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HEARTBURNIN LATE PREGNANCY. MANOMETRICSTUDIESOF ESOPHAGEALMOTORFUNCTION*

By RICHARDNAGLERAND HOWARDM. SPIRO

(From the Department of Internal Medicine, Yale University School of Medicine,New Haven, Conn.)

(Submitted for publication May 27, 1960; accepted January 13, 1961)

Heartburn is a burning, often hot sensationwhich may localize in the throat or substernal re-gion. It is especially common during pregnancy.Gastroesophageal reflux and neuromuscular dys-function of the esophagus have been suggested asunderlying pathophysiological mechanisms, butcontradictory evidence has prevented a clear defini-tion of the cause of heartburn.

A prospective clinical study of 560 pregnantwomen disclosed that 50 per cent developed heart-burn which invariably disappeared after delivery(1). The self-limited character of pregnancymakes it an ideal experimental period duringwhich to study heartburn. Transducer pressurerecordings of esophageal motility are well adaptedto such a study.

This paper reports the results of serial esopha-geal motility studies in pregnant women with andwithout heartburn and in a group of asymptomaticnormal women of similar age.

METHODS

Subjects. Fifty-seven esophageal motility studies wereperformed on 20 pregnant women who complained ofheartburn during pregnancy. The 8 primiparae and 12multiparae ranged in age from 16 to 39 years, with anaverage age of 28. Similarly, 63 recordings were ob-tained from 19 pregnant women who never developedheartburn throughout pregnancy; in this group were 10primiparae and 9 multiparae, 20 to 35 years old, with anaverage age of 26. Each women was studied at leastonce during and after pregnancy, but the total numberof studies in each subj ect depended on the month ofpregnancy when the patient was first seen. Fourteenasymptomatic normal nonpregnant women, 22 to 44 yearsold, with an average age of 26, served as controls; eachsubject was studied 6 times at monthly intervals.

Technique. The technique of recording esophagealmotility utilizes 3 polyethylene catheters, each with aninternal diameter of 1.5 mm, which are fastened togetherand sealed at the tips. A single lateral opening in each

* Supported in part by United States Public HealthService Grants C2578, A1785, and A3473 and the Nor-wich Chapter of the Connecticut Heart Association.

at 5-cm intervals permits simultaneous recording ofpressure changes developing from 3 sites within theesophagus and its sphincters. The catheters are water-filled and transmit pressures to 3 Sanborn electroma-nometers, the changes in pressure being recorded on aSanborn multi-channel direct writing recorder. Duringevery recording the vertical position of the electromanom-eters is readjusted to the same level as the subject'sesophagus. This minimizes any hydrostatic effect andpermits consistency in serial recording techniques.Swallowing is signaled by simultaneous recordings oflaryngeal movement by means of a specially adapted San-born pulse wave attachment placed on the skin adjacentto the thyroid cartilage. A pneumographic belt aroundthe chest indicates respiratory movements.

Patients fast for a minimum of 6 hours prior to exam-ination. The catheters are passed through the mouthinto the stomach without the use of a local anesthetic.With the patient supine, they are withdrawn, centimeterby centimeter, while pressure changes are continuouslyrecorded in the resting state, and also following a "dry"swallow and the ingestion of approximately 10 ml ofwater.

When the tip of the catheter lies below the diaphragm,inspiration produces a positive pressure response whichreflects increased intra-abdominal pressure. When thetip is above the diaphragm, the normal decrease in pres-sure in the thorax on inspiration produces a negative de-flection. This point of pressure reversal occurs at thediaphragm and is called the "effective diaphragmatichiatus." This convenient physiological landmark per-mits localization of the catheters without the use ofX-ray or fluoroscopy.

All records are analyzed in a uniform manner. Thezero point is the pressure recorded from the stomach 5cm distal to the point of respiratory reversal in eachsubject. The catheters are held in this position, as muchas possible, by a trained technician to avoid any verticalmovement. The fundal esophageal pressure gradient isobtained by subtracting the mean resting intra-esophagealpressure from the mean resting fundal or zero pressure.A high pressure zone from 1 to 4 cm long, extendingusually from just below the effective diaphragmatic hiatusto a point 1 to 2 cm above it, functions as an intrinsicsphincter mechanism and is called the inferior esophagealsphincter or vestibule (2-5). Sphincter tone is recordedas the mean resting end-expiratory pressure, which isrepresented by the pressure gradient between the fundusof the stomach and the sphincter during expiration.

954

HEARTBURNIN LATE PREGNANCY

The best defined resting pressure recorded during with-drawal of the 3 catheters through the sphincter was se-lected as representative. Relative to resting sphincterpressure, negative and positive readings in this zone de-velop in response to deglutition and are believed to rep-resent relaxation and contraction of the sphincter, re-spectively; these are expressed only in qualitative terms.Primary peristalsis (Figure 2A) is represented by thepeak positive pressures produced by the muscular con-traction moving down the esophagus in response to swal-lowing (6-10). Both maximal and mean pressures fromthe middle third of the esophagus are tabulated. Sec-ondary peristalsis (Figure 1) differs from primary peri-stalsis only in the mode of initiation; primary peristalticwaves follow deglutition while secondary peristalticwaves are initiated by distention (11-13). The frequencyof nonpropulsive responses to swallowing (Figure 2B,C) is expressed as a percentage of the total number ofswallows. An effort was made to standardize the num-ber of swallows per recording, but a few individualswere less cooperative and swallowed more often. Wehave arbitrarily considered nonpropulsive responses tomore than 25 per cent of the swallows as abnormal.This is based upon the observation that almost all ofour asymptomatic, young, normal control subjects hadless than this percentage of nonpropulsive responses toswallowing. Spontaneous nonpropulsive contractions(Figure 2D) are designated as "only a few" (less than 10

