IVF and other ART in low- and middle-income countries

IVF and other ART in low- andmiddle-income countries a systematiclandscape analysisTendai M Chiware 12 Nathalie Vermeulen 3Karel Blondeel 24 Roy Farquharson3 James Kiarie2Kersti Lundin35 Thabo Christopher Matsaseng26Willem Ombelet78 and Igor Toskin 21Department of Obstetrics Gynecology amp Reproductive Sciences University of Vermont Medical Center Burlington VT USA2Department of Reproductive Health and Research UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of ResearchDevelopment and Research Training in Human Reproduction (HRP) World Health Organization Geneva Switzerland 3European Societyof Human Reproduction and Embryology Central Office Grimbergen Belgium 4Faculty of Medicine and Health Sciences GhentUniversity Ghent Belgium 5Reproductive Medicine Sahlgrenska University Hospital Gothenburg Sweden 6Reproductive Medicine UnitDepartment of Obstetrics amp Gynaecology Stellenbosch University Cape Town South Africa 7Faculty of Medicine and Life SciencesHasselt University Hasselt 3500 Belgium 8Genk Institute for Fertility Technology ZOL Hospitals Genk 3600 Belgium

Correspondence address Department of Reproductive Health and Research UNDP-UNFPA-UNICEF-WHO-World Bank SpecialProgramme of Research Development and Research Training in Human Reproduction (HRP) World Health Organization GenevaSwitzerland Tel thorn41-22-791-5096 E-mail toskiniwhoint (IT) University of Vermont Medical Center Department of ObstetricsGynecology amp Reproductive Sciences 111 Colchester Ave Smith 422 Mailstop 251 SM4 Burlington VT 05401 USATel thorn1-718-283-8600 E-mail tendaichiwarehotmailcom (TMC) httpsorcidorg0000-0001-6380-3597

Submitted on March 14 2018 resubmitted on August 6 2020 editorial decision on August 31 2020

TABLE OF CONTENTSbull Introductionbull Methods

Search strategy and selection criteriaRisk of bias and data analysis

bull ResultsART reports within regionsCost-limiting initiatives aiming at affordable ARTRisk of bias across studies

bull DiscussionLimitations

BACKGROUND Infertility affects 485 million couples worldwide with a prevalence estimated at 35ndash167 in low- and middle-incomecountries (LMIC) and as high as 30ndash40 in Sub-Saharan Africa ART services are not accessible to the majority of these infertile couplesdue to the high cost of treatments in addition to cultural religious and legal barriers Infertility and childlessness particularly in LMIChave devastating consequences which has resulted in considerable interest in developing affordable IVF procedures However there is apaucity of evidence on the safety efficiency and ability to replicate techniques under different field conditions and how to integrate moreaffordable ART options into existing infrastructures

OBJECTIVE AND RATIONALE This review was performed to investigate the current availability of IVF in LMIC and which other ARToptions are under development This work will unfold the landscape of available and potential ART services in LMIC and is a key elementin positioning infertility more broadly in the Global Public Health Agenda

VC The Author(s) 2020 Published by Oxford University Press on behalf of European Society of Human Reproduction and EmbryologyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (httpcreativecommonsorglicensesby-nc40) whichpermits non-commercial re-use distribution and reproduction in any medium provided the original work is properly cited For commercial re-use please contactjournalspermissionsoupcom

Human Reproduction Update Vol27 No2 pp 213ndash228 2021Advance Access Publication on November 25 2020 doi101093humupddmaa047

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nloaded from httpsacadem

icoupcomhum

updarticle2722136006235 by guest on 06 February 2022

SEARCH METHODS A systematic literature search was performed of articles and gray literature on IVF and other ART options inLMIC published between January 2010 and January 2020 We selected studies on IVF and other ART treatments for infertile couples ofreproductive age (18ndash44 years) from LMIC The review was limited to articles published after 2010 based on the recent evolution in thefield of ART practices in LMIC over the last decade Citations from high-income countries including data prior to 2010 and focusing onspecialized ART procedures were excluded The literature search included PubMed Popline CINHAL EMBASE and Global IndexMedicus No restrictions were applied with regard to study design or language Two reviewers independently screened the titlesand abstracts and extracted data A search for gray literature was performed using the lsquoGooglersquo search engine and specific databases(worldcatorg greylitorg) In addition the reference lists of included studies were assessed

