amathematicalmodelrelatingpitocinuseduringlaborwith ... · 2019. 7. 30. · pitocin in the maternal...

Research ArticleA Mathematical Model Relating Pitocin Use during Labor withOffspring Autism Development in terms of Oxytocin ReceptorDesensitization in the Fetal Brain

Mark M Gottlieb

1700 Shattuck Avenue 114 Berkeley CA 94709 USA

Correspondence should be addressed to Mark M Gottlieb markgottlieb2010gmailcom

Received 16 January 2019 Accepted 7 June 2019 Published 11 July 2019

Academic Editor Anna Tsantili-Kakoulidou

Copyright copy 2019 Mark M Gottlieb is is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

is paper develops a mathematical model describing the potential buildup of high oxytocin concentrations in the maternalcirculation during labor in terms of continuous Pitocin infusion rate half-life and maternal weight Oxytocin override of thedegradation of oxytocin by placental oxytocinase is introduced to model the potential transfer of oxytocin from the maternalcirculation across the placenta into the fetal circulation and from there into the brain of the fetus e desensitization unit Dequal to 18E6 (pgmiddotmin)ml is employed to establish a desensitization threshold and by extension a downregulationthreshold as a function of oxytocin override concentration and continuous Pitocin infusion time that could be a factor in thesubsequent development of autism among offspring Epidemiological studies by Duke University [1] Yale University [2]and Harvard University [3] are discussed regarding Pitocin use and offspring autism development for an explanation of theweak correlations they identified e findings of the Harvard epidemiological study are reinterpreted regarding Pitocin useand its conclusion questioned Further evaluations of the findings of these three epidemiological studies are called for toincorporate medical information on quantity of Pitocin used continuous Pitocin infusion rate length of labor and maternalweight to determine if a correlation can be established with offspring autism development above an empirically determineddesensitization threshold for Pitocin use Suggestions for research are discussed including an alternative to continuousPitocin infusion pulsatile infusion of Pitocin during labor induction which may mitigate possible offspringautism development

1 Introduction

An epidemiological study by Duke University published in2013 that was conducted in North Carolina found a modestassociation between labor induction and labor augmentationwith the incidence of autism among the offspring [1] isstudy also found a weak correlation between the use ofPitocin artificial oxytocin during labor and offspring autismdevelopment Oxytocin receptor (OTR) desensitizationfollowed by downregulation by oxytocin in the fetal brainwas proposed as a possible cause of the offspring autismdevelopment An epidemiological study in Denmark by YaleUniversity published in 2015 found a mild association inmales between use of Pitocin during labor augmentation andthe incidence of autism among the offspring [2] More

recently an epidemiological study by Harvard Universitypublished in 2016 investigated the association between laborinduction and autism in Sweden and initially identified aweak correlation that could point to the use of Pitocin as acause of the offspring autism development [3] Howeverusing a novel statistical approach involving a family modelrelating the incidence of autism with labor induction amongthe offspring of mothers with multiple offspring the Har-vard study concluded that there was no correlation betweenlabor induction and by inference the use of Pitocin and theincidence of autism among the offspring

e objective of this paper is to provide a mathematicalmodel relating the desensitization of oxytocin receptors(OTRs) in the brain of the fetus to the continuous infusion ofPitocin during labor and by this mathematical model

HindawiComputational and Mathematical Methods in MedicineVolume 2019 Article ID 8276715 13 pageshttpsdoiorg10115520198276715

demonstrate that for long labors having long Pitocin in-fusion times with high Pitocin infusion rates desensitizationof OTRs in the brain of the fetus may occur Oxytocinreceptor desensitization may be followed by downregulationof oxytocin receptors [4] which was a concern of the DukeUniversity study as a possible factor causing the develop-ment of autism in ospring [1]shyis paper demonstrates thatautism attributable to OTR desensitization arising from theuse of Pitocin would be shown not to occur for labor in-ductions that have usual time frames which can go from sixhours [5] to 12 hours or more for continuous Pitocin in-fusion [6]

However this mathematical model does indicate thatOTR desensitization may occur in some cases of long laborinduction and long labor augmentation in which highPitocin infusion rates are administered over long labors withlong Pitocin infusion times OTR desensitization and sub-sequent downregulation may be associated with the devel-opment of autism [1] Hence the conclusion of the Harvardstudy may be in error in that the outcome that they claimdoes not occur no correlation of autism with labor in-duction and may occur for high infusion rates of Pitocinwith long Pitocin infusion times during long labor in-ductions Extrapolating data from these epidemiologicalstudies to the population of the United States it is possible toinfer from the ndings of this study that several hundred toone thousand or more ospring a year may be at risk ofdeveloping autism following the use of large quantities ofPitocin by their mothers at high infusion rates during longlabors shyis comes to 05 to 10 of the number of cases ofautism occurring each year in the United States

shyis model was developed by the author to follow anearlier paper [7] in which it was shown that doses of Pitocinof 6mUmin administered during 12-hour labors were afactor of 10 below the OTR desensitization limit and henceautism attributable to OTR desensitization would not occurHowever the earlier paper did not consider the eects ofhigh continuous infusion rates over the course of long laborswith long Pitocin infusion times on OTR desensitizationwith possible ospring autism development which thispaper does

2 Development and Exposition ofMathematical Model

21 Explanation of Figure 1 To understand the buildup ofPitocin in the maternal circulation from a mathematicalperspective it is important to note that the concentration ofPitocin in the maternal circulation increases as a function ofthe half-life of Pitocin shye half-life of Pitocin in the ma-ternal circulation is an indication of the relative eciency ofthe liver and kidneys in removing Pitocin from the maternalcirculation Higher half-lives indicate lower Pitocin removaleciency shye graph in Figure 1 indicates the relationship ofthe half-life of oxytocin in the blood with the percentoxytocin removal by the liver and kidneys and the percentoxytocin remaining in the blood after the removal shyeindicated removal and retention of oxytocin is for a one-minute cycle of the blood circulation

22 Buildup of Pitocin Concentration in the MaternalCirculation In this section I will oer a mathematicalanalysis to explain the appearance of concentrations ofseveral hundred pgml or more of Pitocin in the maternalcirculation arising from Pitocin infusion into a vein in theuterus shye numbers follow arise out of an infusion rate of20mUmin where 1U or Unit of Solution measuring oneliter introduced into the uterus contains 10 iU or In-ternational Units of Pitocin with each iU containing2micrograms of Pitocin [8 9]shye blood volume is 47 literswhich is for a 160-pound adult female since the volume ofblood for a woman is 65mlkg [10]

shye average half-life of Pitocin in the maternal bloodcirculation decreases during pregnancy [11] However thehalf-life of OT in the maternal blood circulation may varyamong women during labor with less ecient removal ofoxytocin by the kidneys and livers reected in longer half-lives shye calculations are done for half-lives of 1 through6minutes which appear in the literature for nonpregnantadults [12] For this example a half-life of 3minutes waschosen During late pregnancy the half-life of oxytocin inthe maternal circulation is reduced [12] though half-lives of3 to 5minutes have been reported [9 11] One minute istaken as the time needed to complete one cycle of thematernal blood circulation

It is important to note that the concentration of Pitocinfrom continuous Pitocin infusion will increase until the rate

100

90

80

70

60

Percent oxytocin remaining

Percent oxytocin removed

50

40

30

20

10

1 2 3 4t12 (min)

5 60

Figure 1 Percent oxytocin removal by the liver and kidneys andpercent oxytocin remaining in blood with one-minute circulationtime as a function of oxytocin half-life in the blood

2 Computational and Mathematical Methods in Medicine

at which it is added to the maternal circulation equals therate at which it is removed by the kidneys and liver [13]

To illustrate the calculations used in this section anamount of Pitocin is added for each one-minute cycle of20mUmin for the continuous infusion of Pitocin duringlabor Note that the infusion of 20mUmin for one minutecorresponds to the addition of 4E5 pg of OT when 10 iU ofPitocin is introduced into a liter of solution referred to as aUnit U and 1 iU of Pitocin equals 2micrograms of Pitocin[12 14] Since this is in 47 liters of blood the concentrationis 85 pgml that is increased during each cycle Howeverthere is also the removal rate of the Pitocin which isexpressed as an exponential term Exp((minusln 2t12)tprime) wheret12 is the half-life for the Pitocin in the maternal circulationln 2 is the natural logarithm of 2 equal to 06931 andtprime 1minute is the time for one cycle in the circulation of thematernal blood

