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Arch Toxicol (2014) 88:575–584DOI 10.1007/s00204-013-1160-z

REVIEW ARTICLE

Oxime‑type acetylcholinesterase reactivators in pregnancy: an overview

Syed M. Nurulain · Tekes Kornelia · Syed Naimul Hassan Naqvi · Charu Sharma · Shreesh Ojha · Abdu Adem

Received: 12 June 2013 / Accepted: 5 November 2013 / Published online: 21 November 2013 © Springer-Verlag Berlin Heidelberg 2013

were obtained for a period of about 47 years. In the liter-ature, there is no report available to demonstrate the risk of using oxime-AChER in pregnancy for the treatment of OPC poisoning. The study reveals that the use of oxime-AChER in pregnancy is largely un-addressed, inconclusive and based on speculation albeit the incidences of OPC poi-soning are quite prevalent. Well-designed studies are war-ranted for a tangible conclusion.

Keywords Acetylcholinesterase reactivators · Acetylcholine · Oximes · Pregnancy · Organophosphorus compound · Fetus

Introduction

There are several groups of organophosphorus compounds (OPCs) which differ structurally and toxicologically, how-ever, possess the same mechanism of action. The OPCs are commonly used as insecticides, pesticides, herbicides, fungicides, helminthoides and nematicides (Carlton et al. 1998) and warfare nerve agents. The toxicity of the OPCs is merely due to the irreversible inhibition of both types of cholinesterase (EC 3.1.1.7 and EC 3.1.1.8) with the active center serine hydroxyl group (Pope 1999). Organophos-phorus (OP) insecticides and pesticides have been reported to cause poisoning whether accidental, intentional or food poisoning that results in high fatalities worldwide including developed and developing countries (Cherian et al. 2005; Gunnell et al. 2007; Kavalci et al. 2009). The incidences of only self-poisoning are estimated about 200,000 per year in developing countries (Eddleston et al. 2008). In addition to agricultural exposure, miscellaneous domestic applications, industrial activities and many other sources may increase the risk of poisoning in humans including pregnant women

Abstract Oxime-type acetylcholinesterase reactivators (oxime-AChER) are used as an adjunct in the treatment for organophosphorus anticholinesterase poisoning. Because of the widespread usage and exposure of organophosphorus compounds (OPCs), its poisoning and fatalities is obvi-ous in pregnant women, embryos and fetuses. OPCs irre-versibly inhibit acetylcholinesterase (AChE) at nerve synapses. Furthermore, the role of AChE other than neu-rotransmission termination has been defined in the litera-ture. The growing evidences show that cholinergic mech-anisms are involved during growth and development of other organ systems. In contrary to the fact, the data on the use of oxime-AChER in OPC poisoning in pregnancy are scanty. The present review aimed to comprehend the status of oximes in pregnancy in lieu of the published lit-erature. A thorough literature search was performed in January 2013, using ten popular search engines including Medline/PubMed, Google scholar, etc., using nine standard keywords. The search period was set from 1966 to present. The search did not reveal substantial data. No considera-ble studies were retrieved which could really demonstrate either the beneficial, harmful or even null effect of oxime-AChER usage in pregnancy. Only eighteen relevant articles

S. M. Nurulain · C. Sharma · S. Ojha (*) · A. Adem Department of Pharmacology and Therapeutics, College of Medicine and Health Science, United Arab Emirates University, P.O. Box 17666, Al Ain, UAEe-mail: shreeshojha@uaeu.ac.ae

T. Kornelia Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary

S. N. H. Naqvi Department of Pharmacology, Baqai Institute of Pharmaceutical Sciences, Baqai Medical University, Karachi, Pakistan