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FIG. 1. ELECTROMANOMETRICRECORDINGOF A SECOND-ARY PERISTALTIC WAVE. This secondary peristaltic waveis propulsive but not preceded by a swallow, which is theonly differentiating feature from the primary peristalticwave that follows swallowing (Figure 2A). The num-bers on the left are distances from the incisors. The re-cording speed used in Figures 1 through 8 was 2.5 mmper second.

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FIG. 2. TYPICAL ESOPHAGEALRESPONSESOF VARIOUS PREGNANTWOMEN. A) Normal propulsive response to a"dry" swallow; B) nonpropulsive response to a "dry" swallow; C) nonpropulsive repetitive response to a "dry"swallow; D) nonpropulsive repetitive response not preceded by a swallow; E) diffuse esophageal spasm after a"dry" swallow. The numbers on the left of each panel are distances from the incisors.

955

.2Q, 0.).

1.

RICHARD NAGLERAND HOWARDM. SPIRO

TABLE I

Control subjects *

Inf.esoph.

sph.Fundal Mean Peristaltic press. Nonprop. cont.esoph. rest. Middle i esoph.

Study press. end-exp. %Total Not prec. bySubject Age no. grad. press. Max. Mean swallows swallow

yrs mmHg mmHgP.C. 23 1 4 16 55 40 <5 0

2 4 15 45 35 <5 Few3 5 12 45 25 0 04 4 15 40 25 0 Few5 4 15 50 25 <5 Few6 5 12 50 30 0 0

A.M. 24 1 5 12 50 35 25 02 6 10 45 35 33 03 5 10 40 20 20 04 5 14 50 35 0 05 5 10 40 25 0 06 5 10 45 30 20 0

M.H. 22 1 3 9 45 35 0 02 2 8 45 30 <5 03 3 9 40 30 0 04 2 10 45 30 <5 05 3 8 45 25 10 06 2 10 40 25 0 0

L.H. 34 1 2 4 90 50 <5 02 2 6 70 30 <5 03 2 5 60 45 0 04 2 5 60 30 0 05 3 5 50 35 0 06 2 6 55 40 0 0

D.G. 44 1 3 14 60 40 33 Many2 3 12 50 35 10 Few3 3 12 50 35 50 Few4 4 13 50 40 33 Many5 4 10 45 30 0 Few6 4 12 50 25 20 Few

E.L. 23 1 4 9 45 30 5 02 4 10 35 25 5 03 5 14 45 25 <5 04 4 9 35 25 0 05 4 12 35 20 0 06 5 10 35 20 5 0

H.N. 22 1 4 10 55 40 0 02 3 9 50 40 <5 05 3 9 60 45 0 04 3 11 70 40 <5 05 4 9 65 45 0 06 3 10 50 35 0 0

A.M. 27 1 6 5 50 35 40 02 7 8 50 35 67 Few3 6 5 55 35 67 Many4 7 8 55 35 33 Few5 7 7 45 30 40 Few6 7 8 45 25 5 0

F.M. 27 1 2 1 45 25 0 02 2 3 45 20 0 03 2 2 45 25 60 04 3 1 45 30 0 05 3 2 45 30 40 06 2 2 40 20 0 0

* No diffuse spasm or secondary peristalsis occurred in any of the control subjects.

956


TABLE i-( Continued)

Inf.esoph.

sph.Fundal Mean Peristaltic press. Nonprop. cont.esoph. rest. Middle j esoph.

Study press. end-exp. %Total Not prec. bySubject Age no. grad. press. Max. Mean swallows swallow

yrs mmHg mmHgB.V. 22 1 4 11 40 30 10 0

2 5 11 45 25 0 Few3 4 10 50 30 10 04 4 8 40 30 <5 Few5 5 9 35 25 <5 Few6 5 12 40 25 0 0

H.T. 23 1 3 5 60 40 <5 02 4 6 50 35 0 Few3 3 6 70 40 0 04 3 5 50 35 20 05 4 7 45 30 20 Few6 3 5 40 25 30 0

C.P. 23 1 3 7 35 25 5 02 2 8 45 25 0 03 3 8 40 25 0 04 3 10 40 30 <5 05 2 10 45 30 0 06 2 9 45 25 0 0

J.D. 23 1 3 9 50 30 50 Many2 4 12 55 30 10 Few3 4 10 60 30 <5 04 4 10 50 25 50 Many5 3 10 50 35 30 Few6 4 14 55 30 0 Few

J.W. 24 1 3 2 25 15 0 02 2 2 25 15 <5 03 3 3 25 15 0 04 3 2 25 15 0 05 3 3 20 15 0 06 3 2 25 15 0 0

per recording) or "many" (greater than 10 per record-ing). Each recording extended for approximately 20minutes. The term "diffuse spasm" (Figure 2E) specifi-cally describes forceful, prolonged, repetitive, nonpropul-sive contractions in the lower two-thirds of the esopha-gus (14).