Hence the concentration of the Pitocin at the end of aone-minute cycle is the product of 85 pgml the amount ofPitocin added in one cycle and the exponential removal rateover one cycle which is Exp(minusln 2t12) for the concentrationof OT after the first cycle is is equal to85 Exp(minusln 2t12)pgml For the next cycle another 85 pgmlincrease in concentration takes place but there is the removalof some of the Pitocin remaining from the first cycle plussome of the Pitocin from the second cycle is can beexpressed as the concentration C for two cycles where

C 85 Expminusln 2t12

1113888 1113889 tprime( 11138571113888 1113889 + Exp2minusln 2t12

1113888 1113889 tprime( 11138571113888 11138891113890 1113891pgml

(1)

is process continues and can be expressed in generalterms as

C 851113944 Exp (i)minusln 2t12

1113888 1113889 tprime( 11138571113888 1113889 pgml (2)

For the buildup concentration C of Pitocin where i runsfrom 1 to some large value n Each hour Pitocin is infusedn 60 assuming a one-minute maternal blood circulationrate Inmathematics this is known as a geometric series [15]e sum C of a geometric series where n is large and i runsfrom 0 to n is given by

C k1

(1minus r)1113890 1113891 (3)

where r is equal to Exp(minusln 2t12) which is the ratio ofsuccessive terms in the geometric series and is less than 1 Inthis example

k [(IR)(10Eminus 3)(10)(2E6)]

Vpgml

(IR)(2E4)

V1113890 1113891pgml

(4)

where k is the concentration in pgml of the Pitocin that isadded to the maternal circulation per minute IR is thecontinuous infusion rate in mUmin and V is the maternalblood volume which is equal to the maternal weightW in kgtimes (65mlkg) [10] In our case IR 20mUmin and the

volume V 47E3ml for a maternal weight of 160 poundserefore k 85 pgml in a one-minute cycle as indicatedabove However since Pitocin is removed during the firstcycle i runs from 1 to n the formula becomes

C k1

(1minus r)minus 11113890 1113891 k

r

(1minus r)1113890 1113891 pgml (5)

where r Exp(minusln 2t12) and the buildup concentration ofoxytocin C k[Exp(minusln 2t12)(1minusExp(minusln 2t12))] pgmle term in the brackets [ ] is referred to as a Multiplier MFor the half-livesconsidered in this paper of 1 to 6minutesthe concentration C comes close to the limit r(1minus r) within20 or 30minutes as it continues to increase with the con-tinuous infusion of Pitocin For a value of t12 3minutesV 47 liters and k 85pgml the concentration C

85(0794(1ndash0794)) pgml 85(385) pgml 327pgml forthe buildup concentration of OT in the maternal blood cir-culation for an infusion rate of 20mUmin with a maternalblood circulation rate of one minute See Figure 2 below for anillustration of this buildup process by the summation of eachsucceeding exponential term

e term r(1minus r) is referred to as a MultiplierM and isunique to each half-life considered Note that the buildupconcentration C is equal toMk or CMk e values forMfor the half-lives considered and the values for k for thebuildup concentrations of Pitocin in one cycle that arisefrom the indicated Pitocin infusion rates IR for maternalweights of 160 pounds and 128 pounds in a 1-minute bloodcirculation cycle are given in Tables 1 and 2

23 Explanation of Figure 2 Figure 2 indicates the in-cremental buildup of the concentration of oxytocin in thematernal circulation as the summation of succeeding ex-ponential terms indicating the remaining oxytocin after each1-minute cycle Note that this buildup has an upper limitexpressed as Mk (see Tables 1 and 2 in Section 22) which isasymptotically approached e 30-minute value of theconcentration is within 01 of the buildup limit Mk and isstable is 30-minute period is the usual length of time thatPitocin is kept at each buildup interval until the buildup ofthe necessary Pitocin concentration during continuousPitocin infusion is reached which is an accepted medicalpractice [12 14]

In actual practice the buildup of the concentration ofPitocin from continuous Pitocin infusion is done in a verygradual manner from one buildup concentration to the nextas the continuous Pitocin infusion level is increased echaracteristics of the buildup process for each individualbuildup concentration of Pitocin at each specific continuousPitocin infusion rate are more complex than indicated inFigure 2 ere is an increase each minute for each suc-ceeding incremental concentration from the prior concen-tration and then a decrease until the stable concentrationlevel CMk is reached when each increase is followed by anearly equal decrease each minute before the next in-cremental concentration is reached However the graph inFigure 2 correctly indicates the characteristics and baselinelevels of the resultant buildup concentration CMk

Computational and Mathematical Methods in Medicine 3

shyemore conservative approach for indicating the lowerbaseline value of the buildup concentration indicated inFigure 2 was chosen to facilitate the mathematical modelingof the buildup concentration since otherwise the actualvalue of the buildup concentration at any given time would

be uncertain because of the nature of the uctuationsresulting from the increase and decrease of the concentra-tion over each 1-minute cycle shye incremental buildupconcentrations shown in Figure 2 above are for their baselinelevels

24 Explanation of Figure 3 shyis graph in Figure 3 depicts alinear relationship for each Pitocin infusion rate for thebuildup concentration of Pitocin in the blood in the ma-ternal circulation plotted against the half-life of Pitocin inthe maternal circulation for mothers with weights of 160pounds and 128 pounds respectively shye relationship be-tween C and t12 over values of t12 from 1minute to6minutes for Pitocin infusion rates of 10mUmin to 50mUmin is given in Figure 3 for women weighing 160 poundswith a blood volume of 47 liters on the left and for smallerwomen weighing 128 pounds 20 less with a volume of38 liters of blood on the rightshye linear relationship of eachinfusion rate with half-life should be noted

shye values of the continuous Pitocin infusion rates aretaken from the values ofM and k in Tables 1 and 2 in Section22 where the baseline buildup concentration CMk foreach combination of M and k Note that the values of thehalf-lives are directly related to the values of M and thevalues of the continuous Pitocin infusion rates and maternalweights are directly related to the values of k Mothers withsmaller weight will have higher concentrations of Pitocin inthe maternal circulation for a given infusion rate than largermothers in that blood volume is proportional to themotherrsquos weight and the same quantity of Pitocin in-troduced into a smaller blood volume will have a higherconcentration that is inversely proportional to the maternalblood volume

shye signicant inuence of the half-life of oxytocin in thematernal circulation on the buildup concentration of oxy-tocin in the maternal circulation as indicated in Figure 3may not have been previously realized Its indication by themathematical model developed in this paper follows fromthe buildup of the Pitocin concentration indicated in Fig-ure 2 shye variations in the eciency of the maternal liverand kidneys in removing oxytocin from the maternal cir-culation are related to the half-life of the Pitocin in thematernal circulation as indicated in Figure 1 Lower e-ciencies of oxytocin removal are reected in higher half-lives and consequently higher oxytocin buildup concen-trations in the maternal circulation as indicated in Figure 3

One observation arising from this graph is that higheroxytocin concentrations in the maternal circulation aremore likely to result in oxytocin diusing through theplacenta

It should be noted as mentioned in Section 22 the half-life is shorter during late pregnancy though values of 3 to5minutes have been reported However it is conceivablethat some mothers with very inecient kidneys and liversmay have longer half-lives for oxytocin removal It shouldalso be noted that for mothers with higher Pitocin infusionrates and higher half-lives Figure 3 indicates that theconcentrations of Pitocin in the maternal blood circulation

Table 1 Values of the Multiplier M for the indicated half-lives

Half-life (min) M1 1002 2413 3854 5295 6736 817

Table 2 Values of k for the concentration of Pitocin that is addedin 1 minute for the indicated Pitocin infusion rates IR and theindicated maternal weights

IR (mUmin) k (160 lb) pgml k (128 lb) pgml10 43 5420 85 10630 128 16040 170 21350 213 266

Buildup concentration limit = MK

Buildup concentration C160lb womenHalf-life t12 = 3minInfusion rate IR = 20mUminM = 385 k = 85pgml

1050 15 20 25t (min)

30 35

500

450

400

350

300

250

pgm

l

200

150

100

50

0

Figure 2 Buildup of the baseline concentration C of Pitocin in thematernal circulation from continuous Pitocin infusion Note shyeparameters of maternal weight infusion rate and half-life and thevalues of the MultiplierM and k which are determined by the half-life and infusion rate in a one-minute blood circulation cycle asindicated in Tables 1 and 2 in Section 22


can be several times higher than the concentrations formothers with lower half-lives and lower Pitocin infusionrates