576 Arch Toxicol (2014) 88:575–584

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(Berman et al. 2011; Vera et al. 2012). Studies have shown an increased exposure of pesticides by women, and chil-dren are indicative of an association between environmen-tal exposure and certain agricultural pesticides in men and women working on or living near farms. During pregnancy, the exposure of OPCs is a serious concern because it may affect pregnant woman, developing fetus and postnatal development. It is evident from the literature that OPCs cross the placental barrier (Astroff and Young 1998) and thus could potentially affect the developing fetus. OPCs have been detected in amniotic fluid, umbilical cord blood, meconium and infant urine, indicating exposure of the human fetus to pesticides (Bradman et al. 2005). A number of epidemiological studies revealed the exposure of OPCs to pregnant women and their consequences such as changes in duration of gestation, altered enzyme activity, impair-ment of fetal growth and development along with neu-rodevelopmental complications (Petit et al. 2010; Eskenazi et al. 2004; Peiris-John and Wickremasinghe 2008; Flaskos 2012; Wang et al. 2012; Lima et al. 2013; Teixidó et al. 2013). The prenatal exposure of OPCs has been reported to cause postnatal neurodevelopment and behavior (Bouchard et al. 2010; Bellinger 2013; Marks et al. 2010; Rauh et al. 2012).

The OPCs irreversibly inhibit acetylcholinesterase (AChE), a neurotransmitter enzyme that terminates neuro-transmission at cholinergic synapses in central and periph-eral nervous systems and causes the accumulation of ace-tylcholine (ACh) at nerve synapse, results into accrual and overabundance of ACh at synapses. Cholinergic mecha-nisms are not involved only to cholinergically innervated tissues but also greatly play an important role in embryonic growth during development and maturation of neural tube as well as other organ systems (Layer et al. 2013). Numer-ous studies demonstrate that it plays many non-classical roles in human physiology and development (Bigbee et al. 2000; Paraoanu and Layer 2008). It has been documented that increased concentration of ACh at the muscarinic and nicotinic receptors stimulates contraction of the uterus as well as autonomic imbalance that may cause utero-placen-tal complications (Arbuckle et al. 2001). Other likely func-tions associated with AChE, and particularly with develop-ment, are the stimulation of neurite outgrowth and neural development (Bigbee et al. 2000; Olivera et al. 2003; Sper-ling et al. 2012), adhesion (Paraoanu and Layer 2008), reg-ulation of cell differentiation (Zhang et al. 2002), apoptosis (Landgraf et al. 2010), hematopoiesis, thrombopoiesis and retinopathy (Bytyqi et al. 2004). ACh levels are also crucial for controlling immune and inflammatory functions, both in the brain and in peripheral tissues and that AChE is a key contributor toward sustaining these levels (Gilboa-Geffen et al. 2012; reviewed in Vogel-Hopker et al. 2012; Layer et al. 2013; Soreq and Seidman 2001).

The standard medical management for OP poisoning consists of atropine + oxime + benzodiazepines (e.g., diaz-epam) along with supportive measures. Oxime-type AChE reactivators, commonly referred as oximes, are used in OP poisoning to reactivate the inhibited AChE. The first clini-cally available oxime AChE reactivator used for OP poi-soning treatment was pralidoxime (Petroianu 2012), and it is still being recommended by WHO for the use as adjunct in OPC poisoning. Further pharmaceutical advancement led to the development of other oximes such as obidoxime, trimedoxime, HI-6, etc. All these oximes differ in their effi-cacy, and none is believed to be a clinically available wide spectrum oxime for OPCs management (van Helden et al. 1996). The reactivation of OPC inhibited AChE by oximes is inadequate in case of different OP agents (Worek et al. 2012). Though the oximes particularly pralidoxime are usu-ally used in the treatment of OPC poisoning, but its safety and efficacy have been controversial (Peter et al. 2006, etc.). Moreover, it is also believed and reported that there is not enough evidence to decide whether oximes are really effective or not, and furthermore, the doses which are more likely to be effective need to be defined. Various authors including Buckley et al. (2011) stressed upon the require-ment of more researches to make evidence-based conclu-sions. Regarding the use of oximes in pregnancy, no clear guidelines or supportive literature is available and there are very few available case studies where pralidoxime has been used or indicated in the management of OPCs poisoning (Jajoo et al. 2010; Kamha et al. 2005).

To understand this important issue and develop a justifi-cation based on available evidences, this review is focused on assessing the available literature and body of evidences in order to recognize the usefulness of oximes in preg-nant woman and their consequence in fetuses. The out-come sought from the available literature would provide an insight of the issue emphasizing the past and present state of research. Further, this review will also address the neglected subject of utmost importance of oximes use in management of OPCs poisoning in pregnant woman and their impact on fetus and neonates.