OUTCOMES The search of the electronic databases yielded 3769 citations After review of the titles and abstracts 283 studies were in-cluded The full texts were reviewed and a further 199 articles were excluded The gray literature search yielded 586 citations most ofwhich were excluded after screening the title and the remaining documents were excluded after full-text assessment due to duplicateentries not from LMIC not relevant or no access to the full document Eighty-four citations were included as part of the review andseparated into regions The majority of the studies were observational and qualitative studies In general ART services are available anddescribed in several LMIC ranging from advanced techniques in China to basic introduction of IVF in some African countries Efforts toprovide affordable ART treatments are described in feasibility studies and efficacy studies however most citations were of low to verylow quality We found no studies from LMIC reporting the implementation of low-cost ART that is effective accessible and affordable tomost of those in need of the services

WIDER IMPLICATIONS The World Health Organization is in a unique position to provide much needed guidance for infertility man-agement in LMIC This review provides insight into the landscape of ART in LMIC in various regions worldwide which will guide efforts toimprove the availability quality accessibility and acceptability of biomedical infertility care including ART in these countries

Key words infertility low- and middle-income countries IVF ART fertility care fertility coverage affordable ART accessible ART

IntroductionThe World Health Organization (WHO) defines health as lsquoa state ofcomplete physical mental and social well-being and not merely the ab-sence of disease or infirmityrsquo (World Health Organization 1948) In2010 an estimated 485 million couples worldwide were infertile de-fined at that time as an inability lsquoto have any live birth over a 5-year pe-riodrsquo (Mascarenhas et al 2012) The overall prevalence of infertility isestimated at 35ndash167 in low- and middle-income countries (LMIC)with the prevalence as high as 30ndash40 in some regions of Sub-SaharanAfrica (Ombelet 2009 Inhorn and Patrizio 2015) Infertility in LMICis more than a health problem it is a social issue and a public healthmatter that continues to be neglected (Bahamondes and Makuch2014)

Infertility is known to cause significant psychological and socialeffects such as fear guilt depression self-blame marital stress emo-tional abuse intimate partner violence divorce and abandonment ofthe partner social isolation economic deprivation loss of social statusand in some regions (eg Africa and Asia) even starvation diseaseviolence-induced suicide and loss of dignity in death (Ombelet et al2008 Hammarberg and Kirkman 2013 Stellar et al 2016)

The most common etiologies of infertility in LMIC are male factorand tubal disease secondary to sexually transmitted infections unsafeabortion and complications of childbirth (Ombelet 2009 van derPoel 2012) Tubal factor infertility is reported to be as high as 85 inSub-Saharan Africa compared with 33 worldwide (Ombelet 2009)The most effective treatment is ART (Sharma et al 2009Bahamondes and Makuch 2014)

Infertility and ART are not considered a priority in many LMICThe most often used arguments against the use of ART are overpopu-lation other health priorities (eg family planning vaccinations malariaHIV) limited government budgets and limited experience of providers

with inadequate facilities for performing sophisticated procedures(Ombelet and Campo 2007) Furthermore in some LMIC ART isconsidered to be expensive only moderately effective with risks ofcomplications and unknown effects on women and their offspring(Ombelet and Campo 2007) In 2008 ESHRE published a series ofmonographs by experts from around the world highlighting the impor-tance of infertility its prevalence access to treatment and outcomes indeveloping countries (ESHRE Special Task Force on lsquoDevelopingCountries and Infertilityrsquo 2008) Along with the WHO and ESHREother non-governmental organizations (NGOs) are involved in initia-tives aimed at improving access to ART in LMIC including theAmerican Society for Reproductive Medicine the InternationalFederation of Gynecology and Obstetrics the International Federationof Fertility Societies and the International Committee for MonitoringAssisted Reproductive Technologies

Providing ART services in an LMIC requires an understanding of thecountry-specific magnitude and character of the issue of infertility aswell as identification of pre-existing resources that may be utilized(Sharma et al 2009 Bahamondes and Makuch 2014) WHO is in aunique position with 194 member states worldwide to assist in evalu-ating the burden of disease by the systematic assessment of infertilityand resources available within various regions

There is complete absence of affordable and accessible ART serv-ices in some LMIC possibly due to high costs of IVF and underdevel-oped infrastructure in addition to cultural religious and legal barriersThis deficiency has led to considerable interest by NGOs policymakers and ART specialists in developing more affordable IVF proto-cols such as minimal ovarian stimulation However there is a paucityof evidence and systematic reviews on the safety and efficiency profileof low-cost ART on the ability to replicate various techniques in differ-ent laboratories and under various field conditions and on how to inte-grate ART into existing health systems and infrastructures