25 Composite Desensitization Unit ldquoDrdquo In the authorrsquosearlier paper [7] a composite unit ldquoDrdquo equal to18E6 (pgmiddotmin)ml relating the product of oxytocin con-centration and oxytocin exposure time for the OTRs wasestablished to describe the desensitization threshold for theOTRs Studies of OTR desensitization as a function ofoxytocin concentration and exposure time are scarce Onestudy was identied [16] From the information in this studyit was possible to develop the value of D by multiplying thenumbers for the concentration of Pitocin 1E4 pgml andthe time 18E2min needed to achieve desensitizationwhich equals 18E6 (pgml)middot(min) and is expressed in termsof the composite unit as 18E6 (pgmiddotmin)ml shyis establishesa relationship between oxytocin concentration C and thetime T for desensitization using the value of D the thresholddesensitization unit as a constant used over a wide range ofoxytocin concentrations and oxytocin exposure times Inother words the oxytocin concentration CDT where theconcentration C is in pgml and the time T is in minutes andD 18E6 (pgmiddotmin)ml

Knowing the average infusion rate in mUmin and thelength of time at that infusion rate it becomes possible usingthe model mentioned above to indicate the possibility of

desensitization to occur To do this the concept of an upperlimit of the ability of placental oxytocinase to degradeoxytocin is introduced shye concentration of oxytocin fromthe maternal circulation that exceeds it results in a smallerconcentration of oxytocin that diuses across the placentawhich is called the oxytocin override concentration If thissmaller oxytocin override concentration is in the rangeindicated in Figure 4 for OTR desensitization to occur thenthe length of time at this smaller concentration the OTRsin the fetal brain are exposed to permit calculations ofdesensitization of the OTRs using the equations aboveCDT shye plausibility of this phenomenon arises from thedevelopment of the mathematical model in this paper thatdepicts the buildup of high oxytocin concentrations in thematernal circulation indicated in Figures 2 and 3 and the useof the desensitization unit D for the calculations indicated inFigure 4

26 Explanation of Figure 4 Oxytocinase which is an en-zyme that degrades oxytocin is found in high concentrationsin the placenta during labor [17] shye contention in thispaper is that very high concentrations of Pitocin in thematernal circulation in the placenta overwhelm the ability ofthe oxytocinase in the placenta to degrade all the Pitocin inthe placenta from the maternal circulation Consequentlysome of the Pitocin may diuse across the placenta and enterthe fetal circulation (Malek 1996) [18] shyis phenomenon isreferred to in this paper as ldquoOxytocin Overriderdquo of placentaloxytocinase degradation of oxytocin

As shown in Figure 3 the infusion of Pitocin into a veinin the uterus during labor can greatly increase the con-centration of Pitocin in the maternal circulation shyemathematical model developed in this paper assumes nearlyall the Pitocin introduced into the vein in the uterus mixeswith the blood in the maternal circulation some of whichgoes into the placenta

shye buildup of Pitocin in the maternal circulation hasbeen discussed in the literature in terms of its eect onoxytocin concentration in the fetal circulation [19] How-ever from the analysis in the paper [19] the concentrationsof oxytocin indicated in the maternal circulation may nothave been sucient to achieve oxytocin override of placentaloxytocinase degradation of oxytocin and thus would notenter the fetal circulation shyis is noteworthy in that theeect of maternal weight and oxytocin removal half-life maynot have been incorporated into the research considerationsthat determined the ndings of that paper

Oxytocin override concentrations and correspondingdesensitization times are given by the following relationship

D

C(override) T (6)

where D the desensitization constant of 18E6 (pgmiddotmin)mldeveloped from the literature [7 16] C(override) oxytocinoverride concentration and T the desensitization time thetime needed to reach the desensitization threshold at thespecied concentration in the fetal circulation equal toC(override)

160lb women 128lb women

Infusion ratemUmin

Infusion ratemUmin

50

40

30

20

1010

20

30

40

50

20 4 6 2t12 (min)

4 6

pgm

l

2500

2250

2000

1750

1500

1250

1000

750

500

250

0

Figure 3 Oxytocin baseline buildup concentrations in maternalcirculation in terms of Pitocin infusion rate oxytocin half-life andmaternal weight as indicated in Tables 1 and 2 in Section 22


shyis relationship is indicated in the graph in Figure 4 forthe desensitization threshold and for 50 desensitizationover a range of oxytocin override concentrations and de-sensitization times in which the 50 desensitization in-crease requires 40 longer desensitization time is indicatedin the literature [16] It is apparent from Figure 4 that OTRdesensitization would require very high oxytocin overrideconcentrations to occur during the usual time frames forlabor induction Labor induction typically occurs in the rst6 hours of labor [5] which is indicated by the 6-hour line onthe graph for continuous Pitocin infusion time and manywomen may need 12 hours or more of Pitocin infusion [6]indicated by the 12-hour line on the graph in Figure 4 shyesetime frames would require very high oxytocin overrideconcentrations that may possibly exceed the oxytocinbuildup concentrations in the maternal circulation indicatedin Figure 3 and would therefore be impossible to achieve

However Figure 4 indicates that longer desensitizationtimes are consistent with lower oxytocin override concen-trations taking into account the use of oxytocin for bothlabor induction and labor augmentation For long laborsindicated by the lines for 24 to 48 hours of Pitocin infusiontime in Figure 4 the indicated oxytocin override concen-trations in Figure 4 are less than the high concentrations ofPitocin in the maternal circulation indicated in Figure 3 atthe higher continuous Pitocin infusion rates and half-livesand are therefore plausible As indicated in Figure 3 high

Pitocin infusion rates longer half-lives and mothers withsmaller weights serve to increase the concentrations ofPitocin in the maternal circulation making oxytocinoverride concentrations high enough to achieve de-sensitization during long labors more likely

3 Discussion of OxytocinReceptor Desensitization

31OxytocinOverride andOxytocinReceptorDesensitizationshye concentration of Pitocin in the fetal circulation may behigh enough to result in desensitization of OTRs in the brainof the fetus if the infusion rate of the Pitocin is high over thecourse of long labors with long Pitocin infusion times Asshown in Figure 4 the relationship between the concen-tration of Pitocin C and the desensitization unit D whereDCT18E6 (pgmiddotmin)ml may be applied to the con-centrations of Pitocin in the cerebral spinal uid

It is noteworthy that the blood-brain barrier of the fetusmay be permeable to oxytocin [20] For the purposes of thisstudy no inhibition of oxytocin crossing the blood-brainbarrier in the fetus has been assumed Pitocin may cross theblood-brain barrier in the fetus in high concentrationsresulting in high concentrations in the cerebral spinal uidin the brain It is possible tomodel the buildup of oxytocin inthe fetal brain in terms of oxytocin override concentrationsand desensitization times for the desensitization of OTRs inthe fetal brain from information in Figure 4 shyis is so sincethe oxytocin concentration in the fetal brain would mostlikely be equal or close to the oxytocin override concen-tration that diuses across the placenta and enters the fetalcirculation since no inhibition of oxytocin transfer across theblood-brain barrier has been assumed

For high enough concentrations of Pitocin in thematernal circulation resulting from high rates of Pitocininfusion the concentration of Pitocin that may enter thefetal circulation may be high However if it is not highenough or is suciently high but not for long enough OTRdesensitization will not occur Also it is important to notethat long Pitocin infusion times imply long labors how-ever long labors do not necessarily imply long Pitocininfusion times as alternative procedures and the stoppingof Pitocin infusion may be done It is noteworthy thatoxytocinase does not leak into the fetal circulation [21]Consequently there is no degradation of oxytocin in thefetal circulation attributable to oxytocinase in the fetalcirculation While it is known that the fetal secretion rate ofoxytocin increases signicantly during labor with oxytocinconcentrations of 73 pgml measured in the umbilical ar-tery [22] this paper does not consider the endogenousproduction of oxytocin by the fetus in its calculations ofoxytocin concentrations in the fetal circulation Likewisethis paper does not consider the endogenous production ofoxytocin in the maternal circulation in its calculations ofoxytocin override concentrations [22]

In this regard one study indicated very high levels ofendogenous oxytocin in the maternal circulation with nocontribution from Pitocin when Pitocin infusion wasperformed during labor [23] However this study indicated

