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The Use of Prostigmin in Heartburn of Pregnancy
THE USE OF PROSTIGMIN IN HEARTBURN OF PREGNANCY CHARLES LEAVITT SULLIVAN, M.D., BROOKLINE, MASS.
(From the Departmrnt of Obstetrics, Sain-t El·izabeth's Hospital, Boston, Ma"'s.)
I
N ITS present-day approach, prenatal care embraces not only those steps essential to the ultimate safety of mother and rhild hut extends even into the field of painless childbirth, as represented by the theories of Grantly Dick Read. This concept takes cognizance of a number of symptom eomplexes and clinieal syndromes, the alleviation of whic·h contributes to the safety of both mother and child and also lessens the discomfort of the physiological changes inherent to pregnancy. The heartburn of pregnane~· hefongs in this category. The na·~ ging persistence of this complaint interferes with proper diet, deprives tlw patient of needed rest, and destroys her sense of well-being. It is in most cases easily and quickly, although temporarily, relieved hy bicarbonate of mda. It is this very fact which nwkes its proper c•disposition to excessive weight gain, longer labors, and pre-ec.lampsia. For the purpose of this study, heartburn is defined as a burning or scalding sensation, localized beneath the sternum in the region of the xiphoid proC'ess. It is reported to be a disturbing factor in two-thirds of all pregnancies, 1 and is more intense in the last trimester. Sixty per cent of cases first appear in the first two trimesters and forty per cent occur from six weeks before term to term. Gastric h,vperacidit.v was accepted for a long time as the causative factor in the production of this syndrome, until it was shown by Jones and Richan1son2• 3 to he due to a neuromuscular phenomenon. By applying pressure to various areas within the esophagus by means of a distended balloon there was g·ained evidence that the symptom is due to spasm of the cardiac sphincter. 'rhis was confirmed by the observation that the same sensation could he reprodueeJ by pouring bland liquiJs at room temperature into the same sites and thus achieving a similar type and degree of distention. Waves of reverse peristalsis were apparent while the sensation persisted. Changes in the gastrointestinal tract dming preg·naney include those of position, serretion, motility, and tone. Hansen• plainly depicted the anatomical distortion of the stomach in advancing pregnancy and Williams 1 corroborated these finding:-; by means of various studies. The enlarging uterus was shown to en(•roach upon the abdominal organs, forring the normally vertical stomaeh out of position. As a result, the gastric fundus lies under the left leaf of th<> diaphragm, the greater eurvature lies near the eardia, and the entire organ is rotated 45 Jegrees to the right. Strauss all
206
S1!LLIVAN
·\m. I. Obit. & Gynec.
Jnly, 19>0
have effectively demonstrated that 7;J per cent of pregnant patients do not secrete normal amounts of hydrochloric acid or pepsin during more than hall the period of gestation, although Labatew points out that there is an improvement in secretion during the last trimester. In any event, unlike the constancy in the nongravid, wide variations in the amount of gastric secretion occur during pregnancy, mostly tending toward diminution. Concomitant with diminished gastric secretion are loss of tone and diminished motility. With the normal emptying time of the stomaeh considered to he about two hours, 11 the increase in pregnanry may amount to 100 per cent, progressing to the onset of labor when there is practically no motility or tone, with a free reflux of 1lnodenal content:;. Such changes are sufficient to bring about diRtf'ntion of the lower esophagu.'l, with the eoru;equent produrtion of heartburn. There seenu:; little doubt that there exists a fundamental l'elationship hf'tween the autonomic nervous syRtem and the endocrine g-landR and accordingly it seems not unreasonable to suppost~ that the profound hormonal changes in pregnancy may, through an influence on the abdominal branches of the vagus, ln·ing about the altered gastrointestinal dw.nges described. However, the exart mechanism of the hormonal effect of pregnancy on the gastrointestinal tract is not known. It is prohably a combination of direet and indirect factors acting through the autonomic nenous system: through ehanges in electrolytic balance peculiar to pregn
Volume 60 Number 1
PROSTIGMIN FOR HEARTBURN OF PREGNANCY
207
that the symptom is experienced most severely toward the end of pregnancy. All patients, from the time of their first visits, were expressly instructed in the value of proper dietary care during pregnancy and received written instructions detailing proper daily food intake. 16 One c.c. of a 1 :2,000 solution (0.5 mg.) of Prostigmin Methylsulfate was injected into the gluteal muscles of patients failing to obtain relief from the medical regime outlined and treatment was judged successful only if followed by the disappearance of heartburn for a period of at least three days. In the great majority of cases with good results there was no return of heartburn for from seven to ten days. Realizing the positive psychic factor in any parenteral injection for a subjective complaint it was decided to adopt a positive approach to the patient, in order, as nearly as possible, to produce the same psychic response to the injection in all patients. Therefore, all women were told at the time of the first inje<'tion that they would obtain relief from their heartburn, as "nine out of ten" women did so. To obtain a further control a certain number of women received, without their knowledge, an injection of distilled water, in some, the controls, on their initial injection, and in those who did obtain relief from Prostigmin, at a subsequent injection for the treatment of recurrence.