214 Chiware et al

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This review investigated the currently available IVF services in LMIC

and potential for future development This work will assist in unfoldingthe landscape of available services and the potential for ART servicesin LMIC This is a key element in positioning infertility more broadly inthe Global Public Health Agenda of WHO This work will also informfuture WHO guidelines concerning the provision of ART in LMIC

MethodsThis review was reported in accordance with the PRISMA andGATHER guidelines (Moher et al 2009 Stevens et al 2016) Theprotocol was registered on 24 April 2017 and published withPROSPERO International prospective register of systematic reviews(ID number CRD42017064413) There were no amendments to theprotocol after registration

Search strategy and selection criteriaThe electronic databases searched included PubMed PoplineCINAHL EMBASE and Global Index Medicus (regional WHO onlinedatabases) Citations were collected from inception until 1 January2020 An internet search was performed using lsquoGooglersquo search enginewith the terms lsquoinfertilityrsquo lsquolow- and middle-income countriesrsquo andlsquoin vitro fertilizationrsquo or lsquoassisted reproductive technologiesrsquo (limited toresults published after 2010) Similar search terms were used for grayliterature databases (worldcatorg greylitorg) In addition the refer-ence lists of included studies were checked Experts and professionalswithin the field of infertility and the members of the ESHRE SpecialInterest Group Global and Socio-cultural Aspects of Infertility(nfrac14 221) were contacted to provide information on any unpublishedpapers or data on the subject of lsquoART in low- and middle-incomecountriesrsquo

Search strategies were customized for each electronic databaseaccording to their individual subject headings and searching structureThe search strategy used for PUBMED is available in Supplementarydata In constructing the search terms accepted definitions of ARTand IVF were used (Zegers-Hochschild et al 2009 et al 2017) LMICwere defined according to the World Bank classification of countriesby Gross National Income per capita (low-income country (LIC) up to$995 lower-middle-income country (lower MIC) $996 to $3895 andupper-middle-income country (upper MIC) $3896 to $12 055)(World Bank Country and Lending Groups) Upper MIC which oftenhave ART services on par with high-income countries were labeled todistinguish them from LIC and lower MIC For this review no restric-tions were applied with regard to study design or language Reviewerswere able to read English French German Italian PortugueseSpanish and Russian studies Reports in other languages were includedand authors were asked to provide a translated version or some ofthe details of the study in English Endnote (Version X8) bibliographicsoftware was used to store the citations and remove duplicates

For inclusion in the review we selected citations on ART for adultwomen and men of reproductive age (18ndash44 years old) from LMIC(experiencing reproductive difficulties or infertility) All identified cita-tions irrespective of language published over the last decade from 1January 2010 to 1 January 2020 were assessed The review was limitedto articles published after 2010 based on the recent evolution in the

field of ART practices in LMIC over the last decade ART is defined asall interventions that include the in vitro handling of both humanoocytes and sperm or of embryos for the purpose of reproductionThis includes but is not limited to IVF and embryo transfer ICSI em-bryo biopsy preimplantation genetic testing assisted hatching gameteintrafallopian transfer zygote intrafallopian transfer gamete and em-bryo cryopreservation semen oocyte and embryo donation and ges-tational carrier cycles (Zegers-Hochschild et al 2017) This reviewfocused on IVF and embryo transfer procedures being performed inLMIC over the last decade Articles focusing solely on ICSI specializedART procedures and that did not discuss IVF were excluded Themain reason for this restriction was these advanced procedures not al-ways being accessible or affordable to the general population in anLMIC where the cost of ART is estimated to be up to 50 higherthan the gross national per capita income of many LMIC (Vayenaet al 2009)

Concerning outcomes articles were assessed for quantitative out-comes on the efficacy of the ART (mainly pregnancy rate or live birthrate (LBR)) or qualitative and quantitative outcomes on feasibility Wedefined feasibility as the process in which low-cost ART are deployedleading to their acceptability and usability All citations were evaluatedbased on the titles and abstracts by two independent reviewers(TMC and NV) In the absence of sufficient data in the abstract toassess relevance the full text was obtained A list of the excludedreports is available from the authors upon request The full-textreports were assessed for relevance and the data extracted by two in-dependent reviewers (TMC and NV) A third reviewer (IT) wasavailable to resolve queries and disagreements Attempts were madeto contact the authors to obtain missing information or clarificationwhenever necessary