Literature assessment of oximes in pregnancy

The published articles on this topic were thoroughly searched using standard nine keywords (Fig. 1) in sev-eral popular and widely used biomedical indexes such as Entrez-PubMed/PubMed central, EMBASE, SCO-PUS, Academic Search Complete, Science Direct, DOAJ, DARE, TOXLINE, DART and Google Scholar. The litera-ture search was initially performed in January 2013 using the keywords. No period was specified to facilitate arti-cles from 1966 to the date of search. The literature search was not restricted to the type of article but limited to the

577Arch Toxicol (2014) 88:575–584

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English language of publication. However, articles other than English language were considered as published lit-erature on the subject and even included if abstracts were available in English language. Articles title and abstracts which were found devoid of any information on the sub-ject were excluded. The articles reported non-AChE reac-tivators’ oximes, and the articles not discussing the use and role of oximes in pregnancy and/or fetuses or thereafter in neonates were excluded. Figure 1 gives schematic outline of the procedure.

The conventional and therapeutically available oxi-mes are depicted in Table 1. The related literature on use of oxime-type AChE reactivator in pregnancy is very lim-ited. All the relevant data which is summarized in Table 2 show that there is an extensive lack of information on the subject, and no research has been undertaken in near recent period as demonstarted by available publications in Fig. 2.

After obliterating the duplicate and irrelevant articles, only eighteen articles were found to be appropriate to the sub-ject. Two studies demonstrated direct research related to the oxime, and the remaining were derived from the other studies where oximes were used as adjunct treatment in treatment of OPCs, unless otherwise indicated. Interest-ing to note that only two studies of direct inference were conducted in more than 50 years of oximes introduction for OPC poison treatment. Two studies represented the in vitro evaluation of pralidoxime in plasma of pregnant and non-pregnant women. In the remaining articles, five (Mein-iel 1974, 1975, 1976, 1978, 1979) were published utilizing the animal models but reported in French language. A total of nine studies conducted on animal models were retrieved, and all of them were performed on avian models. Eleven articles were of clinical/case reports of OPCs poisoning during pregnancy. In two case reports, pralidoxime was not

Search Engines

Key words

Review articles, n= 0 ClinicalAnimal

In Vivo, n=6 In vitro, n=2 Randomized control

trials, n=1

Case studies, n=09

Pubmed, EMBASE, Scopus, Academic Search complete, Science direct DOAJ, Toxline, DART, Google

Scholar

Pralidoxime, pregnancy; Pralidoxime, placenta; Pralidoxime, embryos; Pralidoxime, reproduction;

Pralidoxime, gestational stages; Pralidoxime, fetuses; Pralidoxime, placental barrier; Aldoximes,

pregnancy; Pralidoxime

Total number of articles by all key words: 19,303

Articles of interest: 136

After removal of duplicates and further

screening: 18

Years set for articles retrieval: 1966 to present

Fig. 1 Schematic presentation of the data retrieved and final outcome

578 Arch Toxicol (2014) 88:575–584

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used because it was not available and accessible to them. However, two other case reports showed the benefits of pra-lidoxime in improving survival efficacy along with absence of teratological observations in neonates following the sub-sequent follow-ups. Although obidoxime and HI-6 are the other therapeutically available promising oximes, pralidox-ime was used in almost all reported studies or case studies. The examination of published reports also disclosed that in some poisoning cases, oximes were not used because the authors believe that the safety of the compound is not established.

Discussion

The present study is an attempt to look into the status of the oxime-type AChER compound (e.g., pralidoxime) in preg-nancy as evidenced in the literature. This review is the first on the topic. The undertaken study is not meant to empha-size and establish the clinical potential or indications dur-ing pregnancy.

In our study, we made enquiries on the published reports, articles based on several questions in order to assess the status of oxime-type AChER compound in preg-nancy. The enquiries made were as follows: (1) what evi-dences are available for a safe use of oxime-type AChER

that is available therapeutically and recommended as an adjunct in the treatment of OP poisoning and (2) How much research is done on the compound which is more than 50 years old and hundreds of similar compounds have been developed and trialed for the same purpose? These were the main questions apart from many secondary issues as stated in earlier sections. The answers for these ques-tions are clearly evident from Table 2 and Figs. 1 and 2; means no sufficient study has been done yet. According to Food and Drug Administration (FDA), USA and the manu-facturer’s leaflet “adequate animal reproduction studies have not been conducted. It is not known whether pralidox-ime can cause fetal harm when administered to a pregnant woman or if these agents can affect reproductive capacity” (Protopam and FDA labeling 2010).This is observed that the issue has been absolutely overlooked and un-addressed. However, considering the incidences of fatalities, high risk of probable toxicities and importance of AChE/ACh dur-ing development, it is difficult to understand the reasons thereof. One possible explanation is the controversy over the use of oximes.