Material and Results A total of 151 patients were included in the stud~'· Of the 136 who received injections of Prostigmin Meth~rlsulfate initially, as outlined above, 124, or approximately 90 per cent, experienced relief lasting for at least three days. The 12 who did not respond were given a second injection, with signifieant relief in only 2. Forty-eight of the 124 who did respond to the initial treatment required at least one subsequent injection because of recurrence of symptoms. In 4 of this group, the recurrence persisted and it may be significant that all of these were within three weeks of term. By way of controls, each of 15 subjects received an injection of sterile distilled water only 2 reported subjective improvement. In addition, to provide a further cheek, 15 of the 136 women who had gained relief from an initial injection of Prostigmin were given a second injection consisting only of distilled water. Some ''improvement'' was reported by 2. The remaining 13 patients of this group, obtaining no relief from distilled water, were then given a second injeetion of Prostigmin and in all instances they reobtained the 1·e1ief that they had experienc<'d with th<' initial injection of Prostigmin. A possible explanation of the ten initial and four secondary failnres in this series is offered by postulating in them the presence of hiatus dilatation and diaphragmatic herniation. Dwyer 17 feels that all esophageal hiatus hernias are congenital in origin and that they can be produced by the increased intraabdominal pressure caused by the enlarging uterus. Ritvo 18 found the incidence of esophageal herniation to be about 1 per cent in 8,000 routine gastrointestinal series and in half of the cases so demonstrated heartburn was a presenting symptom. The incidence of hiatus hernia in the third trimester of pregnancy h; 12.8 per cent. 19 Evans and Bouslog20 report four intractable cases of heartburn in pregnancy which they ascribed to hiatus hernia and after delivery, with amelioration of symptoms, none could be rcdemonstrated. It is interesting to note and difficult to explain why only about 40 per cent of the women required repeated injections of Prostigmin following their initial • relief. Of those requiring repeated injections for a return of symptoms, 9R per cent obtained relief. It is probable that heartburn peculiar to pregnaney, in the majority of cases, is capable of undergoing spontaneous remissions and exacerbations and that it is possible that the Prostigmin so ".iolts" the lagging intestinal tract as to cause a remission of symptoms fl)r an extended period
of time.
~ULLIVAN
2011
Am.
J.
Ob,t. & Gyncc
.Tnly, 191!1
At the onset of the fltud.v there was some hesitancy about using Prostig·min because of reports in the literature of indueed vaginal bleeding in the nonpregnant by the pl'Oduction of a uterine hyperemia 21 • 22 • 23 ; because of the experience of Lubin and Waltman 24 in their attempts to induce abortion with it; because of the attempts of Robins 25 to induce labor with it; and because of the observations of Woodbury and ro-workers 26 of an oxytocir effect in the attempted treatment of pre-eelampsia with it. Del-lpitt' our initial hesitancy, we ob~erved no case in which vaginal bleeding, nterinr contraetions, induction of labor, or a demonstrable drop in blood pressure followed treatmrnt with Prostigmin.
