MA)
with a 3D6-2 probe with the subject in
the lithotomy position and the hips
slightly exed and abducted. The subject
was maintained parallel to the oor
with no more than a 30-degree incline.
Research
www.AJOG.org
TABLE 1
Variable
Third
trimester
Change
first to third
trimester
P valuea
POP-Q points
n
173
149
149
Aa
e2.3 0.7
e2.3 0.7
0.1 0.9
.131
Ba
e2.3 0.8
e2.3 0.7
0.1 0.9
.084
e6.0 1.3
e6.7 1.2
e0.6 1.7
< .001
e8.0 1.4
e8.5 1.2
e0.5 1.7
.001
Ap
e2.7 0.5
e2.5 0.4
0.2 0.5
< .001
Bp
e2.7 0.6
e2.5 (0.4)
0.2 (0.7)
.008
TVL
8.7 1.4
9.2 (1.1)
0.5 (1.5)
< .001
GH
2.5 0.6
2.8 (0.6)
0.3 (0.7)
< .001
PB
4.3 0.7
4.4 (0.8)
0.1 (0.9)
.309
50
41
50
Rest
Circumference, mm
Area, mm
139.0 19.6
143.2 18.6
4.2 14.9
.082
.111
Valsalva
Circumference, mm
Area, mm
144.6 20.0
153.3 22.5
8.7 18.0
.004
.005
R ESULTS
P values reflect paired comparisons for women with data at both time points (n 149).
Statistical analyses
We assessed changes in pelvic organ support by POP-Q, levator hiatal dimensions
1.e3
Research
www.AJOG.org
TABLE 2
Uncomplicated
spontaneous
VD, yes
Uncomplicated
spontaneous
VD, no
P valuea
Demographic,
n 150
Age, y
First-trimester BMI,
kg/m2
25.8 5.4
26.8 6.6
28.1 5.4
29.3 7.5
.010
.037
Delivery
n 149
n 145
38.7 1.9
3241.8 57.4
38.9 2.2
3352.2 572.9
.760
.201
Ba
e2.2 0.8
e2.4 0.5
.019
e6.5 1.1
e7.1 1.3
.002
e8.3 1.2
e8.9 1.2
.016
Bp
e2.5 0.4
e2.6 0.4
.153
TVL
9.2 1.0
9.6 1.2
.019
GH
2.9 0.7
2.6 0.5
.004
PB
4.4 0.8
4.4 0.9
.963
Circumference, mm
145.2 19.9
140.5 17.4
.449
1430.4 337.8
1416.9 335.6
.902
Circumference, mm
153.4 21.5
152.1 24.8
.862
1697.8 496.6
1733.4 600.5
.841
Third-trimester
POP-Q (n 140)
Levator hiatus
dimensions: third
trimester (n 39)
Rest
Area, mm
Valsalva
Area, mm
Research
www.AJOG.org
C OMMENT
FIGURE
TABLE 3
2.422 (1.224e4.792)
.011
First-trimester BMI
0.905 (0.848e0.966)
.003
0.807 (0.592e1.098)
.173
Age
0.875 (0.802e0.956)
.003
2.093 (1.361e3.218)
.001
4.115 (1.866e9.074)
< .001
P value
Model controlled for first-trimester BMI and gestational age at time of first-trimester vaginal swab collection. In addition, all
variables with P < .20 found in Table 2 were included for consideration in model building. The previously mentioned variables
represent our final model.
BMI, body mass index; POP-Q, Pelvic Organ Prolapse Quantification.
Oliphant. Maternal adaptations for uncomplicated delivery. Am J Obstet Gynecol 2014.
Our data suggest that signicant maternal adaptations occur during pregnancy
in preparation for vaginal birth. These
adaptations are evidenced by POP-Q
changes over trimesters, suggesting overall vaginal lengthening, hiatal widening,
and posterior vaginal relaxation. Similarly, ultrasound measures of levator hiatal dimensions demonstrated hiatal
widening at maximal strain across trimesters. We found rst-trimester elastase
levels to be strongly associated with uncomplicated spontaneous VD.
The importance of early elastase activity in the delivery process suggests that
the remodeling process occurs quite
early in pregnancy. In a model controlling for age, rst-trimester BMI and
sampling time, apical and genital hiatus
relaxation in late pregnancy as measured
by POP-Q and higher elastase activity in
rst trimester were each strongly and
independently associated with vaginal
delivery success.
Many studies have reported an association between vaginal delivery and pelvic
organ prolapse.6,9,22 Although this association has been attributed largely to the
delivery event, it is possible that vaginal
delivery is on the causal pathway between
vaginal descent during pregnancy and
pelvic organ prolapse. In this instance,
some of the risk attributed to the delivery
event could be due to the fact that
women with more vaginal descent during
pregnancy are more likely to deliver
vaginally.
The degree of POP-Q support change
seen across trimesters in this cohort,
although statistically signicant, may lack
immediate clinical signicance because
of the small degree of overall change.
However, we do not fully understand the
long-term ramications of this support
alteration on future pelvic oor health.