Desensitizationthreshold

48hr

24hr

12hr

6hr

50 desensitization

4002000 600 800 1000pgml

1200 1400

100

90

80

70

60

50hr

40

30

20

10

0

Figure 4 Oxytocin override desensitization threshold and 50desensitization level as functions of Pitocin infusion time T duringlabor and oxytocin override concentration C whereCTD 18E6 (pgmiddotmin)ml for the oxytocin override de-sensitization threshold


that oxytocin was not extracted from the samples of plasmawhich underwent enzyme-limited immunoassays to mea-sure the oxytocin levels In a separate study on oxytocinmeasurement it was found that oxytocin samples thatunderwent enzyme limited immunoassay without extractionof the oxytocin from the plasma could lead to measurementsthat were a factor of a hundred or more in error [24]erefore the findings indicated in the first study [23] areconsidered erroneous

e action of oxytocinase during pregnancy has beenexamined in the literature [25 26] It is realistic to presumethat there is an upper limit to the ability of placental oxy-tocinase to degrade all the oxytocin entering the placentafrom the maternal circulation While oxytocin override hasnot been confirmed by measurements it is plausible that thehigher the concentration of oxytocin in the maternal cir-culation the more likely the oxytocin override is to occur

Earlier studies of Pitocin infusion showing that thetransport of oxytocin from the maternal circulation acrossthe placenta into the fetal circulation does not occur [19 26]may not have considered the cases indicated in this paper forhigh infusion rates for smaller women with kidneys andlivers that are less efficient at removing oxytocin whichwould be reflected in longer half-lives and higher oxytocinconcentrations as indicated in Figure 3 e oxytocinconcentrations in the maternal circulation in these studies[19 26] may not have exceeded the limit of placental oxy-tocinase to degrade the oxytocin

32 Possible Factors Affecting Oxytocin Receptor De-sensitization during Labor in the Fetal Brain e followingfactors may affect the concentration of Pitocin during laborand the possible desensitization of OTRs in the fetal brain

(1) e initial factor relating the use of Pitocin duringlabor with OTR desensitization and the possibledevelopment of autism among some of the offspringis the total quantity or units of Pitocin used sincethis relates directly with the Pitocin infusion rateand the Pitocin infusion time

(2) A second factor relating the use of Pitocin duringlabor with OTR desensitization and the possibledevelopment of autism among some of the off-spring is the continuous Pitocin infusion rate inmUmin [14] during the labor where a unit U ofPitocin is 10 iU (International Units of Pitocinwhere 1 iU 2 ug of Pitocin) in 1 liter of solutione higher the infusion rate of Pitocin the higherthe potential oxytocin override and subsequentOTR desensitization

(3) It can be shown mathematically that high infusionrates of Pitocin may result in a disproportionatelyhigh concentration of Pitocin in the fetal circula-tion relative to the same quantity of Pitocin in-troduced at lower infusion rates e placenta canonly produce a limited amount of oxytocinase todegrade the Pitocin from the maternal circulationOnce the maximum ability of the oxytocinase to

degrade the Pitocin is reached additional Pitocinmay get though with more getting through forhigher infusion rates than for the same quantity ofPitocin used in lower infusion rates e implica-tion from the discussion in this paper for the use ofPitocin during long labors with long Pitocin in-fusion times at high Pitocin infusion rates is thatwhere possible Pitocin should be used at lowerinfusion rates since that may limit the possibledevelopment of autism in the offspring

(4) e concentration and quantity of oxytocinase inthe placenta may decrease during labor by means ofleakage from the maternal circulation in the pla-centa into the maternal blood circulation as a whole[25] A lower concentration of oxytocinase in thematernal circulation in the placenta may result andlead to greater oxytocin override since the upperlimit of Pitocin degradation by oxytocinase in theplacenta would be lower e concentration ofoxytocinase in the maternal circulation as a wholewould increase increasing the degradation ofoxytocin in the maternal circulation however thedegradation of oxytocin in the maternal circulationby oxytocinase is small [26] It can be shownmathematically that leakage of oxytocinase from theplacenta to the blood would not compensate for alower concentration of oxytocinase in the placentaand the reduction of its upper limit to degradeoxytocin Consequently due to the leakage ofoxytocinase from the placenta the placental oxy-tocinase limit for the degradation of oxytocin maydecline and the oxytocin override concentrationmay increase is may result in a greater likelihoodand degree of desensitization of OTRs in the brainof the fetus Placentas may vary in the concentrationand quantity of oxytocinase they produce and inthe extent of their leakage of oxytocinase and thetime over which it occurs

(5) Another possible factor is the potential increase inthe concentration of oxytocin in the cerebral spinalfluid resulting from the addition of Pitocin to thecerebral spinal fluid that crosses the blood-brainbarrier e added concentration of Pitocin in thecerebral spinal fluid may itself lead to Pitocinrsquosaction as a neurotransmitter and neuromodulatoracting on magnocellular neutrons in the hypo-thalamus that produce the oxytocinis may causethe production of even more oxytocin which mayresult in a further increase in the concentration ofoxytocin in the cerebral spinal fluid is could be afactor affecting the desensitization of the OTRs andmay cause OTR desensitization to occur at loweroxytocin override levels

(6) Another possible factor affecting the desensitizationof OTRs by Pitocin is the half-life of the Pitocin inthe maternal blood circulation which is directlyrelated to the efficiency of the kidneys and liver ofthe mother in removing oxytocin As shown in


Figures 2 and 3 the concentration of Pitocin in thematernal circulation is strongly influenced by thehalf-life of the Pitocin in the maternal circulationHigher half-lives may result in significantly higherconcentrations of Pitocin in the maternal circula-tion and hence greater oxytocin override whichmay result in greater desensitization of OTRs in thebrain of the fetus

(7) Another possible factor affecting the concentrationof Pitocin entering the cerebral spinal fluid that maycause OTR desensitization in the brain of the fetus isthe blood volume of the maternal circulation inthat for the same Pitocin infusion rate a smallerblood volume in the maternal circulation will have ahigher concentration of Pitocin as indicated inFigure 3 since blood volume and Pitocin concen-tration are inversely proportional Higher Pitocinconcentrations may result in greater oxytocinoverride and hence greater desensitization of OTRsin the brain of the fetus

(8) e potential fluctuations of the buildup concen-trations mentioned in Section 24 that increase themagnitude of these buildup concentrations abovethe baseline may result in fluctuations in the oxy-tocin override concentrations that are indicated inFigure 4 ese fluctuations may vary as a functionof both the continuous Pitocin infusion rate and thehalf-life of the Pitocin in the maternal circulationese fluctuations may result in a reduction of thetime during labor that is needed for OTR de-sensitization in the brain of the fetus that is in-dicated in Figure 4

(9) e presence and concentration of OTRs in thebrain of the fetus at term bears discussion It hasbeen found that just before birth estradiol has avery important role in influencing the number andconcentration of OTRs in the brain of the fetusincreasing them by as much as a factor of five [27]Variation in the ambient concentration of estradiolmay significantly influence the concentration ofoxytocin receptors in the brain of the fetus whichmay be a factor in the onset of autism [28] Highoxytocin concentrations in the cerebral spinal fluidmay interfere with the development of new OTRs inthe brain of the fetus as they do for existing OTRsduring desensitization and downregulation is inaddition to the reduction in the numbers of OTRsthat may result from lower levels of estradiol [27]may cause the possible development of autism to bemore severe is is so because lower levels ofestradiol may serve to augment the desensitizingaction of oxytocin override in reducing the numberof OTRs

(10) It has been found in a study by Stanford Universitythat genetic variability in the OTR gene may be arisk for the development of autism [29] It isconceivable that because of the genetic variabilityof the OTR gene the OTRs of autistic children may

be more vulnerable to desensitization and conse-quently undergo desensitization in a manner de-scribed by a smaller desensitization Unit DConsequently there may be less time needed fordesensitization for any given oxytocin overrideconcentration or a lower oxytocin override con-centration for any given desensitization time forfetuses having the variability in the OTR gene de-scribed in the Stanford study e effect if any ofthe genetic variability of OTRs on their vulnerabilityto desensitization by oxytocin was not addressed inthe Stanford study Likewise it is conceivable thatthese OTRs may not respond to the presence ofestradiol during labor in the same way as the normalOTRs indicated in point (9) (in Section 32) eeffect if any of the influence of estradiol on thedevelopment of the OTRs with genetic variability asdiscussed for normal OTRs in point (9) (in Section32) was also not discussed in the Stanford study

(11) Fetal production of oxytocin [22] may conceivablyoccur with the presence of oxytocin override con-centrations entering the fetal circulation iswould increase the concentration of oxytocin in thefetal circulation beyond the oxytocin override levelsand consequently lower the time frames for de-sensitization of OTRs in the fetal brain or increasethe likelihood or degree of this desensitization for agiven time frame Similarly endogenous oxytocinin the maternal circulation could serve to increasethe oxytocin override concentration and its impacton desensitization of the OTRs in the fetal brain[22]