Summary and C-onclusions Heartburn peeuliar to pregnaney if! a nenromus(~ular phenomenon wltieh ma.v oeeur at any time throughout gestation. Subject to spontaneous remission:-: and exacerbations, it is most common and most Hrvere during the last trimester. It is probably due to the hormonal effects i1widental to pregnancy on the gastrointestinal tract. Tt oeems in about two-thirds of all pregnancies, 60 per cent in the first two trimesters and 40 per C('llt .in the last third. Seventy-five per (•ent can be controlled h~' a medical reginw but practi(·ally a1l snch cases have their onset before tvvent:~-six weeks. Pro,;tigmin Methylsulfate 1:2,000 (0.5 mg.) intramuscularl.v will provide relief for at least three days, and generally from Heven to ten days, in 90 per eent of the l'Pmaining (•ases. No adverse efferts from doses of this size were noted in this study. Intractable rases may he due to a temporar~' diaphragmatic hemiation due to ilw1·eased intl·a-abdominal Jli'CSSUl'C.
'J'he ProHtigmin uHe
~tudy
waH pmvirie
[11(·.
References 1. WilliumR, N.H.: A:.I. .J. OBS'l', & (ly~Jc<~. 42: Sl~, Hl±l. 2..JoneH, C.: Dige~tive 'l'rad Pain, New York, Hl38, The Muewillan ComrHtn,v. ;\ .. lone~, C., and Richardson, W.; .r. Clin. Investigation 2: ti 11!, IH:W. ±. Ramen, R.: Zentralbl. f. Gynak. 61: 2:30fi. Hlill . .i. Strauss, M., and Castle, W.: Am . .T, M. Hr. 184: tj;)fi, ]\);~~. ti. NtrauHR, M., and Castle, W.: Am. ,J. ~'L 8e. 184: llfi:l, lP:l:;, 7. Arzt, }'.: AM . •T. 0BST. & ClYNE<.'. 20: :382, HlilO. S. Mason, Colorado Med. 28: ;{!J2, ]!l:H. D. TetRntHaroo, N.: Tokio J. Biochem. 5: 4ti•!, 1\1:!.!. 10. Labate, J.: AM. J. OBS'l'. & GYNEC. 38: 6fi0, 193!!. 11. Mose~. W.: New England .r. Med. 237: 60B, l!HI. 12. Zondek, H. G.: DeutHche med. WchnH<'hr. 2: J:i20, 1!121. 1:~. Wiley, H.: AM .. J. OBST. & GvN•:c. 51: :321, l!l±fl. 1±. Roth, D.: ,J. M. Hue. N<>w .ler~t'.\" 43: 4iiti, l!J4ti. Iii. Wolf, H., and Wolf, If.: Human
(From the Departmrnt of Obstetrics, Sain-t El·izabeth's Hospital, Boston, Ma"'s.)
I
N ITS present-day approach, prenatal care embraces not only those steps essential to the ultimate safety of mother and rhild hut extends even into the field of painless childbirth, as represented by the theories of Grantly Dick Read. This concept takes cognizance of a number of symptom eomplexes and clinieal syndromes, the alleviation of whic·h contributes to the safety of both mother and child and also lessens the discomfort of the physiological changes inherent to pregnancy. The heartburn of pregnane~· hefongs in this category. The na·~ ging persistence of this complaint interferes with proper diet, deprives tlw patient of needed rest, and destroys her sense of well-being. It is in most cases easily and quickly, although temporarily, relieved hy bicarbonate of mda. It is this very fact which nwkes its proper c•
206
S1!LLIVAN
·\m. I. Obit. & Gynec.