Risk of bias and data analysisThe protocol for this review included assessment of risk of bias for allindividual articles The majority of included articles did not assess quan-titative outcomes (efficacy or others) related to a therapeutic or diag-nostic intervention but merely reported on feasibility (currentpractice) in a narrative fashion For studies assessing efficacy of inter-ventions the majority were either very small feasibility or pilot studies(assessed as high to very high risk of bias) or they were available onlyas an (conference) abstract For the remaining interventional studiesrisk of bias was assessed with the risk of bias in non-randomized stud-ies of interventions (ROBINs)-1 tool (Sterne et al 2016) Risk of biaswas only assessed when the full-text paper could be retrieved Thecollected data were as expected highly heterogeneous Statisticalcomparison of the data was not possible due to the variable studydesign and quantitative data in the included citations The resultsfrom included citations were collated in a descriptive fashion andmeta-analysis was not feasible

ResultsAn extensive search of the databases yielded 3769 citations afterremoval of duplicate entries After review of the titles and abstracts283 articles were included (Fig 1) The full texts of 283 articles werereviewed including case reports review papers commentaries gray

IVF in low- and middle-income countries 215

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literature and abstracts from conference proceedings A further 199citations were excluded The gray literature search yielded 586 cita-tions of which 334 were excluded after screening of the title Furtherassessment of the remaining gray literature documents resulted in allcitations being excluded Exclusion of citations was based on duplicateentries from the database searches not LMIC not relevant or no ac-cess to the full document Of the 84 included articles 63 citationsmostly qualitative and observational studies described an overall pic-ture (efficacy feasibility and acceptability) of ART in LMIC Thesearticles were summarized into regions (Supplementary Tables SI-VIFig 2) Fourteen studies reported on the efficacy and feasibility ofcost-limiting initiatives aimed at affordable ART in LMIC (Table I) Asystematic review of literature was conducted however due to theheterogeneity of the included articles the results are collated and pre-sented here in a narrative fashion

ART reports within regionsEast Asia and PacificART in the region of East Asia and Pacific is described as a rapidlygrowing business (Wahlberg 2016) A survey reported that in thecountries within this region for which information was collected(China Indonesia Korea Malaysia Mongolia Myanmar PhilippinesSingapore Thailand and Vietnam) IVF is available for couples although

subsidized only in Singapore and Korea (Li et al 2018) Nine citationsreported mostly on the current practice in China and Thailand whichare upper MIC and may not be representative of the practice in LMICwithin this region (Supplementary Table SI) China is depicted as havinghigh standards of practice and technological developments are aggres-sively pursued (Ha 2013) Efficacy of ART in China was described assimilar to efficacy in developed high-income European countries suchas France and Spain (LBR per started cycle of 47 in womenlt35 years old from ART) (Audibert and Glass 2015) As expectedChina with a high population is also unique in the high number of IVFcycles and the term lsquoscaled up IVFrsquo has been used with 145 108 livebirths reported after ART in 2013 (Wahlberg 2016) Other countriesin this region report the use of ART to a lesser extent but there wereno articles describing the efficacy of treatments (Ye et al 2013)

With regards to the feasibility of ART a study from Indonesiareported barriers to access which included low confidence in infertilitytreatment high rates of switching between providers due to treatmentfailure the number and location of clinics the lack of a well-established referral system the cost of treatment and patients withfear of receiving the diagnosis of infertility fear of vaginal examinationsor embarrassment (Bennett et al 2012) In Thailand ART treatmentis considered out of reach for most average-income people In addi-tion three-quarters of infertility clinics are located in urban centerslimiting physical accessibility for rural populations (Whittaker 2016)

Records idenfied through database search

(n = 3868)

Screen

ing

Inclu

ded

Eligibility

Iden

ficao

n

Addional records idenfied through other sources

(n = 586)

Records aer duplicates removed (n = 3769)

Records screened (n = 3769)

Records excluded (n = 3486)

Full-text arcles assessed for eligibility

(n = 283)

Full-text arcles excluded with jusficaon

(n = 199)

Studies included in qualitave synthesis

(n = 84)

Studies included in quantave synthesis

(meta-analysis) (NA)