(12) e desensitization unit D which is treated as aconstant equal to 18E6 (pgmiddotmin)ml throughoutthis paper may vary over the ranges of Pitocinconcentrations and exposure times during laborconsidered in this paper Should it be found todecrease for lower concentrations the oxytocinoverride exposure times corresponding to the in-dicated Pitocin concentrations during labor inFigure 4 would likewise decreasee factors discussed in points (1) to (12) (in Section32) may serve to reduce the time needed for givenoxytocin override concentrations to cause de-sensitization of the OTRs in the fetal brain as in-dicated in Figure 4 which may lead to offspringautism development

4 Discussion of Epidemiological Studies

41 Explanation for theWeak Correlation Observed in RecentEpidemiological Studies is section will attempt to clarifythe finding of a weak correlation inferred for Pitocin useduring labor and the subsequent development of autism inthe offspring observed in recent epidemiological studies byDuke University in 2013 [1] Yale University in 2015 [2] andinitially in the study by Harvard University in 2016 [3]mentioned in the Introduction section What is lacking in


the attempts by these studies to interpret the findings of aweak correlation is the realization that there may be a de-sensitization and hence a downregulation threshold for theuse of Pitocin during labor below which no desensitizationand subsequent downregulation will occur is de-sensitization threshold is the product of the Pitocin con-centration and the exposure time of OTRs in the fetal brainto the Pitocin equal to D 18E6 (pgmiddotmin)hr which by theanalysis in this paper can be related to parameters such asquantity of Pitocin used during labor Pitocin infusion ratematernal weight length of time for labor and half-life foroxytocin removal in the maternal circulation that have beendiscussed in Sections 23 24 25 26 and 31 Consequentlyfor Pitocin use below this threshold there will be no OTRdesensitization in the brain of the fetus and hence nocorrelation between Pitocin use during labor and the pos-sible development of autism among the offspring Howeverabove this threshold a correlation may exist

From the analysis elsewhere in this paper and in aprevious paper by this author [7] most labors will requiremuch less Pitocin than the amount needed for an oxytocinoverride concentration to occur or if it occurs to reach thedesensitization thresholds indicated in Figure 4 Hence formost labors there will be no development of autism amongthe offspring that is attributable to OTR desensitizationarising from the use of Pitocin and subsequent down-regulation However as indicated in Figure 4 for long laborswith long Pitocin infusion times at high Pitocin infusionrates a desensitization threshold may be reached andexceeded resulting in the desensitization of OTR receptorsin the brain of the fetus with subsequent downregulation Itmay be possible to establish correlations of long laborshaving long Pitocin infusion times with high Pitocin in-fusion levels with offspring autism development above thispotential desensitization threshold

e weak correlations indicated in the epidemiologicalstudies may be explained in terms of Pitocin usage bycombining no correlation for the majority of the cases ofPitocin use that are below a potential desensitizationthreshold with a much smaller number of cases havingmodest to strong correlations that are above this potentialdesensitization threshold is combination may result in aweak correlation for the entire population

A more exacting analysis may be done by examining themedical information concerning Pitocin usage if it isavailable that is associated with the cases examined in theepidemiological studies by Duke University Yale Universityand Harvard University where Pitocin use and offspringdevelopment of autism occur ese epidemiological studiesdid not examine the medical information associated withPitocin use in the cases they examined to enable possiblecorrelations of Pitocin use with offspring autism develop-ment e possibility of such correlations indicates thenecessity for these studies to be pursued with detailed ep-idemiological analysis

Such examination of the medical information con-cerning Pitocin use associated with the epidemiologicalstudies if it is possible may permit the determination of apossible correlation between Pitocin use and the subsequent

offspring autism development By examining the correla-tion if it is found it may be possible to identify an actualempirical desensitization threshold Further analysis of themedical information on Pitocin use if it is available maypermit the determination of risk factors for the developmentof autism correlated to quantity or units of Pitocin usedPitocin infusion rate length of time for labor and maternalweight for cases above the empirical desensitizationthreshold that may be established It may also be possible toestablish a correlation between these factors and the severityof the autism in the offspring In the event the medicalinformation concerning Pitocin usage is not available fromthe epidemiological studies by Duke University Yale Uni-versity and Harvard University new epidemiologicalstudies could be undertaken

42 Reassessment of Harvard Epidemiological Study Findingsand Conclusion e approach indicated above should beseen in light of the findings of the recent epidemiologicalstudy by Harvard University of the occurrence of autismamong the offspring of mothers who underwent labor in-duction with or without Pitocin in Sweden [3] e initialdata for the Harvard study suggested the possibility of acorrelation between labor induction and the subsequentdevelopment of autism in offspring However the Harvardstudy used original statistical methods involving a familymodel to demonstrate that there was no correlation betweenthe occurrence of autism during labor induction and byinference with the use of Pitocin with a hazard ratio of 099for a 95 confidence interval of (088ndash110) for theircomplete case category

e analysis in this paper indicates that autism attrib-utable to the use of Pitocin during labor would not occurduring the time frames for most labor inductions which cango from 6 hours [5] to 12 hours or more for many womenundergoing continuous Pitocin infusion [6] Consequentlya correlation between offspring autism development andPitocin usage would not exist However by the analysis inthis paper offspring autism development may be associatedwith high Pitocin infusion rates during long labor inductionswith long Pitocin infusion times especially for smallermothers with less-efficient kidneys and livers for the removalof oxytocin e number of cases would be relatively smalland may not be reflected in the statistics the Harvard studypresented One factor influencing this is that the Harvardstudy considered labor induction as a whole and not justcontinuous Pitocin infusion for labor induction Harvardrsquosanalysis could dilute the indication of the possible influenceof continuous Pitocin infusion during labor induction onoffspring autism development that may not be evident in thestatistics they presented for their complete case category

Taking these factors into account and using other datafrom the family model used in the Harvard study namelytheir sensitivity analysis for the category of first born ofmaternal cousins which indicates a hazard ratio of 102 witha 95 confidence interval of (083ndash126) there may be anindication of a correlation between labor induction withPitocin and offspring autism development First births are


generally longer [30] and this category in the Harvardfindings first born of maternal cousins may more readilyreflect the outcome of autism attributable to Pitocin usageindicated in Figure 4 where long labor inductions with longPitocin infusion times using large quantities of Pitocin are afactor in OTR desensitization which may lead to offspringautism development

Consequently there may be a higher percentage of casesof offspring autism development in the category of first birthsof maternal cousins which has a 102 hazard ratio than in thecomplete case category which has a 099 hazard ratio ismay suggest a weak correlation between labor induction andoffspring autism development A stronger correlation mayhave been suggested in the Harvard study had continuousPitocin infusion been considered separately for labor in-duction Labor induction with Pitocin accounted for 63 ofinduced labors in the United States in 2016 [31] and thepercentage of induced labors in Sweden in 2016 when theHarvard study was conducted in Sweden is likely similar

is hazard ratio of 102 may reflect the small incidenceof labors with high levels of continuous Pitocin infusion forlong labor inductions with long Pitocin infusion timesnecessary to achieve the oxytocin override levels indicated inFigure 4 which could result in OTR desensitization in thebrain of the fetus and possible offspring autism develop-ment Consequently the conclusion of the Harvard studythat ldquothe findings of this study provide no support for acausal association between induction of labor and offspringdevelopment of autismrdquo and the inference that follows thatcontinuous Pitocin infusion during labor induction has nocausal association with offspring development of autismmay be in error

5 Research Considerations

51 Research to Address the Findings of is Paper

(1) An analysis of the medical information for the casesof autism among offspring whose mothers receivedPitocin during labor if this medical information isavailable may indicate a correlation between theoccurrence of offspring autism development frommothers who had long labors with large quantitiesof Pitocin with high Pitocin infusion rates above anempirically determined desensitization thresholde previous epidemiological studies by DukeUniversity in North Carolina Yale University inDenmark and initially by Harvard University inSweden mentioned in the Introduction section andin Sections 41 and 42 infer a weak correlationbetween Pitocin use during labor with the sub-sequent development of autism in some of theoffspring e acquisition of medical information ifpossible on the number of Units of Pitocin usedthe rates of Pitocin infusion the length of the la-bors and the weights of the mothers during laborfor the cases where the offspring developed autismmay enable the determination of modest to strongcorrelations of Pitocin use with offspring autism

development above an empirically determineddesensitization thresholde information needed for this determinationshould be available in the medical records of themothers in the cases in the epidemiological studieswhere Pitocin use and offspring autism developmentwas found to occur Obtaining this information forthese cases if it is possible and performing thesubsequent statistical analysis would shed light onthe validity of the desensitization model presented inthis paper and even more so may provide in-formation for medical practitioners to evaluate therisk of autism in the offspring of the patients theytreat with continuous Pitocin infusion during laborIn the event this information is not available newepidemiological studies could be undertaken