Some authors consider that oximes are not beneficial in OPCs poison treatment (Peter et al. 2006 etc.). However, there is no conclusive evidence for this assumption (Bewan 2009). Along with these existing controversies of oxi-mes benefits in OPCs poisoning treatment, World Health

Table 1 Summary of conventional and therapeutically available oximes

The octanol–water partition coefficient (log P) values used as a predictor of the oximes to cross the biological barriers are also provided (Lorke and Petroianu 2009). Substances with positive log P values crosses the biological barrier whereas with negative means no or very week barrier penetration

Name of oximes Other names Structure and chemical name Geographical usage Year of development Log P value

PralidoximeCAS # 51-15-0Mol wt. 172.61 g/mol

Protopam chloride,2-PAM,P2S

H3C N+

NHO Most of the countries

including USA and Europe

1956 −2.31

ObidoximeCAS # 7683-36-5Mol wt. 288.31 g/mol

Toxogonin,Pirrangit,ToxobindinLüH-6

N+ N+N

OH

O

NHO Europe 1964 −3.12

HI-6CAS # 34433-31-3Mol wt. 359.21 g/mol

Asoxime chloride,HI6 chloride,HJ6,Transant

N + O N +NH 2

NOH

O Canada, Sweden 1967 −3.39

TrimedoximeCAS # 56-97-3Mol wt. 446.19 g/mol

Dipyroxime,TMB-4,Trimedoxime bromide,

N+

NHO

N+N

OH

Europe 1957 −2.07

MethoximeCAS # 2058-89-1Mol wt. 418.08 g/mol

MMB4(ICD-039)

N+ N+N

OHN

HO

1,1’-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate

Europe 1959 −2.60

579Arch Toxicol (2014) 88:575–584

1 3

Tabl

e 2

Sum

mar

y of

the

stud

ies

show

ing

OPC

s in

toxi

catio

n an

d ro

le o

f ox

imes

Aut

hor

Type

of

stud

yO

xim

es u

sed/

disc

usse

dFi

ndin

gs o

f th

e st

udy

Rol

e of

oxi

mes

in m

anag

emen

t

Ede

ry e

t al.

(196

6)R

esea

rch

artic

le, i

n vi

vo s

tudy

P2S

Low

dos

e of

P2S

did

not

cro

ss th

e pl

acen

ta b

arri

er b

ut h

igh

dose

and

co

ntin

uous

infu

sion

of

P2S

cros

sed

plac

enta

l bar

rier

Low

dos

e of

oxi

me

did

not r

eact

ivat

e th

e te

trae

thyl

pho

spha

te in

hibi

ted

AC

hE in

fet

uses

but

in m

othe

r. H

ow-

ever

, hig

h do

se r

eact

ivat

ed A

ChE

in

both

mot

her

and

fetu

ses

And

erse

n an

d B

arst

ad (

1974

)Pl

acen

ta b

arri

er s

tudy

, in

vivo

stu

dyPy

ridi

nium

AC

hE r

eact

ivat

ors

Exh

ibite

d si

gnifi

cant

but

mod

est

pene

trat

ion

into

fet

uses

The

dif

fere

nt o

xim

es w

ere

alm

ost

sim

ilar

in e

ffica

cy

Mei

niel

(19

74)

Tera

tolo

gica

l stu

dy w

ith O

P po

ison

ing

on q

uail

embr

yo, i

n vi

vo s

tudy

Pral

idox

ime

Para

thio

n ca

used

tera

tolo

gica

l def

ects

Pral

idox

ime

redu

ced

the

tera

tolo

gica

l ef

fect

s ca

used

by

para

thio

n

Mei

niel

(19

76)