Figure 1 PRISMA flow diagram of included and excluded studies of the review

216 Chiware et al

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icoupcomhum


One report from China found lower cost with recombinant FSH com-pared to highly purified FSH with similar pregnancy outcomes and LBRbetween the groups (Ye et al 2013) Concerning acceptability it isreported that shame and stigma have decreased over time and ART isnow an accepted way to conceive (Whittaker 2016) Although ARTis well developed in China it is still out of reach for most infertile cou-ples due to an enormous demand for treatment resulting in long wait-ing times and costs estimated between US$5000 and US$16 000 perIVF cycle which is not covered by public or private insurance (Qiaoand Feng 2014 Audibert and Glass 2015)

Europe and Central AsiaART in Europe is widely studied and reported by the European IVFMonitoring Programme Six citations were included from LMIC whichwere all from upper MIC (Supplementary Table SII) Large differencesstill exist between the number of cycles per 1 million women (aged15ndash45 years) in these countries but overall there is reportedly goodaccess to ART services (European IVF monitoring Consortium (EIM)for the European Society of Human Reproduction and Embryologyet al 2017) Regarding efficacy of IVF the data reported from LMICare comparable to those in other higher income European countries(European IVF monitoring Consortium (EIM) for the European Societyof Human Reproduction and Embryology et al 2017) An LBR of172 per transfer was reported in Bosnia Herzegovina and 265 inSerbia both upper MIC (Balic 2011 Mitic et al 2012)

With regard to the feasibility and acceptability the costs of treat-ment are most often discussed along with legislative issues and regula-tions In Turkey government funding is reportedly provided (up to

two IVF cycles in women aged 23ndash39 years old) only if all otheroptions have been exhausted (Urman and Yakin 2010) Turkish ARTcenters are required to be licensed by the government (Aytoz 2012)In contrast other countries have reported very little regulation andART is influenced by market forces For example in Bulgaria whereminimal regulation of ART is described access and outcomes arepoor with 10 IVF clinics and low financial support for IVF treatments(Balabanova and Simonstein 2010) Within Europe a recent collabora-tive audit between ESHRE and the patient organization Fertility Europedemonstrated clear discrepancies in availability accessibility and fundingsupport within nine selected European Union countries (2017 FertilityEurope and European Society of Human Reproduction andEmbryology (ESHRE) 2017) Only one study reported on the attitudestoward ART a survey of 136 medical students nurses and doctors inRussia (upper MIC) reporting that 972 of respondents knew enoughabout ART and had a positive attitude toward it (Khamoshina et al2010)

Latin America and the CaribbeanData on the number of IVF clinics and treatment cycles are reportedin the Latin American Registry of Assisted Reproduction (REDLARA)(Zegers-Hochschild et al 2013 2014 2015 2016) The number ofcenters and countries in this region reporting data is increasing with13 citations included in the review (Supplementary Table SIII)Countries like Argentina and now Uruguay with a consistent policy to-ward recognizing the human right to start a family and ensuring accessto care demonstrated the highest number of ART cycles per popula-tion in contrast to countries where treatment depends on the

Figure 2 Results of studies from LMIC summarized within regions The numbers in parentheses represent the number of studies foundwithin regions and a summary of their themes is shown LMIC low- and middle-income countries Adapted from SDG Atlas 2018 The World ByRegion httpdatatopicsworldbankorgsdgatlasthe-world-by-regionhtml


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icoupcomhum


Tab

leI

Stu

dies

repo

rtin

gon

the

effi

cacy

and

feas

ibili

tyof

cost

-lim

itin

gin

itia

tive

sth

atar

eai

med

atpr

oduc

ing

affo

rdab

leA

RT

inL

MIC

(glo

bally

)

Ref

eren

ceC

ount

ryA

fford

able

AR

TO

ptio

nsC

ompa

rato

rE

ffica

cyF

easi

bilit

yR

isk

ofbi

as

Aff

ord

able

stim

ula

tio

np

roto

cols

Ale

yam

ma

etal

(2

011)