RESULTS

Control subjects. Although the pressure profilevaries among individuals (Table I), certain find-ings are characteristic of the control group. Dif-fuse esophageal spasm and secondary peristalsiswere not seen. The average fundal-esophagealpressure gradient of 3 to 4 mmof mercury wasconstant on serial studies on each subject. Theinferior esophageal sphincter (represented by thedifference of pressure between the high pressurezone and the gastrickfundus) measured from 1 to16 mmof mercury. In contrast to the observedvariation from one individual to another, serial

studies of the sphincter on the same subject gen-erally demonstrated consistently reproduciblepressure profiles. The consistency of this pressureresponse was notable. After a "dry" swallow, afall in pressure followed by a rise above restingpressure took place in the sphincter region of allcontrol subjects.

Primary peristaltic pressures from 15 to 90 mmof mercury delineated the normal range. Onserial study, 6 subjects inconsistently developedfrequent nonpropulsive responses to "dry" swal-lowing, although a normal peristaltic response in-variably followed a swallow of 10 ml of water.Numerous simultaneous contractions not precededby a swallow occurred in only 3 patients.

Pregnant women without heartburn. As inthe control subjects, variability exists among indi-viduals (Table II). Since these women are sub-ject to the physiological effects of an advancing

957


TABLE II

Pregnant women without heartburn *

Inf.esoph.

sph.Fundal Mean Peristaltic press. Nonprop. cont.

Month of esoph. rest. Middle I esoph.pregnancy press. end-exp. %Total Not prec. by

Patient Age studied grad. press. Max. Mean swallows swallow

yrs mmHg mmHg32P 6 2 10 80

8 3 6 100PP 3 10 70

24P 4 5 10 555 6 12 506 7 12 507 8 10 558 9 10 45PP 3 10 50

26P 5 2 9 509 6 10 40PP 3 8 50

20M 7 2 10 508 9 10 40PP 4 9 45

23M 4 6 7 605 8 6 506 8 7 707 7 8 558 8 7 50PP 5 7 50

28M 5 8 9 558 10 10 50PP 6 12 50

23P 4 5 6 405 4 4 456 4 5 307 4 6 309 5 6 40PP 4 5 35

21P 6 8 12 507 9 10 559 8 10 50PP 6 10 50

22M 8 4 2 25PP 3 3 35

26P 7 5 6 50PP 5 10 55

26M 8 5 5 50PP 2 5 50

35M 6 3 7 258 7 3 20PP 2 10 25

27M 8 5 1 459 5 2 40PP 2 5 40

35M 8 4 8 45PP 4 9 50

40 4045 5035 5

45 2540 2040 5045 4035 3040 <5

30 2020 5030 0

25 3025 3025 50

30 5030 7040 4030 7030 7030 50

30 535 035 0

30 5020 7020 3020 6625 5020 <5

30 8040 4030 3335 0

15 9020 60

35 7035 25

40 3030 0

15 7015 3015 <5

25 4020 5020 <5

35 1030 0

0Few0

00ManyFewFew0

000

000

0ManyFewFewManyMany

000

0ManyFewManyManyFew

ManyFew00

FewFew

FewMany

FewFew

Few00

0Few0

00

* P = primipara; M = multipara; PP = post partum. No diffuse spasm or secondary peristalsis occurred in thepregnant women without heartburn.

D.R.

S.M.

P.S.

S.K.

E.W.

J.J.

S.F.

S.B.

N.S.

C.S.

A.E.

E.V.

M.S.

I.G.

958


TABLE ii-( Continued)

Irif.esoph.


Month of esoph. rest. Middle } esoph.pregnancy press. end-exp. %Total Not prec. by

Patient Age studied grad. press. Max. Mean swallows swallow

yrs mmHg mmHgL.W. 26P 6 2 5 30 15 60 Few

8 4 3 35 20 25 Few9 6 2 35 15 30 0PP 2 6 35 15 <5 0

D.G. 23P 6 5 5 45 30 80 Few8 8 6 50 30 60 FewPP 3 5 40 25 60 Few

F.D. 25P 8 5 6 35 10 60 0PP 3 5 35 25 0 0

N.H. 24M 9 7 6 40 25 40 ManyPP 3 7 45 20 60 Few

C.C. 31P 6 5 10 55 35 50 08 8 12 65 40 30 0PP 5 10 80 40 40 Few

pregnancy, the results of serial esophageal mo-tility changes during pregnancy are presented,each woman serving as her own control. Neitherdiffuse esophageal spasm nor secondary peristal-sis was seen. The average fundal esophagealpressure gradient of 6 to 7 mmof mercury washigher than that recorded in the controls. Thisgradient generally rose with advancing pregnancyand fell post partum to levels similar to those de-termined in the normal nonpregnant group. Themean resting end-expiratory pressure developedby the inferior esophageal sphincter varied from 1to 12 mmof mercury. Fourteen women main-tained a consistent sphincter pressure profilethroughout pregnancy and after delivery, whilefive subjects demonstrated a fall in sphinctericpressure as pregnancy advanced, with a return toprevious levels post partum. After a "dry" swal-low, a fall in sphincter pressure followed by a riseabove resting levels occurred in all but two patientsduring pregnancy. Both of these women demon-strated a barely perceptible high pressure zone.The return of normal sphincteric function afterdelivery coincided with a rise in the resting sphinc-ter pressure. During pregnancy, the inferioresophageal sphincter was confined at or just abovethe effective diaphragmatic hiatus in 63 per cent ofsubjects. This represented a significant departurefrom its usual anatomical position, which in

most women ordinarilynal segment.