Jnly, 19>0
have effectively demonstrated that 7;J per cent of pregnant patients do not secrete normal amounts of hydrochloric acid or pepsin during more than hall the period of gestation, although Labatew points out that there is an improvement in secretion during the last trimester. In any event, unlike the constancy in the nongravid, wide variations in the amount of gastric secretion occur during pregnancy, mostly tending toward diminution. Concomitant with diminished gastric secretion are loss of tone and diminished motility. With the normal emptying time of the stomaeh considered to he about two hours, 11 the increase in pregnanry may amount to 100 per cent, progressing to the onset of labor when there is practically no motility or tone, with a free reflux of 1lnodenal content:;. Such changes are sufficient to bring about diRtf'ntion of the lower esophagu.'l, with the eoru;equent produrtion of heartburn. There seenu:; little doubt that there exists a fundamental l'elationship hf'tween the autonomic nervous syRtem and the endocrine g-landR and accordingly it seems not unreasonable to suppost~ that the profound hormonal changes in pregnancy may, through an influence on the abdominal branches of the vagus, ln·ing about the altered gastrointestinal dw.nges described. However, the exart mechanism of the hormonal effect of pregnancy on the gastrointestinal tract is not known. It is prohably a combination of direet and indirect factors acting through the autonomic nenous system: through ehanges in electrolytic balance peculiar to pregn
Volume 60 Number 1
PROSTIGMIN FOR HEARTBURN OF PREGNANCY
207
that the symptom is experienced most severely toward the end of pregnancy. All patients, from the time of their first visits, were expressly instructed in the value of proper dietary care during pregnancy and received written instructions detailing proper daily food intake. 16 One c.c. of a 1 :2,000 solution (0.5 mg.) of Prostigmin Methylsulfate was injected into the gluteal muscles of patients failing to obtain relief from the medical regime outlined and treatment was judged successful only if followed by the disappearance of heartburn for a period of at least three days. In the great majority of cases with good results there was no return of heartburn for from seven to ten days. Realizing the positive psychic factor in any parenteral injection for a subjective complaint it was decided to adopt a positive approach to the patient, in order, as nearly as possible, to produce the same psychic response to the injection in all patients. Therefore, all women were told at the time of the first inje<'tion that they would obtain relief from their heartburn, as "nine out of ten" women did so. To obtain a further control a certain number of women received, without their knowledge, an injection of distilled water, in some, the controls, on their initial injection, and in those who did obtain relief from Prostigmin, at a subsequent injection for the treatment of recurrence.
Material and Results A total of 151 patients were included in the stud~'· Of the 136 who received injections of Prostigmin Meth~rlsulfate initially, as outlined above, 124, or approximately 90 per cent, experienced relief lasting for at least three days. The 12 who did not respond were given a second injection, with signifieant relief in only 2. Forty-eight of the 124 who did respond to the initial treatment required at least one subsequent injection because of recurrence of symptoms. In 4 of this group, the recurrence persisted and it may be significant that all of these were within three weeks of term. By way of controls, each of 15 subjects received an injection of sterile distilled water only 2 reported subjective improvement. In addition, to provide a further cheek, 15 of the 136 women who had gained relief from an initial injection of Prostigmin were given a second injection consisting only of distilled water. Some ''improvement'' was reported by 2. The remaining 13 patients of this group, obtaining no relief from distilled water, were then given a second injeetion of Prostigmin and in all instances they reobtained the 1·e1ief that they had experienc<'d with th<' initial injection of Prostigmin. A possible explanation of the ten initial and four secondary failnres in this series is offered by postulating in them the presence of hiatus dilatation and diaphragmatic herniation. Dwyer 17 feels that all esophageal hiatus hernias are congenital in origin and that they can be produced by the increased intraabdominal pressure caused by the enlarging uterus. Ritvo 18 found the incidence of esophageal herniation to be about 1 per cent in 8,000 routine gastrointestinal series and in half of the cases so demonstrated heartburn was a presenting symptom. The incidence of hiatus hernia in the third trimester of pregnancy h; 12.8 per cent. 19 Evans and Bouslog20 report four intractable cases of heartburn in pregnancy which they ascribed to hiatus hernia and after delivery, with amelioration of symptoms, none could be rcdemonstrated. It is interesting to note and difficult to explain why only about 40 per cent of the women required repeated injections of Prostigmin following their initial • relief. Of those requiring repeated injections for a return of symptoms, 9R per cent obtained relief. It is probable that heartburn peculiar to pregnaney, in the majority of cases, is capable of undergoing spontaneous remissions and exacerbations and that it is possible that the Prostigmin so ".iolts" the lagging intestinal tract as to cause a remission of symptoms fl)r an extended period
of time.