Indi

aIV

FIC

SIus

ing

min

imal

stim

u-la

tion

prot

ocol

C

onve

ntio

nal

AR

Tcy

cle

PRfo

llow

ing

one

two

and

thre

eem

-br

yotr

ansf

ers

wer

e22

3

3an

d34

r

espe

ctiv

ely

The

LBR

and

clin

i-ca

lPR

per

embr

yotr

ansf

erw

ere

19

and

22

LBR

per

initi

ated

cycl

ew

as14

(2

014

3)T

hem

ultip

lePR

was

26

with

noca

seof

OH

SS

Ave

rage

dire

ctco

stpe

rcy

cle

was

US

$675

for

IVF

and

US

$725

for

ICSI

trea

tmen

tcyc

leI

nse

ven

wom

ena

d-di

tiona

lem

bryo

son

Day

3cu

lture

dto

blas

tocy

stst

age

and

vitr

ified

A

lthou

ghag

ains

tpro

toco

lth

isw

asat

anad

ditio

nalc

osto

fUS$

50

Serio

us

De

Beer

etal

(2

016)

Sout

hA

fric

aEf

fort

sto

mak

eA

RT

mor

eaf

-fo

rdab

lean

dac

cess

ible

AR

Tem

ploy

edat

publ

icin

stitu

tion

Stan

dard

ICSI

IV

Fem

bryo

cultu

rean

dtr

ansf

erm

etho

dsw

ere

used

Non

e36

7pa

tient

s26

4(7

02

)cyc

les

resu

lted

inem

bryo

tran

sfer

(183

ICSI

11

7IV

F)A

vera

ge3

66oo

cyte

sre

-tr

ieve

dan

d2

16em

bryo

str

ansf

erre

dPR

ET

for

allt

rans

fers

was

162

9(4

326

4)an

din

fem

ale

agelt

38gt

1em

bryo

tran

sfer

red

244

8[3

514

3]

Not

repo

rted

Crit

ical

Elug

aet

al

(201

0)U

gand

aLo

w-c

ostA

RTe

200

per

IVF

cycl

eus

ing

loca

llab

orat

ory

loca

llytr

aine

dem

bryo

logi

stan

dor

alco

ntra

cept

ive

clom

idov

aria

nst

imul

atio

npr

otoc

ol

Non

eA

llpa

tient

sha

doo

cyte

retr

ieva

l(1ndash

4oo

cyte

s)1

patie

ntdi

dno

thav

etr

ans-

fer

(no

norm

alfe

rtili

zatio

n)u

pto

4em

bryo

str

ansf

erre

d3

patie

nts

had

atle

ast1

top

qual

ityem

bryo

Une

xpec

ted

prob

lem

sdu

ring

stud

y(p

roof

ofre

alag

eof

patie

nts

relia

ble

ultr

asou

ndfo

ran

tral

folli

cle

coun

ttr

ansp

ortp

robl

ems

for

mon

itorin

g)re

late

dto

loca

lcirc

umst

ance

s

Full

text

not

avai

labl

efo

ras

sess

men

t

Muk

herje

eet

al

(201

2)In

dia

Seve

rem

ale

fact

orL

etro

zole

and

low

dose

rFSH

GnR

H-

anta

goni

stst

arte

dat

folli

cle

size

of14

inbo

thgr

oups

O

vula

tion

trig

gere

dby

hCG

follo

wed

byIV

F-ET

Con

tinuo

usst

imul

atio

nw

ithst

anda

rd-

dose

rFSH

PR36

in

letr

ozol

egr

oup

vers

us33

in

cont

rolg

roup

(not

sign

ifica

nt)

Low

erra

teof

OH

SSin

letr

ozol

egr

oup

(04

2vs

75

2)

Per

cycl

em

ean

expe

nditu

rew

asre

-du

ced

by34

in

the

letr

ozol

egr

oup

Mod

erat

e(R

ando

miz

edC

ontr

olle

dT

rial(

RC

T))

Nag

ulap

ally

etal

(2

012)

Indi

aT

ubal

fact

orM

inim

alst

imul

a-tio

nw

ithcl

omip

hene

citr

ate

alte

rnat

eda

yH

MG

from

Day

4an

dce

tror

elix

daily

until

day

ofhC

Gin

ject

ion

Sam

em

inim

alst

imul

atio

npr

otoc

olw

ithle

troz

ole

PRpe

rcy

cle

(30

vs5

)

per

oocy

tere

trie

valc

ycle

(33

3vs

58

)a

ndpe

rem

bryo

tran

sfer

cycl

e(4

285

vs

6

66

)all

high

erin

clom

iphe

neci

trat

egr

oup

Sim

ilar

cost

sFu

llte

xtno

tav

aila

ble

for

asse

ssm

ent

Ozo

rnek

etal

(2

013)