included an intra-abdomi-

Primary peristaltic pressures ranged from 10 to100 mmof mercury and compared closely withcontrol values. Seventeen women consistentlydeveloped frequent nonpropulsive pressure re-sponses to "dry" swallowing during pregnancy,although a normal peristaltic wave usually fol-lowed a swallow of 10 ml of water. Six womenshowed numerous nonpropulsive contractions notpreceded by a swallow. After delivery, the inci-dence of abnormal motor responses approachedthe controls. Neither parity nor age correlatedwith the changes observed.

Pregnant women with heartburn. The results(Table III) illustrate the changing esophagealpressure profile during pregnancy, each womanserving as her own control. Forty-five per centdemonstrated secondary peristalsis which disap-peared post partum, but which was never seen ineither of the other two groups. The averagefundal esophageal pressure gradient of 6 to 7 mmof mercury was similar to that of the group ofpregnant women without heartburn, but higherthan that of the controls. This gradient generallyrose with advancing pregnancy and fell post par-tum to levels similar to those found in the normalnonpregnant group. The mean resting end-ex-piratory pressure of the inferior esophageal

959

RICHARD NACLRRAND HOWARDM. SPIRO

TABLE III

Pregnant women with heartburn *

Inf.esoph.sph.

Fundal Mean Peristaltic press. Nonprop. cont.Month of esoph. rest. Middle f esoph.pregnancy press. end-exp. %Total Not prec. by Diffuse Secondary

Patient Age studied grad. press. Max. Mean swallows swallow spasm peristalsis

yrs min Hg mmHgJ.W. 21P 7 3

9 5PP 2

D.B. 28M 9 8PP 4

R.T. 29M 9 3PP 4

A.D. 30P 6 57 78 8PP 3

R.K. 31M 8 59 7PP 3

B.H. 25P 8 8PP 4

B.R. 25M 6 58 9PP 4

H.U. 39M 8 69 8PP 5

J.H. 29P 9 4PP 3

M.R. 25M 4 56 67 88 99 8PP 5

R.C. 35M 8 79 6PP 2

P.M. 21P 9 8PP 3

J.L. 27M 8 79 7PP 2

C.F. 26M 7 48 5PP 5

E.H. 35M 9 9PP 3

D.W. 23P 9 8PP 5

5 703 458 45

1 556 45

7 908 140

9 456 353 45

10 45

5 506 406 40

8 607 70

12 506 50

10 70

4 305 305 30

6 805 95

5 204 303 302 252 206 20

12 10015 11012 80

2 406 50

2 601 504 50

6 455 509 45

0 406 45

2 253 40

502530

4035

4570

35253025

252520

4040

353045

152520

3540

151510101010

505035

3040

403535

353530

2025

1520

<5 0

0 0

0 0

<5 00 0

90 Many +90 Few +

<5 010 080 Few

0 0

5 010 0

<5 0

75 Few +70 Many +

20 Many50 Few30 Few

50 070 0

5 0

75 Many +50 Many +

75 Few60 Few90 Many60 Many90 Many

<5 Few

67 067 033 0

<5 0<5 0

50 Few50 Few

0 0

30 Few50 Few

5 0

0 0

0 0

60 Few50 0

+

* P = primipara; M = multipara; PP = post partum.

960

961HEARTBURNIN LATE PREGNANCY

TABLE mi-( Continued)

Inf.esoph.


Month of esoph. rest. Middle 1 esoph.pregnancy press. end-exp.% Total Not prec. by Diffuse Secondary

Patient Age studied grad. press. Max. Mean swallows swallow spasm peristalsis

yrs mmHg mmHgH.C. 38M 9 5 5 45 30 80 Many +

PP 2 5 40 25 20 0

E.M. 16P 9 5 2 45 25 60 FewPP 4 6 55 30 0 Few

A.V. 18P 7 6 8 55 30 50 Few9 7 4 45 20 75 FewPP 4 10 45 25 50 Few

E. D. 30M 5 3 6 40 25 50 06 5 3 50 25 33 Few7 6 3 50 30 75 Many +9 8 2 45 20 50 Many +PP 2 8 40 25 <5 Few

sphincter varied from 0 to 15 mmof mercury.Eight women maintained a consistent sphincterpressure profile during pregnancy and post partumwhile 12 demonstrated a fall in sphincteric pres-

sure which returned to previous levels after de-livery. The response to a "dry" swallow was

present in all but two patients during pregnancy.In one woman the inferior esophageal sphincter

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FIG. 3. ELECTROMANOMETRICRECORDINGSOF PATIENT E. D. IN THE FIFTH, SEVENTH AND

EIGHTH MONTHSOF PREGNANCY,AND AFTER DELIVERY (LEFT TO RIGHT). Note the progressivediminution of inferior esophageal sphincter response to a "dry" swallow with advancing preg-nancy and the return to normal post partum. The patient experienced heartburn frequently inthe last trimester of pregnancy. Calibrations are the same throughout. The numbers on theleft of each panel are distances from the incisors.