(2) Such a correlation between the use of high levels ofPitocin use over long labors and offspring autismdevelopment if it is found would argue for a morecircumspect use of Pitocin during labor lowering theinfusion rates where possible for a lower total use ofPitocin Along these lines it may be useful to revisitthe application of pulsatile infusion of oxytocin forlabor induction Research into pulsatile infusion ofoxytocin indicates that pulsatile infusion is moreconsistent with the natural pulsed secretion ofoxytocin from the pituitary gland than continuousPitocin infusion is research has found that pul-satile infusion used 80 less oxytocin than contin-uous infusion [32 33] with the highest infusion ratesof pulsatile infusion of oxytocin in one study 43lower than those for continuous infusion of oxytocin[34] Pulsatile infusion of oxytocin has been found tobe as safe and effective as continuous oxytocin in-fusion for labor induction [32ndash35] and may mitigatethe concerns raised in this paper regarding possibleoxytocin override concentrations high enough tocause desensitization in the brain of the fetusFurther research is needed to more fully evaluate thepotential benefit of pulsatile infusion to determine ifthe pulses of oxytocin themselves may produce highoxytocin override concentrations for the duration ofthe pulse and if so what the effects may be on OTRdesensitization in the brain of the fetus Pulsatileinfusion of Pitocin has been found to be less safe andless effective than continuous Pitocin infusion forlabor augmentation [32 33] Recent clinical trials forfurther study of pulsatile infusion of Pitocin havebeen proposed or undertaken [36 37] If it is foundto be suitable for general use in hospital settings theapplication of pulsatile Pitocin infusion could beused as an alternative to or in conjunction withcontinuous Pitocin infusion for labor induction Itspotential utility for the purposes of this paper may bein keeping Pitocin use below possible desensitizationthresholds that may be found to exist by the analysisof the epidemiological studies called for in point (1)(in Section 51)


(3) e extrapolation used in this paper for the pre-sumed proportionality of the oxytocin overrideconcentration C and OTR exposure time T involvingthe desensitization unit D [7] which was introducedin Section 25 arising from the constant value of thedesensitization unit D 18E6 (pgmiddotmin)mlCTmust be examined with further research into thedesensitization of oxytocin receptors as a function ofthe indicated range of oxytocin concentrations andOTR exposure times in Figure 4 is research couldbe similar to the research in the study referenced inSection 25 on desensitization as a function of Pitocinconcentration and Pitocin exposure time [16] isresearch is necessary to validate more precisely theconclusions of this paper and achieve a more preciseunderstanding of the role of high levels of Pitocininfusion during long labors with long Pitocin in-fusion times and the possible development of autismamong the offspring It should be noted that in astudy of the effects of oxytocin on prairie voles it wasfound that long-termlow-dose administration ofoxytocin may have caused possible desensitizationwith detrimental effects persisting long beyondtreatments themselves [38] is finding may arguefor extending the desensitization threshold to lowerlevels of oxytocin concentrations than indicated inthe literature [16] and may support the extrapola-tions indicated in this paper underlying the re-lationship between oxytocin override concentrationsand desensitization thresholds indicated in Figure 4

(4) If a relationship can be found between the efficienciesof the kidneys and liver for removing oxytocin andthe results of standard tests of kidney and liverfunction it may be possible to determine the half-lifeof oxytocin in the maternal circulation during laborwithout the use of additional Pitocin which couldinterfere with the labor itself is would enable theidentification of mothers potentially at risk for highconcentrations of oxytocin arising from continuousPitocin infusion during long labors as indicated inFigure 3 which could lead to OTR desensitizationIdentifying these at-risk mothers may enable pre-cautions to be taken that may circumvent the pos-sibility of offspring autism development

(5) e mathematical model in this paper describingoxytocin override assumes an upper limit for pla-cental oxytocinase degradation in the maternal cir-culation which has not been established and whichmay change over the course of the labor itself andmay differ among the placentas of different mothersproducing the oxytocinase Oxytocin override ofplacental oxytocinase degradation of oxytocin maybe possible to study in animal models to evaluate theclaims for OTR desensitizationmade in this study forhigh oxytocin infusion rates

(6) e production of increased concentrations ofoxytocin in the cerebral spinal fluid of the fetuswhich may result from the concentration of Pitocin

entering the cerebral spinal fluid from the maternalcirculation and binding with the OTRs in themagnocellular neurons as discussed in point (5) (inSection 32) may be shown if the generation ofoxytocin producing magnocellular neurons fromadult stem cells from human beings can be doneis may permit in vitro research showing howincreasing the concentration of Pitocin in the fluidsurrounding these magnocellular neurons may resultin further increase in the production of oxytocinfrom these neurons by means of oxytocinrsquos functionas a neurotransmitter and neuromodulator acting onthem

(7) e data to establish the value of the desensitizationunit D are taken from rat uterine explants not humanneurons e generation of neurons from adult stemcells from human beings if possible may permitfurther studies of desensitization and downregulationof OTRs on neurons It may also permit a more ac-curate determination of the value of the desensitizationunit D for OTRs in the neurons of human beings andmay permit a more accurate determination if D variesover a range of oxytocin concentrations and exposuretimes in human neurons And it may permit de-termination if OTR gene variation that is associatedwith autism is associated with greater vulnerability ofthese OTRs to desensitization

6 Conclusion

Although there are gaps in the scientific information neededto fully support the thesis presented in this paper it isplausible that OTR desensitization in the brain of the fetus ispossible during long labors with long Pitocin infusion timeswith high continuous Pitocin infusion rates especially forsmaller mothers with less-efficient kidneys and livers forremoving oxytocin In making this claim this paper is moredescriptive than prescriptive and calls for consideration ofthe medical information if available in the epidemiologicalstudies by Duke University in 2013 Yale University in 2015and Harvard University in 2016 in which autism amongoffspring occurred along with the use of Pitocin by theirmothers during labor

e quantity of Pitocin used the average infusion ratethe length of the labor and the weight of the mother at thetime of birth are factors that could affect a correlation be-tween the use of Pitocin during labor and the occurrence ofautism among the offspring is paper asserts that thiscorrelation if found may occur above an empirically de-termined desensitization threshold associated with the de-sensitization of the OTRs in the brain of the fetus

e weak correlations observed in the epidemiologicalstudies referenced in Section 42 may be explained asresulting from the combination of no correlation betweenthe use of Pitocin during labor with autism for the majorityof labors which are below an empirically determined de-sensitization threshold that may be established for Pitocinuse and a strong correlation for the much smaller number oflabors that are above this desensitization threshold


e findings of the Harvard epidemiological study arereinterpreted and its conclusion is questioned to allow forthe possibility of offspring autism development arising fromthe use of high infusion rates of Pitocin over long laborinductions with long Pitocin infusion times especially forsmaller mothers with less-efficient kidneys and livers for theremoval of oxytocin

is paper establishes the relationship between contin-uous Pitocin infusion rate half-life and the maternal weightwith oxytocin concentration in the maternal circulationindicating the significance of what may be the previouslyunknown influence of maternal oxytocin half-life on oxy-tocin concentration in the maternal circulation e con-cepts introduced of oxytocin override and the limit ofplacental oxytocinase degradation of oxytocin may explainthe possible buildup of oxytocin in the fetal circulation andthe possible desensitization of OTRs in the brain of the fetusthat may follow for long labors with long Pitocin infusiontimes with high Pitocin infusion rates

e concern of this paper is to argue that a de-termination be made if there is a correlation betweenPitocin use during long labors and offspring autism de-velopment frommedical information if it is available thatis associated with the epidemiological studies by DukeUniversity Yale University and Harvard Universitywhile presenting a mathematical model that strongly al-ludes to the plausibility of such a determination Limi-tations in the availability of scientific information thatcould support the mathematical model presented in thispaper preclude a more accurate determination of thepossible correlation between Pitocin use during labor andthe development of autism among the offspring Howeverthe inferences drawn from the mathematical model pre-sented in this paper are that for long labors with longPitocin infusion times at high Pitocin infusion rates forsmaller mothers with higher than average half-lives foroxytocin removal from the maternal circulation theoffspring may be at greater risk for OTR desensitizationand the possible development of autism Higher de-sensitization levels may be shown to indicate a greater riskand severity of autism

e possibility of the correlation between Pitocin useduring labor and offspring development of autism discussedabove which may affect five hundred to one thousand ormore offspring a year in the United States corresponding to05 to 10 of the cases of autism should be motivation towarrant further investigation of the medical information ifit is available that is associated with the epidemiologicalstudies by Duke University Yale University and HarvardUniversity or the undertaking of new epidemiologicalstudies is would allow for the possible development ofrisk factors for the potential onset of autism among theoffspring that may call for a more circumspect use of Pitocinduring long labors involving large quantities of Pitocin athigh infusion rates is may include the application ofpulsatile oxytocin administration for labor induction as wellas consideration of alternative medical procedures duringlong labors in lieu of the use of large quantities of Pitocin athigh infusion rates