Tur

key

Min

imal

stim

ulat

ions

with

letr

ozol

ein

dom

etha

cin

from

Day

6un

tilH

CG

Con

vent

iona

lst

imul

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nSa

me

clin

ical

PRb

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sscr

yopr

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-va

tion

due

tode

crea

sed

num

ber

ofre

trie

ved

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tes

Min

imal

stim

ulat

ion

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eco

stef

fect

ive

Full

text

not

avai

labl

efo

ras

sess

men

t

Shah

Naw

azan

dA

zhar

(201

4)Pa

kist

anA

rom

atas

ein

hibi

tors

with

gona

dotr

opin

san

din

dom

eth-

acin

until

retr

ieva

l

Stan

dard

GnR

Han

alog

ues

The

sam

epr

egna

ncy

rate

(22

8)

and

take

hom

eba

byra

tes

(18

5)

wer

ere

port

ed

Not

repo

rted

Full

text

not

avai

labl

efo

ras

sess

men

t Con

tinue

d

218 Chiware et al

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icoupcomhum


Tab

leI

Con

tinu

ed

Ref

eren

ceC

ount

ryA

fford

able

AR

TO

ptio

nsC

ompa

rato

rE

ffica

cyF

easi

bilit

yR

isk

ofbi

as

Mo

difi

ed

cult

ure

con

dit

ion

s

Kha

net

al

(201

3)Pa

kist

anIn

trav

agin

alcu

lture

(IVC

)N

one

The

fert

iliza

tion

rate

was

714

2(5

7

ova)

IN

VO

cell

devi

cew

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ella

ccep

ted

non-

trau

mat

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ffect

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st-e

ffect

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rnat

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ajor

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kept

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zers

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ired

toen

sure

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uous

supp

lyof

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tric

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hich

cont

ribut

esto

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high

cost

ofIV

Fan

dun

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ssar

yin

IVC

Crit

ical

(cas

ere

port

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(201

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de-

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prel

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f35

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otile

sper

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retr

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Ode

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s(9

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oups

also

had

high

erim

plan

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ncy

and

abor

tion

rate

s

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-cos

tAR

Top

tion

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e

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bele

teta

l(2

014)

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ium

Sim

plifi

ed(t

)WE

lab

syst

emmdash

acl

osed

syst

emin

tend

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lefe

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nan

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yode

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run

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kom

etal

(2

014)

Belg

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IVF

with

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repr

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gene

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lcu

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3fo

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em(1

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8)

and

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oder

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Con

tinue

d


Dow


icoupcomhum


Tab

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Con

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Ref

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TO

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isk

ofbi

as

and

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reco

nditi

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ortn

orm

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rtili

zatio

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nem

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tthe

need

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pmen

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plifi

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)w

ere

sim

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With

the

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plifi

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lture

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em8

23

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yos

impl

ante

don

em

isca

r-rie

dat

8w

eeks

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have

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born

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(201

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lotp

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ctim

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gba

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cin

fert

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rba

tch

To

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mbe

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days

over

1or

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onth

s)

Non

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alpr

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ncy

occu

rred

in18

0(3

00

)of5

04w

omen

(84

0)

who

unde

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bryo

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sfer

Oft

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0pr

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(66

)

ende

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tion

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)w

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ecto

pic

Of3

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ies

(60

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)tr

iple

tsan

d28

(46

)

twin

soc

curr

edT

wo

(03

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iple

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gnan

cies

ende

din

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tion

at16

and

20w

eeks

Oft

he28

twin

preg

nanc

ies

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)en

ded

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ortio

n8

(13

)

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epr

eter

ma

nd12

(20

)

deliv

-er

edat

37w

eeks

OH

SSoc

curr

edin

6(1

0

)of

the

wom

en

The

cost

ofIV

For

ICSI

isab

outU

S$3

000

(for

good

resp

onde

rsp

oor

resp

onde

rsne

eded

mor

edr

ugs

and

ther

efor

epa

idm

ore)

com

pare

dan

aver

age

cost

ofU

S$4

000ndash

5000

for

conv

entio

nalm

etho

dsM

edia

was

used

for

only

1ba

tch

and

ther

ew

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wst

affd

edic

atio

n

Serio

us

220 Chiware et al

Dow


icoupcomhum


couplersquos capacity to pay (Zegers-Hochschild et al 2016) An IVF unitin Jamaica reported ART outcomes similar to high-income countries(LBR of 168 comparable to 213 in the UK) Furthermore the pa-per reports that establishment of this dedicated unit has contributedto educating the public about infertility and ART with increasing de-mand from infertile couples and also from less traditional families(Pottinger et al 2012)