962 ~~~~RICHARDNAGLERAND HOWARDM. SPIRO

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FIG. 4. ELECTROMANOMETRICRE-

CORDINGS OF PATIENT M. R. IN THEFOURTH (TOP PANEL) AND SEVENTH

(MIDDLE PANEL) MONTHS OF PREG-

NANCY, AND AFTER DELIVERY (BOTTOMPANEL). The numbers across the topof each panel are distances from theincisors. The middle tracing on eachpanel is from the sphincter; the bot-tom tracing is front the fundus. Toppanel: Respiratory responses in thefundus and sphincter are the same in-dicating that the sphincter is belowthe effective diaphragmatic hiatus, i.e.,an intra-abdominal segment first iden-tified 39 cm from the incisors. Mid-dle panel: Respiratory responses inthe fundus and sphincter are oppositeindicating that the entire sphincter isin the thorax beginning 38 cm fromthe incisors at the point of respiratoryreversal. Bottom panel: The intra-abdominal segment of the sphincterreappears 39 cm from the incisors.Several drops in pressure following a

swallow are evident.

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FIG. 5. ELECTROMANOMETRICRECORDINGS OF PATIENT B. H. IN THE EIGHTH MONTHOF PREGNANCY(LEFT) AND2 MONTHSAFTER DELIVERY (RIGHT). The numbers at the left of each panel are distances from the incisors. Leftpanel: Diffuse esophageal spasm. The patient had severe heartburn during the third trimester of pregnancy.Right panel: Diffuse esophageal spasm still present. The patient had been completely asymptomatic since delivery.

could not be demonstrated, and in the other it wasbarely perceptible (Figure 3). Both patients,however, revealed normal function post partum,coincident with a substantial rise in the restingsphincteric pressure. A most important findingduring pregnancy was that an intra-abdominalsegment of the sphincter was identified in only15 per cent of women in this group; it reappearedafter delivery in most subjects (Figure 4).

Three women had a pressure profile typical ofdiffuse esophageal spasm, following both a "dry"and "wet" swallow, but in the asymptomatic post-partum period, motility remained similarly dis-turbed (Figure 5). In each instance, the inferioresophageal sphincter was well developed and dem-onstrated normal function.

Primary peristaltic pressures varied from 10 to110 mmof mercury, which compared closely withcontrol values. Fifteen women consistently de-veloped frequent nonpropulsive pressure responsesto "dry" swallowing during pregnancy, althougha normal primary peristaltic wave usually followeda swallow of 10 ml of water. Seven womenshowed numerous simultaneous contractions notpreceded by a swallow. After delivery, the fre-quency of abnormal motor responses approached

control values. Neither parity nor age correlatedwith these results.

Three women experienced heartburn during themanometric study and are reported in greater de-tail.

Sutbject 1. J. L., a 27 year old gravida II, hadheartburn for the first time in the sixth month ofpregnancy. Episodes of a burning, hot sensationlocalized to the throat, associated with the oc-currence of sour-tasting fluid in the mouth, were

brought on by large meals and the supine position.Antacids gave prompt relief. During an esopha-geal motility study performed in the eighth monthof pregnancy, the patient complained of waves ofheartburn; simultaneously, secondary peristalticwaves appeared on the graph (Figure 6). Thefundal esophageal pressure gradient was 7 mmofmercury. The inferior esophageal sphincter waslocated entirely above the effective diaphragmatichiatus and developed a mean resting end-expira-tory pressure of 2 mmof mercury. Numerousnonpropulsive pressures developed both spontane-ously and in response to swallowing. During theninth month of pregnancy, heartburn again was

associated with the appearance of secondary peri-staltic waves. With the catheters in place, the pa-

963


tient was given 30 ml of a liquid antacid whichpromptly relieved the heartburn. The motilityrecord, however, was unchanged.

After delivery the patient became asymptomaticand a recording 6 weeks later was normal. Thefundal esophageal pressure gradient fell to 2 mmof mercury and the inferior esophageal sphincterwhich was now observed, both below and abovethe effective diaphragmatic hiatus, developed a

resting pressure of 4 mmof mercury.Comment. Esophageal motility studies demon-

strated secondary peristalsis simultaneously withsymptoms of heartburn. Nonpropulsive activitywas also present. A liquid antacid effectively re-lieved the heartburn, but the pressure profile was

unchanged, suggesting that motor phenomena arenot the only determinants of heartburn.

Subject 2. E. H., a 35 year old gravida II, hadheartburn for the first time in the seventh monthof pregnancy. A burning sensation in the sub-sternal area radiating to the throat was precipitated

by bending, stooping, or lying flat especially aftereating. All antacid preparations nauseated her.The patient complained of persistent heartburnduring an esophageal motility study performed inthe ninth month of pregnancy, and again secondaryperistalsis was seen (Figure 7). The fundalesophageal pressure gradient was 9 mmof mer-

cury, the inferior esophageal sphincter could notbe identified, and nonpropulsive activity was notobserved.