Data Availability

ere are no underlying data associated with my manu-script which is based on metaresearch applied to an originalmathematical model

Conflicts of Interest

e author declares that they have no conflicts of interest

References

[1] S G Gregory R Anthopolos C E Osgood C A Grotegutand M L Miranda ldquoAssociation of autism with induced oraugmented childbirth in North Carolina birth record (1990-1998) and education research (1997-2007) databasesrdquo JAMAPediatrics vol 167 no 10 pp 959ndash966 2013

[2] O Weisman E Agerbo C S Carter et al ldquoOxytocin-augmented labor and risk for autism in malesrdquo Behav-ioural Brain Research vol 284 pp 207ndash212 2015

[3] A S Oberg B M DrsquoOnofrio M E Rickert et al ldquoAssociationof labor induction with offspring risk of autism spectrumdisordersrdquo JAMA Pediatrics vol 170 no 9 article e1609652016

[4] A F Bell E N Erickson and C S Carter ldquoBeyond Labor therole of natural and synthetic oxytocin in the transition tomotherhoodrdquo Journal of Midwifery and Womenrsquos Healthvol 59 no 1 pp 35ndash42 2014

[5] L M Harper A B Caughey A O Odibo K A RoehlQ Zhao and A G Cahill ldquoNormal progress of inducedlaborrdquo Obstetrics and Gynecology vol 119 no 6 pp 1113ndash1118 2012

[6] South Shore Medical Center ldquoHealth resources pregnancyguide when you need labor inducedrdquo 2018 httpwwwssmedcentercomhealthy_pregnancylabor_inducedcfm

[7] M M Gottlieb ldquoPitocin and autism an analysis of oxytocinreceptor desensitization in the fetusrdquo Behavioural BrainResearch vol 298 pp 246-247 2016

[8] Medi Lexicon International Ltd Craythorne House BurnsideMews London Road Bexhill-on-Sea TN39 3LE CompanyNumber 05744408 httpswwwmedilexiconcomdictionary95735

[9] Global RPhcom httpwwwglobalrphcomoxytocin_dilutionhtm

[10] M Morgan and Murray Clinical Anesthesiology 3rd EditionMedscape 2011 httpsreferencemedscapecomcalculatorestimated-blood-volume

[11] G Ryden and I Sjoholm ldquoHalf-life of oxytocin in blood ofpregnant and non-pregnant womenrdquo Acta Endocrinologicavol 61 no 3 pp 425ndash431 1969

[12] ldquoPitocin (oxytocin injection USP) synthetic Reference ID3638684rdquo 2014 httpswwwaccessdatafdagovdrugsatfda_docslabel2014018261s031lblpdf

[13] M Gonser ldquoLabor induction and augmentation with oxy-tocin pharmacokinetic considerationsrdquo Archives of Gyne-cology and Obstetrics vol 256 no 2 pp 63ndash66 1995

[14] Drugscom ldquoPitocin dosagerdquo httpswwwdrugscomdosagepitocinhtml

[15] E W Weisstein ldquoGeometric Series Math World A Wolframweb resourcerdquo httpmathworldwolframcomGeometricSerieshtml

[16] C Robinson R Schumann P Zhang and R C YoungldquoOxytocin-induced desensitization of the oxytocin receptorrdquo


American Journal of Obstetrics and Gynecology vol 188pp 497ndash502 2003

[17] M Oya M Yoshivo S Miyutani and T Wakabayashi ldquoeorigin of human pregnancy serum oxytocinaserdquo Gynecologicand Obstetric Investigation vol 5 no 5-6 pp 276ndash2831974

[18] A Malek E Blann and D R Mattison ldquoHuman placentaltransport of oxytocinrdquo Journal of Maternal-Fetal Medicinevol 5 no 5 pp 245ndash255 1996

[19] C Patient J M Davison L Charlton P H Baylis andS ornton ldquoe effect of labour and maternal oxytocininfusion on fetal plasma oxytocin concentrationrdquo BJOG AnInternational Journal of Obstetrics and Gynaecology vol 106no 12 pp 1311ndash1313 1999

[20] N R Saunders S A Liddelow and K M DziegielewoskaldquoBarrier mechanisms in the developing brainrdquo Frontiers inPharmacology vol 3 no 46 2012

[21] T Chard ldquoFetal and maternal oxytocin in human parturi-tionrdquo American Journal of Perinatology vol 6 no 2pp 145ndash152 1989

[22] M Y Dawood and F Fuchs ldquoMaternal and fetal oxytocinlevels at parturition in a paraplegic womanrdquo European Journalof Obstetrics and Gynecology and Reproductive Biology vol 12no 1 pp 1ndash6 1981

[23] M Prevost P Zelkowitz T Tulandi et al ldquoOxytocin inpregnancy and the postpartum relations to labor and itsmanagementrdquo Frontiers in Public Health vol 2 2014

[24] A Szeto P M McCabe D A Nation et al ldquoEvaluation ofenzyme immunoassay and radioimmunoassay methods forthe measurement of plasma oxytocinrdquo Psychosomatic Medi-cine vol 73 no 5 pp 393ndash400 2011

[25] S E J Melander ldquoOxytocinase activity of plasma of pregnantwomenrdquo Nature vol 191 no 4784 pp 176-177 1961

[26] J Sjoholm ldquoOxytocinase and its possible significance in thedegradation of oxytocin during pregnancyrdquo FEBS Lettersvol 4 no 3 1969

[27] M S Soloff M A Fernstrom S Periyasamy S SoloffS Baldwin and M Wieder ldquoRegulation of oxytocin receptorconcentration in rat uterine explants by estrogen and pro-gesteronerdquo Canadian Journal of Biochemistry and Cell Bi-ology vol 61 no 7 pp 625ndash630 1983

[28] S G Gregory J J Connelly A J Towers et al ldquoGenomic andepigenetic evidence for oxytocin receptor deficiency in au-tismrdquo BMC Medicine vol 7 no 1 2009

[29] K J Parker J P Garner R A Libove et al ldquoPlasma oxytocinconcentrations and OXTR polymorphisms predict socialimpairments in children with and without autism spectrumdisorderrdquo Proceedings of the National Academy of Sciencesvol 111 no 33 pp 12258ndash12263 2014

[30] J Pete ldquoEssential baby Labour the second time aroundmdashis iteasierrdquo February 2014 httpwwwessentialbabycomaubirthstages-of-labourlabour-the-second-time-round--is-it-easier-20140219-3326n

[31] ldquoQuick facts about labor induction National partnership forwomen amp familiesrdquo August 2016 httpwwwnationalpartnershiporgresearch-librarymaternal-healthquick-facts-about-labor-inductionpdf

[32] R J Willcourt D Pager J Wendel and R W Hale ldquoIn-duction of labor with pulsatile oxytocin by a computer-controlled pumprdquo American Journal of Obstetrics and Gy-necology vol 170 no 2 pp 603ndash608 1994

[33] R M Tribe S E Cranshaw P Seed A H Sherman andP N Baker ldquoPulsatile vs continuous administration ofoxytocin for induction and augmentation of labor two

randomized controlled trialsrdquo American Journal of Obstetricsand Gynecology vol 206 no 3 pp 230e1ndash230e8 2012

[34] R R Odem B A Work Jr and M Y Dawood ldquoPulsatileoxytocin for induction of labor a randomized prospectivecontrolled studyrdquo Journal of Perinatal Medicine vol 16 no 1pp 31ndash37 1988

[35] J Liu Y Yi and X Weiwei ldquoEffects of increased frequencyhigh dose and pulsatile oxytocin regimens on abnormal labordeliveryrdquo Medical Science Monitor vol 24 pp 2063ndash20712018

[36] A A M Riad Continuous Oxytocin Infusion versus PulsatileIntravenous Oxytocin for Augmentation of First Stage of LaborNIH US Natl Lib Med Bethesda MD USA Clinical trialsidentifier NCT02723461 2016 httpsclinicaltrialsgovct2showNCT02723461