Animal data have demonstrated a relative
suppression of elastase during pregnancy
followed by a postpartum surge, presumably for tissue recovery and repair.23
Whether such a surge is identied in
humans is the focus of future study.
Our study is unique in that we used a
combination of biological and clinical
data to explore pelvic support in human
1.e5
Research
pregnancy, thus providing a needed
groundwork for future work in this area.
Although this study is exploratory, our
population enrolled at 2 sites exhibits
reasonable diversity. However, we were
able to perform ultrasound evaluation
on only a subset of women because of
funding constraints. A smaller sample
for ultrasound data may in part explain
a lack of association between levator hiatus measures and our composite
outcome of uncomplicated spontaneous
VD.
Alternatively, the data may suggest
that remodeling of the vagina and its
supportive tissues is more critical for an
uncomplicated spontaneous vaginal delivery then hiatal widening. We are
limited in our ability to fully describe
maternal adaptations because our rst
data collection occurred in the rst
trimester and not before conception;
although ideal, pregestational data
collection is likely not feasible in an
observational cohort of this nature.24
Another notable limitation is that the
parent study included women with prior
pregnancies lasting less than 20 weeks
gestation and those with prior cervical
surgeries, both of which have the potential for unmeasured impact on tissue
adaptations in the current pregnancy.
We are able to measure only the relationship of the variables included in our
data collection and analysis; thus, we
may not have captured all relevant
contributing factors.
Because this is a preliminary study, we
chose to include all cesarean deliveries in
the complicated delivery group, and it is
biologically plausible that the same adaptations that inhibit vaginal delivery
might also predispose to nonreassuring
fetal status (for example, by descent
against a too tight outlet). Including these
cesarean deliveries, if in fact there is no
association between elastase and nonreassuring fetal status, breech, or other
indications other than arrest of descent/
dilatation, would bias our results toward
the null hypothesis. Thus, the magnitude
of the true effect may be greater than we
observed, which is supported by our
sensitivity analyses. In addition, we did
have missing data at various time points,
www.AJOG.org
a limitation common in longitudinal
cohort designs, although overall subject
retention was high.
Future work is needed to further
explore how maternal adaptations affect
uncomplicated spontaneous vaginal delivery. The ability to distinguish women
most likely to deliver atraumatically via
uncomplicated spontaneous vaginal
birth has the potential to have a great
impact on obstetrical care, perhaps
guiding mode of delivery counseling, the
site of delivery, operative delivery practices, and maternal and provider expectations for the delivery event.
In the long term, increased understanding of these maternal adaptations
may allow for injury prevention strategies
to reduce the future incidence of symptomatic pelvic oor disorders. Further
human studies are needed to understand
the role of elastase and other biomarkers
in pregnancy adaptations, postpartum
recovery, and the subsequent development of pelvic oor disorders.
ACKNOWLEDGMENTS
We thank the nuMoM2b (NCT01322529) for
their support and assistance of this ancillary
project and Leslie Meyn, PhD, of the MageeWomens Research Institute and Foundation,
for her assistance with statistical analysis.
REFERENCES
1. Nygaard I, Barber MD, Burgio KL, et al.
Prevalence of symptomatic pelvic oor disorders
in US women. JAMA 2008;300:1311-6.
2. Patel DA, Xu X, Thomason AD, Ransom SB,
Ivy JS, DeLancey JO. Childbirth and pelvic
oor dysfunction: an epidemiologic approach
to the assessment of prevention opportunities
at delivery. Am J Obstet Gynecol 2006;195:
23-8.
3. Leijonhufvud A, Lundholm C, Cnattingius S,
Granath F, Andolf E, Altman D. Risks of
stress urinary incontinence and pelvic organ
prolapse surgery in relation to mode of childbirth.
Am J Obstet Gynecol 2011;204:70.e1-7.
4. Swift SE. The distribution of pelvic organ
support in a population of female subjects seen
for routine gynecologic health care. Am J Obstet
Gynecol 2000;183:277-85.
5. Handa VL, Blomquist JL, McDermott KC,
Friedman S, Muoz A. Pelvic oor disorders after
vaginal birth: effect of episiotomy, perineal
laceration, and operative birth. Obstet Gynecol
2012;119(2 Pt 1):233-9.
6. Handa VL, Blomquist JL, Knoepp LR,
Hoskey KA, McDermott KC, Muoz A. Pelvic oor
Research
www.AJOG.org
dysfunction. Am J Obstet Gynecol 1996;175:
10-7.
21. Dietz HP. Ultrasound imaging of the pelvic
oor. Part II: three-dimensional or volume imaging. Ultrasound Obstet Gynecol 2004;23:
615-25.
22. Progetto
Menopausa
Italia
Study
Group. Risk factors for genital prolapse in
non-hysterectomized
women
around
menopause: results from a large crosssectional study in menopausal clinics in
Italy. Eur J Obstet Gynecol Reprod Biol
2000;93:135-40.
23. Wieslander CK, Marinis SI, Drewes PG,
Keller PW, Acevedo JF, Word RA. Regulation of
elastolytic proteases in the mouse vagina during
1.e7