The pressure profile was normal 8 weeks postpartum; she had experienced no heartburn afterdelivery. The fundal esophageal pressure gradientfell to 3 mmof mercury and the inferior esopha-geal sphincter could now be identified both be-low and above the effective diaphragmatic hiatuswith a mean resting end-expiratory pressure of 6mmof mercury. A pneumatic bag was then placedaround the patient's waist and 300 ml of waterrapidly instilled directly into the stomach. Uponinflation of the bag to exert a pressure of 100 mm

..~~~~~~~~~~~~~~~~~~~~~~~~~~~~...

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notpreceded by~~~~~~~... a swallow... . B..an..aeprmr..rst.icwvs.feraswloasthepatientattempted to clear acid-tasting material which had refluxed intothe~~~~~~~~~~~~~.

throat.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~........

964

HPEAfTBUJRN IN LATE- PREONANCY96

.. ... .. ..

--.............:

. A ....$I ....C..FIG.7.ELECTROMANOMETRIC~~~................ RECORDINGS.... OF SUBJECT......2 (E... H.). Th

numbers at the........ left... are.... distances from... teicsr. A,....B. and........ C. are.. primary.....

pumeristalti rhesponest afterdsaneswalowh ncsr.DEadFAre secondary peristarti

waves not preceded by a swallow. The patient had heartburn throughoutthis recording.

of mercury secondary peristalsis promptly en-sued, but she experienced no heartburn.

Comment. Heartburn occurred during themanometric demonstration of secondary peristalsisin the absence of nonpropulsive motor activity. Asimilar pressure profile induced post partum wasobserved without heartburn, suggesting that heart-burn does not depend on secondary peristalsis.

Subject 3. H. C., a 38 year old gravida, V, hadheartburn for the first time in the sixth month ofpregnancy. A burning, choking sensation in thethroat associated with the occurrence of sour-tasting material in the mouth was aggravated byemotional tension and the supine position especiallyafter meals. She never tried antacids, but notedtransient relief from drinking a glass of cold water.An esophageal motility study in the ninth monthof pregnancy demonstrated secondary peristalsisand prominent nonpropulsive activity not pre-ceded by a swallow. During the first part of the

study she complained of heartburn. Immediatelyafter a single swallow of approximately 20 ml ofwater at room temperature, a normal primaryperistaltic wave developed which was promptlyfollowed simultaneously by the sudden cessationof heartburn and an abrupt change in the motilitypattern to normal (Figure 8). The fundal esoph-ageal pressure gradient was 5 mmof mercury.Inferior esophageal sphincter activity occurredonly above the effective diaphragmatic hiatus anddeveloped a mean resting end-expiratory pressureof 5 mmof mercury.

She became asymptomatic after delivery; a fol-low-up motility study 7 weeks later was normal.The fundal esophageal pressure gradient fell. to 2mmof mercury, but the mean resting end-expira-tory pressure of the inferior esophageal sphincter,however, could now be identified. A pneumaticbelt was then placed about her waist and 300 mlof water instilled directly into the stomach. Upon

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inflation of the bag to 100 mmof mercury, second-ary peristalsis and spontaneous nonpropulsivewaves promptly occurred, but the patient experi-enced no heartburn.

Comment. Heartburn was associated with sec-

ondary peristalsis and prominent nonpropulsivemotor activity during pregnancy. A swallow ofwater resulted in relief of heartburn simultaneouswith the appearance of a normal pressure profile.This might be explained by. the offending materialhaving been washed from the esophagus. Sec-ondary peristalsis, induced post partum, was'ac-companied by similar nonpropulsive motor ac-

tivity, but no heartburn was present. Thissuggests that such motor dysfunction may beasymptomatic.

DISCUSSION

Secondary peristalsis, which indirectly indicatesthat gastroesophageal reflux is taking place, oc-curred exclusively in a group of women with

Swall low

heartburn during pregnancy, but in only 45 percent of the group. Neither heartburn nor second-ary peristalsis was observed post partum. Whatevidence is there that secondary peristalsis indi-cates reflux? By simultaneous manometric andfluoroscopic studies, Creamer demonstrated an as-sociation between secondary peristalsis and gas-troesophageal reflux (15). The first pressure de-flection seen in the secondary peristaltic complexesin our study (Figures 1, 6, 7 and 8) is character-istic of primary peristalsis following a liquidbolus, but is absent during a "dry" swallow. Sucha pressure rise is associated with the sudden in-troduction of material into the esophagus. Sinceno material was introduced into the esophagusfrom above during these recordings, the appear-ance of this initial deflection suggests that material.was entering the esophagus from below. It isevident, however, that a certain amount of fluidmust distend the esophagus to elicit this response.We introduced 300 ml of water containing a dye

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FIG.8.ELECTROMANOMETRIC...... ...... RECORDINGS- OFSUBJECT.3.(H C.).... Thenuber-athe.left.are ditace. fotheinisorsTheptientexperinced eartbun durng theappeaance o numeous seondar perisalticwaves

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directly into the stomach of 10 control subjectsand increased intragastric pressure by inflating apneumatic abdominal belt. Secondary peristalticwaves appeared in four subjects in whom, at thesame time, more than 40 ml of dyed material wasaspirated from the distal esophagus. In the othersix subjects who did not develop secondary peri-staltic waves, less than 10 ml was aspirated fromthe esophagus, suggesting that the initiation ofsuch a motor response depends upon the regurgi-tation of relatively large. volumes of fluid. Wetake these results to confirm the relation betweensecondary peristalsis and gastroesophageal reflux.