Tera

tolo

gica

l stu

dy w

ith O

P po

ison

ing

on q

uail

embr

yo, i

n vi

vo s

tudy

Pral

idox

ime

Test

ed O

PC c

ause

d ab

norm

aliti

es in

ve

rteb

ral c

olum

nV

erte

bral

defi

cien

cies

wer

e gr

eatly

alle

-vi

ated

or

abol

ishe

d by

pra

lidox

ime

Lan

daue

r (1

977)

Tera

tolo

gica

l stu

dy w

ith O

P po

ison

ing

in c

hick

en e

mbr

yos,

in v

ivo

stud

yP2

S, P

2M, t

oxog

onin

Test

ed O

PCs

caus

ed v

erte

bral

def

ects

an

d m

uscu

lar

hypo

plas

iaO

xim

es g

reat

ly r

educ

ed th

e te

rato

logi

-ca

l eff

ects

cau

sed

by O

PCs.

Effi

cacy

le

vel w

as o

bser

ved

diff

eren

t for

the

thre

e ox

imes

Gad

oth

and

Fish

er (

1978

)C

ase

repo

rt/c

linic

al s

tudy

Obi

doxi

me

(tox

ogon

in)

Patie

nt s

urvi

ved

but m

edic

al te

rmin

a-tio

n of

pre

gnan

cy w

as p

erfo

rmed

Use

of

oxim

e w

as a

wis

e st

ep in

the

trea

tmen

t

Bel

l et a

l. (1

979)

Enz

yme

reac

tivat

ion

(in

vitr

o) s

tudy

in

non-

preg

nant

, pre

gnan

t and

neo

nate

pl

asm

a

Pral

idox

ime

Pral

idox

ime

reac

tivat

ed th

e O

P-in

duce

d in

hibi

tion

of c

holin

este

rase

in

non

-pre

gnan

t, pr

egna

nt a

nd

neon

ate’

s pl

asm

a

Pral

idox

ime-

med

iate

d po

tenc

y of

en

zym

e re

activ

atio

n w

as s

igni

fican

tly

grea

ter

in n

on-p

regn

ant f

emal

e pl

asm

a th

an p

regn

ant a

nd n

eona

tes

plas

ma

Car

ring

ton

da C

osta

et a

l. (1

982)

Cas

e re

port

/clin

ical

Stan

dard

ther

apy

prov

ided

, but

oxi

me

nam

e is

not

men

tione

d5-

mon

th p

regn

ant f

emal

e ex

pose

d to

met

hyl d

emet

on a

nd d

eliv

ered

no

rmal

ly a

t ter

m

Stan

dard

ther

apy

whi

ch in

clud

es o

xim

e sh

owed

pro

mis

ing

resu

lt

Wei

s et

al.

(198

3)C

ase

repo

rts/

clin

ical

Oxi

mes

wer

e no

t use

dB

oth

mot

her

and

neon

ates

sur

vive

d on

ly a

fter

atr

opin

e tr

eatm

ent

Did

not

use

pra

lidox

ime

beca

use

they

un

ders

tand

that

ther

e is

no

bene

fit o

f us

ing

oxim

e

Wyt

tenb

ach

and

Hw

ang

(198

4)Te

rato

logi

cal s

tudy

with

dia

zino

n in

ch

ick

embr

yos

(in

vivo

stu

dy)

Pral

idox

ime

Tera

tolo

gica

l mal

form

atio

n in

the

noto

chor

d an

d ne

ck w

as o

bser

ved

with

hig

her

dose

s of

dia

zino

n

Co-

inje

ctio

n of

dia

zino

n w

ith p

ral-

idox

ime

impr

oved

the

cond

ition

s

Kar

allie

dde

et a

l. (1

988)

Cas

e re

port

/clin

ical

Pral

idox

ime

Mot

her

surv

ived

and

del

iver

ed n

orm

al

term

infa

nts

Pral

idox

ime

was

use

d as

par

t of

stan

d-ar

d th

erap

y an

d fo

und

usef

ul

Men

eguz

et a

l. (1

989)

Enz

yme

reac

tivat

ion

(in

vitr

o) s

tudy

Pral

idox

ime,

obi

doxi

me

Mat

erna

l and

fet

al e

nzym

es s

how

ed

good

rea

ctiv

atio

n of

inhi

bite

d di

ffer

-en

t for

ms

of C

hE

Bot

h pr

alid

oxim

e an

d ob

idox

ime

wer

e fo

und

effe

ctiv

e in

rea

ctiv

atio

n of

dif

-fe

rent

mol

ecul

ar f

orm

of

ChE

Oku

mur

a et

al.