[37] A J W Kendrick and J P Neilson ldquoContinuous versuspulsatile oxytocin administration for the augmentation oflabour (protocol)rdquo Chochrane data base of systemic reviews(protocol) no 5 article CD011632 2015

[38] K L Bales A M Perkeybile O G Conley et al ldquoChronicintranasal oxytocin causes long-term impairments in partnerpreference formation in male prairie volesrdquo Biological Psy-chiatry vol 74 no 3 pp 180ndash188 2013


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Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom

demonstrate that for long labors having long Pitocin in-fusion times with high Pitocin infusion rates desensitizationof OTRs in the brain of the fetus may occur Oxytocinreceptor desensitization may be followed by downregulationof oxytocin receptors [4] which was a concern of the DukeUniversity study as a possible factor causing the develop-ment of autism in ospring [1]shyis paper demonstrates thatautism attributable to OTR desensitization arising from theuse of Pitocin would be shown not to occur for labor in-ductions that have usual time frames which can go from sixhours [5] to 12 hours or more for continuous Pitocin in-fusion [6]

However this mathematical model does indicate thatOTR desensitization may occur in some cases of long laborinduction and long labor augmentation in which highPitocin infusion rates are administered over long labors withlong Pitocin infusion times OTR desensitization and sub-sequent downregulation may be associated with the devel-opment of autism [1] Hence the conclusion of the Harvardstudy may be in error in that the outcome that they claimdoes not occur no correlation of autism with labor in-duction and may occur for high infusion rates of Pitocinwith long Pitocin infusion times during long labor in-ductions Extrapolating data from these epidemiologicalstudies to the population of the United States it is possible toinfer from the ndings of this study that several hundred toone thousand or more ospring a year may be at risk ofdeveloping autism following the use of large quantities ofPitocin by their mothers at high infusion rates during longlabors shyis comes to 05 to 10 of the number of cases ofautism occurring each year in the United States

shyis model was developed by the author to follow anearlier paper [7] in which it was shown that doses of Pitocinof 6mUmin administered during 12-hour labors were afactor of 10 below the OTR desensitization limit and henceautism attributable to OTR desensitization would not occurHowever the earlier paper did not consider the eects ofhigh continuous infusion rates over the course of long laborswith long Pitocin infusion times on OTR desensitizationwith possible ospring autism development which thispaper does

2 Development and Exposition ofMathematical Model

21 Explanation of Figure 1 To understand the buildup ofPitocin in the maternal circulation from a mathematicalperspective it is important to note that the concentration ofPitocin in the maternal circulation increases as a function ofthe half-life of Pitocin shye half-life of Pitocin in the ma-ternal circulation is an indication of the relative eciency ofthe liver and kidneys in removing Pitocin from the maternalcirculation Higher half-lives indicate lower Pitocin removaleciency shye graph in Figure 1 indicates the relationship ofthe half-life of oxytocin in the blood with the percentoxytocin removal by the liver and kidneys and the percentoxytocin remaining in the blood after the removal shyeindicated removal and retention of oxytocin is for a one-minute cycle of the blood circulation

22 Buildup of Pitocin Concentration in the MaternalCirculation In this section I will oer a mathematicalanalysis to explain the appearance of concentrations ofseveral hundred pgml or more of Pitocin in the maternalcirculation arising from Pitocin infusion into a vein in theuterus shye numbers follow arise out of an infusion rate of20mUmin where 1U or Unit of Solution measuring oneliter introduced into the uterus contains 10 iU or In-ternational Units of Pitocin with each iU containing2micrograms of Pitocin [8 9]shye blood volume is 47 literswhich is for a 160-pound adult female since the volume ofblood for a woman is 65mlkg [10]

shye average half-life of Pitocin in the maternal bloodcirculation decreases during pregnancy [11] However thehalf-life of OT in the maternal blood circulation may varyamong women during labor with less ecient removal ofoxytocin by the kidneys and livers reected in longer half-lives shye calculations are done for half-lives of 1 through6minutes which appear in the literature for nonpregnantadults [12] For this example a half-life of 3minutes waschosen During late pregnancy the half-life of oxytocin inthe maternal circulation is reduced [12] though half-lives of3 to 5minutes have been reported [9 11] One minute istaken as the time needed to complete one cycle of thematernal blood circulation

It is important to note that the concentration of Pitocinfrom continuous Pitocin infusion will increase until the rate

100

90

80

70

60

Percent oxytocin remaining

Percent oxytocin removed

50

40

30

20

10

1 2 3 4t12 (min)

5 60

Figure 1 Percent oxytocin removal by the liver and kidneys andpercent oxytocin remaining in blood with one-minute circulationtime as a function of oxytocin half-life in the blood







1113888 1113889 tprime( 11138571113888 11138891113890 1113891pgml

(1)



1113888 1113889 tprime( 11138571113888 1113889 pgml (2)


C k1

(1minus r)1113890 1113891 (3)


k [(IR)(10Eminus 3)(10)(2E6)]

Vpgml

(IR)(2E4)

V1113890 1113891pgml

(4)



C k1

(1minus r)minus 11113890 1113891 k

r

(1minus r)1113890 1113891 pgml (5)















Half-life (min) M1 1002 2413 3854 5295 6736 817





1050 15 20 25t (min)

30 35

500

450

400

350

300

250

pgm

l

200

150

100

50

0











D

C(override) T (6)



Infusion ratemUmin

Infusion ratemUmin

50

40

30

20

1010

20

30

40

50

20 4 6 2t12 (min)

4 6

pgm

l

2500

2250

2000

1750

1500

1250

1000

750

500

250

0












48hr

24hr

12hr

6hr

50 desensitization

4002000 600 800 1000pgml

1200 1400

100

90

80

70

60

50hr

40

30

20

10

0



















































6 Conclusion









Data Availability




References















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
























1113888 1113889 tprime( 11138571113888 11138891113890 1113891pgml

(1)



1113888 1113889 tprime( 11138571113888 1113889 pgml (2)


C k1

(1minus r)1113890 1113891 (3)


k [(IR)(10Eminus 3)(10)(2E6)]

Vpgml

(IR)(2E4)

V1113890 1113891pgml

(4)



C k1

(1minus r)minus 11113890 1113891 k

r

(1minus r)1113890 1113891 pgml (5)















Half-life (min) M1 1002 2413 3854 5295 6736 817





1050 15 20 25t (min)

30 35

500

450

400

350

300

250

pgm

l

200

150

100

50

0











D

C(override) T (6)



Infusion ratemUmin

Infusion ratemUmin

50

40

30

20

1010

20

30

40

50

20 4 6 2t12 (min)

4 6

pgm

l

2500

2250

2000

1750

1500

1250

1000

750

500

250

0












48hr

24hr

12hr

6hr

50 desensitization

4002000 600 800 1000pgml

1200 1400

100

90

80

70

60

50hr

40

30

20

10

0



















































6 Conclusion









Data Availability




References















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



























Half-life (min) M1 1002 2413 3854 5295 6736 817





1050 15 20 25t (min)

30 35

500

450

400

350

300

250

pgm

l

200

150

100

50

0











D

C(override) T (6)



Infusion ratemUmin

Infusion ratemUmin

50

40

30

20

1010

20

30

40

50

20 4 6 2t12 (min)

4 6

pgm

l

2500

2250

2000

1750

1500

1250

1000

750

500

250

0












48hr

24hr

12hr

6hr

50 desensitization

4002000 600 800 1000pgml

1200 1400

100

90

80

70

60

50hr

40

30

20

10

0



















































6 Conclusion









Data Availability




References















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



























D

C(override) T (6)



Infusion ratemUmin

Infusion ratemUmin

50

40

30

20

1010

20

30

40

50

20 4 6 2t12 (min)

4 6

pgm

l

2500

2250

2000

1750

1500

1250

1000

750

500

250

0












48hr

24hr

12hr

6hr

50 desensitization

4002000 600 800 1000pgml

1200 1400

100

90

80

70

60

50hr

40

30

20

10

0



















































6 Conclusion









Data Availability




References















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




























48hr

24hr

12hr

6hr

50 desensitization

4002000 600 800 1000pgml

1200 1400

100

90

80

70

60

50hr

40

30

20

10

0



















































6 Conclusion









Data Availability




References















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



































































6 Conclusion









Data Availability




References















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























Data Availability




References















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















amathematicalmodelrelatingpitocinuseduringlaborwith ... · 2019. 7. 30. · pitocin in the maternal...

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