The type of material refluxed may bear uponthe incidence of heartburn. Reflux occurs inasymptomatic subjects and may be demonstratedduring X-ray study of the esophagus and stomach.It is pertinent to note that no symptoms occurredafter abdominal pressure was increased by infla-tion of a pneumatic abdominal belt around thewaist in some normal subjects, despite the appear-ance of secondary peristalsis when 300 ml of wa-ter was introduced into the stomach. In con-trast, Tuttle, Bettarello and Grossman determinedesophageal pressure and intraluminal pH simul-taneously; after 300 ml of 0.1 N hydrochloricacid had been introduced into the stomach, heart-burn occurred when the pH in the distal esophagusfell below pH 4 (16). In our Patient 1, the re-flux of acid appeared, at least from our indirectevidence, to be more important than the merepresence of reflux. Severe heartburn occurred si-multaneously with the appearance of secondaryperistaltic waves. Although symptoms were re-lieved with a liquid antacid, the pressure profileremained unchanged. It is true that basal gastricacid is diminished in late pregnancy, and that pep-tic ulcers are rare during pregnancy (17, 18).Nevertheless, whatever acid and peptic material isavailable may repeatedly gain access to the esopha-geal mucosa and over a long period of time mayproduce esophagitis. In animals, acid gastricjuice may devastate esophageal mucosa (19).

A number of factors may contribute to reflux.Increased intragastric pressure is the most ob-vious: the enlarging uterus allows less room forstomach contents. Many pregnant women ex-perience symptoms of reflux when bending orstooping, actions which result in a sharp rise inintragastric pressure (20). Such a rise in pres-

sure alone might be responsible for reflux, butwhile the fundal esophageal pressure gradient in-creased in most pregnant subjects as the uterusenlarged, the women in whomreflux occurred hadno higher intragastric pressure than those withoutreflux, nor did Creamer find that the fundal esoph-ageal pressure gradient rose during spontaneousreflux in nonpregnant subjects (15). Apparently,elevated intragastric pressure must be associatedwith diminished resistance of the normal barriersif significant reflux is to occur.

Three mechanisms probably help to preventgastroesophageal reflux: a direct compression or"pinch-cock" action on the esophagogastric junc-tion exerted by the right crus of the diaphragm, anintrinsic sphincter mechanism in the distal esoph-agus, and a passive mucosal valve formed by theacute angle of entry of the esophagus into thestomach (21, 22). These three barriers probablyreinforce each other when properly aligned. Wehave studied only the sphincteric mechanism.

The variation in the mean resting end-expira-tory pressure of the inferior esophageal sphincterfrom one individual to another is considered bysome observers to represent a technical failureof recording methods (23, 24). Serial studies inour control subjects, however, demonstrate thatsome normal people simply have a well developedintrinsic sphincter mechanism while others do not,but that the tone of the sphincter is relatively con-stant for the individual. In contrast, in 55 percent of the pregnant women with heartburn andin 20 per cent of those without heartburn, the rest-ing sphincter pressure decreased with advancingpregnancy and returned to normal levels after de-livery. The fall in sphincter pressure may resultfrom gastric atony during pregnancy (25) ex-tending to involve the distal esophagus, whichwould lower the pressure barrier to reflux. Morelikely, however, this decrease in resistance togastroesophageal reflux may be related to loss ofthe intra-abdominal segment of the sphincter; anintra-abdominal segment was demonstrated in 80per cent of the controls, but in only 15 per centof the pregnant women with heartburn and in37 per cent of those without heartburn. Fyke,Code and Schlegel originally emphasized that anintra-abdominal segment of the sphincter providesan effective barrier to reflux since its intrinsicresistance is supported by the intraperitoneal pres-

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sure (2). Further, it has been graphically dem-onstrated that when intraperitoneal pressure rises,the pressure in the intra-abdominal segment ofthe sphincter also rises to preserve the normalpressure gradient (26). The intrathoracic seg-ment does not respond with such an increase inpressure, so that if the sphincter is confined to thethorax, as it is in many pregnant women, thenormal pressure barrier may be diminished.

In addition, the acute angle of entry of theesophagus into the stomach, so essential in main-taining the flap valve mechanism, is altered by thedisplacement of the stomach to a more horizontalposition by the enlarging uterus (25), and thisbarrier to reflux may be lost.

A consideration of factors causing gastroesopha-geal reflux in pregnancy must include hiatushernia. Three manometric findings are usuallyinterpreted as indicative of hiatus hernia: con-tinuation of intra-abdominal pressures into thethorax, demonstration of the inferior esophagealsphincter more than 3 cm above the effective dia-phragmatic hiatus and recognition of a "biphasic"point of respiratory reversal (14, 27, 28). Weob-served only the latter phenomenon in severalwomen. Since careful roentgenologic examinationfailed to identify a hiatus hernia in 12 subjectswith a biphasic point of respiratory reversal thatwe have studied, we cannot say with any suretywhich of the pregnant women had hiatus hernia.Of 195 women in the last trimester of pregnancy,hiatus hernia was radiographically demonstratedin 18.1 per cent of the multiparae and in 5.1 percent of the primiparae, a combined incidence of12.8 per cent (29). No relation to heartburn wasevident, but those women who showed refluxoften had heartburn (29). Although hiatus herniaoccurs more often in multiparae, we found no dif-ference in the incidence of secondary peristalsisbetween primiparae and multiparae. This sug-gests that while hiatus hernia may have been afactor in some of our patients, it is not an essentialfactor.