(199

6)C

ase

repo

rt/c

linic

al (

Toky

o su

bway

te

rror

ist a

ttack

)O

xim

es w

ere

not u

sed

All

surv

ived

Did

not

use

pra

lidox

ime

beca

use

the

safe

ty o

f sa

fety

issu

e (s

ee r

ef. 4

)

Kam

ha e

t al.

(200

5)C

ase

repo

rt/c

linic

alPr

alid

oxim

eD

iazi

non

pois

onin

g at

26

wee

k of

ge

stat

ion.

Sta

ndar

d tr

eatm

ent w

as

prov

ided

Mot

her

surv

ived

and

at 3

6 w

eek

of g

es-

tatio

n, d

eliv

ered

a h

ealth

y ch

ild

580 Arch Toxicol (2014) 88:575–584

1 3

Organization (WHO) still recommends pralidoxime as adjunct treatment for OP poisoning along with atropine and benzodiazepine. Furthermore, controversy on their use was projected in last two decades, whereas the compounds are existent for the last six decades. Another possibility is that OP poisoning during pregnancy has not been often reported (Tenenbein 1996), although a number of case studies in lit-erature have been cited (see Table 2). On the other hand, if we look at the literature, chances of exposure to OP pesti-cides have been increased to pregnant woman that is clearly evident from many epidemiological studies. Over 60 % of the pregnant woman has been reported to use some form of household insecticides or pesticides during their preg-nancy period (Berman et al. 2011). Indeed, there may be many more unreported cases and means of OP exposure and related toxicity to pregnant woman. The outcome of OPC exposure to pregnant woman is not only restricted to fetal growth rather it affects the postnatal and even produce long-term consequences. For instance, prenatal exposure to OPCs has been reported to cause reduced IQ scores in children (Bellinger 2013) and attention deficit hyperactivity disorder (Bouchard et al. 2010).

An organophosphorus anticholinesterase compound shows its toxic effect by inhibiting the enzyme, AChE at nerve synapse and that is achieved by phosphorylation or phosphorylation. AChE contains one catalytic center, which is composed of two compartments: the esteratic sub-site and anionic subsite. The role of anionic site is to orient the charged part of the substrate that enters the active site (Patocka et al. 2005). Oximes reactivate phosphorylated cholinesterase by displacing the phosphoryl moiety from the enzyme owing to their high affinity for the enzyme and their potent nucleophilicity. In general, it is envisaged that oximes exert a nucleophilic attack on the phosphorus of the enzyme-inhibitor (OP) complex and further splitting of this enzyme-inhibitor (OP)-oxime complex leaves the regen-erated enzyme. It is well known that several significant physiological, endocrine and other biochemical changes occur in the woman during pregnancy which causes an altered maternal metabolism and physiology. This altered physiology may influence the effectiveness of AChER. For instance, pregnancy has been found to associate with lower PON 1 activity in both rats and human (Weitman et al. 1983). The decreased level of PON1 increases the suscep-tibility of OPC poison. Berkowitz et al. (2004) reported the low maternal levels of PON 1 (paraoxanase) were associ-ated with a significant but small reduction in head circum-ference on prenatal chlorpyrifos exposure. Moreover, Bell et al. (1979) found that the oximes reactivation potency in plasma of pregnant was significantly lower than the non-pregnant.

It is well established that an active cholinergic system exists in the placenta and ACh, a natural substrate for AChE Ta

ble

2 c

ontin

ued

Aut

hor

Type

of

stud

yO

xim

es u

sed/

disc

usse

dFi

ndin

gs o

f th

e st

udy

Rol

e of

oxi

mes

in m

anag

emen

t

Solo

mon

and

Moo

dley

(20

07)

Cas

e st

udy/

clin

ical

Oxi

mes

wer

e no

t use

dM

othe

r su

rviv

ed a

nd in

fant

die

d 2

days

aft

er b

irth

Oxi

mes

wer

e no

t ava

ilabl

e fo

r us

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581Arch Toxicol (2014) 88:575–584