~ULLIVAN
2011
Am.
J.
Ob,t. & Gyncc
.Tnly, 191!1
At the onset of the fltud.v there was some hesitancy about using Prostig·min because of reports in the literature of indueed vaginal bleeding in the nonpregnant by the pl'Oduction of a uterine hyperemia 21 • 22 • 23 ; because of the experience of Lubin and Waltman 24 in their attempts to induce abortion with it; because of the attempts of Robins 25 to induce labor with it; and because of the observations of Woodbury and ro-workers 26 of an oxytocir effect in the attempted treatment of pre-eelampsia with it. Del-lpitt' our initial hesitancy, we ob~erved no case in which vaginal bleeding, nterinr contraetions, induction of labor, or a demonstrable drop in blood pressure followed treatmrnt with Prostigmin.
Summary and C-onclusions Heartburn peeuliar to pregnaney if! a nenromus(~ular phenomenon wltieh ma.v oeeur at any time throughout gestation. Subject to spontaneous remission:-: and exacerbations, it is most common and most Hrvere during the last trimester. It is probably due to the hormonal effects i1widental to pregnancy on the gastrointestinal tract. Tt oeems in about two-thirds of all pregnancies, 60 per cent in the first two trimesters and 40 per C('llt .in the last third. Seventy-five per (•ent can be controlled h~' a medical reginw but practi(·ally a1l snch cases have their onset before tvvent:~-six weeks. Pro,;tigmin Methylsulfate 1:2,000 (0.5 mg.) intramuscularl.v will provide relief for at least three days, and generally from Heven to ten days, in 90 per eent of the l'Pmaining (•ases. No adverse efferts from doses of this size were noted in this study. Intractable rases may he due to a temporar~' diaphragmatic hemiation due to ilw1·eased intl·a-abdominal Jli'CSSUl'C.
'J'he ProHtigmin uHe
~tudy
waH pmvirie
[11(·.
References 1. WilliumR, N.H.: A:.I. .J. OBS'l', & (ly~Jc<~. 42: Sl~, Hl±l. 2..JoneH, C.: Dige~tive 'l'rad Pain, New York, Hl38, The Muewillan ComrHtn,v. ;\ .. lone~, C., and Richardson, W.; .r. Clin. Investigation 2: ti 11!, IH:W. ±. Ramen, R.: Zentralbl. f. Gynak. 61: 2:30fi. Hlill . .i. Strauss, M., and Castle, W.: Am . .T, M. Hr. 184: tj;)fi, ]\);~~. ti. NtrauHR, M., and Castle, W.: Am. ,J. ~'L 8e. 184: llfi:l, lP:l:;, 7. Arzt, }'.: AM . •T. 0BST. & ClYNE<.'. 20: :382, HlilO. S. Mason, Colorado Med. 28: ;{!J2, ]!l:H. D. TetRntHaroo, N.: Tokio J. Biochem. 5: 4ti•!, 1\1:!.!. 10. Labate, J.: AM. J. OBS'l'. & GYNEC. 38: 6fi0, 193!!. 11. Mose~. W.: New England .r. Med. 237: 60B, l!HI. 12. Zondek, H. G.: DeutHche med. WchnH<'hr. 2: J:i20, 1!121. 1:~. Wiley, H.: AM .. J. OBST. & GvN•:c. 51: :321, l!l±fl. 1±. Roth, D.: ,J. M. Hue. N<>w .ler~t'.\" 43: 4iiti, l!J4ti. Iii. Wolf, H., and Wolf, If.: Human