The passage of a tube into the stomach mightbe responsible for reflux. We have not founda tube to induce reflux by cineradiographic studiesof cardioesophageal competence during short-term gastric intubation (30).

Although reflux of an acid may initiate heart-burn, the immediate pathogenesis of the symptom

is controversial. Muscular dysfunction of theesophagus induced either by distention or by acidreflux may be the final pathway resulting in symp-toms of heartburn. Nonpropulsive esophagealpressures developed in patients with heartburninduced by continuous intra-esophageal infusionof 0.1 N hydrochloric acid or equally when heart-burn resulted from infusions of other fluids (31).These motor phenomena, however, particularly inthe lower two-thirds of the esophagus, are evidentin all people, and increase with age (21). Sixof 14 asymptomatic young persons whomwe havestudied demonstrated inconsistently such activity(32). The pregnant women in this study had amarked increase in the frequency and consistencyof nonpropulsive responses, but no differencewas noted between those women with and with-out heartburn. The findings in Subjects 2 and 3are pertinent. Subject 2 demonstrated secondaryperistalsis, but nonpropulsive activity did not ap-pear, suggesting that heartburn may occur in itsabsence. Subject 3 also demonstrated secondaryperistalsis, but in addition developed numeroussimultaneous nonperistaltic responses representingirritability of the esophagus. When this subjectwas examined post partum a similar pressure pro-file was induced but without heartburn, indicatingthat this motor abnormality may be asympto-matic. Nonpropulsive activity does not appearto be the final common pathway in the pathogene-sis of heartburn in pregnancy.

Why pregnant women appear to have an in-creased frequency of nonpropulsive activity is notclear. Increased intragastric pressure duringpregnancy could force air or liquid into the esoph-agus, which might rapidly transmit pressurealong the esophageal lumen so that a pressureresponse in one area of the organ might be im-mediately apparent in an adjacent area (33).This is supported by the observation that a normalperistaltic pressure sequence invariably occurredafter a swallow of 10 ml of water which coulddrive air or liquid from the esophagus back intothe stomach. In addition, Creamer observed non-propulsive activity when air was regurgitated intothe esophagus (15).

During pregnancy three women with heartburnshowed a pressure profile consistent with diffuseesophageal spasm which remained similarly dis-turbed in the asymptomatic postpartum period.

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This does not support a causal relationship. Onthe other hand, since this pressure profile was ob-served only in pregnant women with heartburn,it is possible that the abnormal pattern is an in-dication of motor derangement that with stimula-tion becomes more profound and produces symp-toms.

SUMMARY

Serial esophageal motility studies on pregnantwomenwith and without heartburn and on a groupof asymptomatic normal young women of similarage indicate that heartburn of late pregnancy isnot determined exclusively by motor changes inthe esophagus. Nonpropulsive motor activity wasseen consistently and with much greater frequencyin the pregnant than in the control subjects, butno difference was noted between pregnant womenwith heartburn and those without heartburn. Itseems likely that such activity is related to preg-nancy but not to heartburn.

Diffuse esophageal spasm was found in threepregnant women with heartburn. After deliverythis abnormal motor pattern persisted, even thoughsymptoms no longer occurred. It is evident thatdiffuse esophageal spasm is not in itself responsi-ble for heartburn, but since it occurred in preg-nant women with heartburn, it may be an as-sociated abnormality.

Acid reflux into the esophagus appears to be afactor in heartburn of late pregnancy. Secondaryperistaltic activity suggests that gastric reflux istaking place into the esophagus and the finding ofthese complexes exclusively in 45 per cent of preg-nant women with heartburn provides indirect evi-dence to support this concept. Gastroesophagealreflux is favored during pregnancy by a combina-tion of factors. Intraperitoneal pressure rises withadvancing pregnancy. The inferior esophagealsphincter, which represents a barrier to reflux,develops progressively weaker resting pressureswith advancing pregnancy in more than one-halfof the pregnant women with heartburn. The in-tra-abdominal segment of the sphincter could notbe identified in the great majority of these women.Maintenance of this segment appears crucial tosustaining the pressure barrier against reflux es-pecially when intraperitoneal pressure is elevated.

ACKNOWLEDGMENTS

We are grateful to Dr. Massimo Calabresi and histechnician, Miss Analee Gelman, for their help in the pre-liminary stages of this study and to Drs. Clarence D.Davis, Walter Herrmann and Luigi Mastroianni for al-lowing us to study their patients, and to Mr. FrankMarks and Miss Barbara Van Duzer for their patienceand fortitude in the seemingly endless withdrawal ofcatheters.

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14. Creamer, B., Donaghue, F. E., and Code, C. F. Pat-tern of esophageal motility in diffuse spasm. Gas-troenterology 1958, 34, 782.

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33. Ingelfinger, F. J. Personal communication.

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