1 3

plays a vital role in the maturation of placenta in addi-tion to many other non-neuronal physiological roles (For detail see, Gupta 2007). The placenta containing AChE and other cholinergic elements remain susceptible to OPs, and a physiologically normal placenta is no doubt a prereq-uisite for development and maturation of a healthy fetus. Anticholinesterase compounds have strong potential for embryo-toxicity, fetotoxicity and teratogenesis. In addi-tion, the OPCs are also known to cross the placental bar-rier (Astroff and Young 1998) therefore believed to effect the fetuses as well. Lipophilic nature (high log P values) of the OPCs makes possible their easy penetration through biological barrier. Moreover, the fetuses already having 50–70 % lesser cholinesterase activity than mother (Jones and McCance 1949) may be at more risk to OPCs poison-ing. Another important aspect is the penetration of oximes to placenta and then to fetuses. There is no evidence to signify the quantity of oxime crosses the placenta barrier. Based on poor blood-brain barrier crossing (Lorke et al. 2008; Kalász et al. 2009) and lower log P value (Table 1), limited capability to cross the biological membranes may be speculated. Thus, it is unclear whether a therapeutic maternal dose of oximes could be useful or harmful to the fetuses. The benefits/harms of oximes are based on specu-lative extrapolations only, because there are only two case reports available where the use of pralidoxime has been (Karalliedde et al. 1988; Kamha et al. 2005) reported to have positive outcomes. Moreover, phosphorylated oxi-mes formed during the reactivation process might be potent inhibitors of cholinesterases, which could cause re-inhibi-tion of the previously reactivated enzyme (Antonijevic and Stojiljkovic 2007). The extent of such situation in fetuses is entirely unknown. Based on available information and paucity of pertinent knowledge, it is clear that only a sys-tematically designed experimental study could justify the usage because the speculation might unreasonably hinder

the beneficial outcome. All these evidences substantiate the importance of research on the use of oximes in preg-nant conditions which seem to be a completely neglected issue. The speculation based on the partially related infor-mation does not reflect the true conditions. Only scientifi-cally and systematically designed experimental and clini-cal studies could imitate the actual standing. There is no pharmacokinetics/toxicokinetics data exist in either mater-nal blood or tissues and the fetuses in human studies or animal models. There is no in vivo study which may point up the reactivation potency under the circumstances of changing physiology of pregnant woman along with preg-nancy period. There is no considerable risk evaluation for teratogenic effect. On the other hand, in order to meet the food supply, parallel to industrialization and agricultural advancement, the use of organophosphorus pesticides or insecticides has been increased worldwide and expected to rise further in future. This overview briefly reveals that despite the high vulnerability of poisoning and toxicity, this important subject is absolutely ambiguous and overlooked. Figure 3 represents the pictorial overview on the subject.

Concluding remarks and future prospects

Based on the critical appraisal of the available literature, we conclude that the use of oxime-type AChER in preg-nancy is ambiguous and un-addressed albeit the circum-stances of OP poisoning are increasing worldwide across all the ages and genders. The information gap on this topic is clearly visible and evident based on the paucity of lit-erature in the past many decades. The probability of OP intoxication and subsequent treatment by oximes is well reported in epidemiological, preclinical and clinical case study reports. Following the rising trend in the usage of OP pesticides globally, it is recently highlighted that due to increasing population and decreasing land availability, the

Fig. 2 Illustrates the number of published papers on this topic from 1966 to 2013. It depicts the paucity of literature and research gap on the topic

582 Arch Toxicol (2014) 88:575–584

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global agrochemical market is expected to grow exponen-tially and organophosphate pesticides are expected to have high market share and growth potential.

The limitations observed in this review were that there is no sizeable data on either of the outlined parameter; there-fore, in absence of such substantial and conclusive data, an appropriate systematic review is very unlikely. This review would encourage the academic and industrial toxicologist and policy makers to think ardently for such important but neglected and un-addressed issue. The only evidence available to suggest the use of the oximes is FDA docu-ment which advises to use pralidoxime in pregnancy when benefit outweighs the risk. This review may also provide a blueprint for conduct of future studies on several concerns viz. the relative safety and efficacy of pralidoxime in preg-nancy, embryo and fetus and, moreover, the superiority or inferiority of other available oximes in these situations. Therefore, research on this topic is clearly warranted to establish evidence-based cogent conclusion in the interest of public, the end users of the OPCs.

Conflict of interest The authors declare that there is no conflict of interest.

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