More studies discussed feasibility and accessibility Health authoritiesin Brazil (upper MIC) have reported that lsquocomplex infertility treat-mentsrsquo referring to ART are unavailable to infertile couples (Makuchand Bahamondes 2012) Despite this a few public institutions arereported to offer infertility evaluation and IVF treatment with somepartially charging for the procedures Access to care is limited due tohigh costs long waiting times complex scheduling processes and lackof political initiatives to implement more affordable ART ART in Brazilis reportedly mostly offered in the private medical sector at high costand health care services are unable to meet the growing demand forinfertility treatment (Makuch and Bahamondes 2012 de Souza 2014Correa and Loyola 2015) It is reported there is no specific legislationregulating assisted conception Political economic and ethical chal-lenges exist for policy makers to decide on allocation of funds forART considering the universal access and free of charge nature of theBrazilian health care system (Garcia and Bellamy 2015) A recentstudy showed among the 4275 newborns enrolled in the Pelotas2015 Birth Cohort Study 18 births (04) were the result of ARTMost ART was IVF (706) and 90 women had double embryotransfer All cycles were performed in private clinics with directout-of-pocket payment In 2012 the right to start a family was em-braced by the Brazilian Unified Health System as a human rightSince then 12 clinics and hospitals received financial support fromthe Brazilian government to provide universal access to ART serv-ices Most of these clinics are situated in S~ao Paulo with no clinicsreported in Northern Brazil (Silva et al 2019) A study alsohighlighted that for people living with HIVAIDS who desire tohave a child face significant barriers to accessing ART treatmentand counseling (Rossi Ada et al 2011)

In some countries until recently laws existed prohibiting IVF InCosta Rica (upper MIC) the Inter-American Court of Human Rightsin 2012 ruled that the Supreme Court of Costa Ricarsquos judgment in2000 prohibiting IVF violated the human right to private and family lifethe human right to found and raise a family and the human right tonon-discrimination on grounds of disability financial means or gender(Zegers-Hochschild et al 2013) On the other hand in Brazil the gov-ernment launched a policy in 2012 establishing ART as a universal rightwithin the National Health System (Silva et al 2019)

REDLARA estimated that Mexico (upper MIC) had the thirdhighest number of reported ART cycles in 2013 (Zegers-Hochschild et al 2016) In 2015 52 ART centers were registeredwith the Federal Commission for the Protection of Sanitary Riskwho initiated a campaign of accreditation to verify that ART clinicsare working to appropriate standards Rather than generating ageneral comprehensive law assisted reproduction specialists inconjunction with representatives of government offices (egMinistry of Health) members of private and public hospitals andNGOs are developing standards of practice for assisted reproduc-tion services (Gonzalez-Santos 2016)

Middle East and North AfricaEight citations from this region were included in the review most fromIran and Egypt (Supplementary Table SIV) Iran (upper MIC) isreported as the only EMRO country in which gamete donation andsurrogacy are practiced The role of ART has become increasingly im-portant for the state which views the rise in voluntary childlessness asa national challenge and is facilitating infertility treatment for couples ofreproductive age (Tremayne and Akhondi 2016)

Over 60 infertility clinics operate in the capital Tehran as well asother major cities in Iran (Tremayne and Akhondi 2016) An ARTcenter in Iran quoted that 241 of IVFICSI cycles were successful(Abutorabi et al 2014) Infertility centers in Iran are reported to oper-ate outside of government-financed health facilities and services areonly provided to those who can afford it Although ART is limited bycosts in Iran the cost is relatively lower than neighboring countrieswhich encourages foreign infertile couples to travel to Iran to undergoART Lack of national auditing supervision and a registry are cited asthe major drawbacks of the quality of care of ART system in Iran(Sadeghi 2015 Abedini et al 2016)

Changes to the stimulation protocols to reduce costs were reportedfrom a single unit in Egypt which performed 3233 IVF and ICSI cyclesover 5 years using HMG-only protocols as a practical and more afford-able method of stimulation The authors describe similar clinical preg-nancy rates with a mean cost reduction of over US$600 in the HMG-only group (Sallam et al 2013) One report highlighted the need todevelop and implement strategies to improve the management of in-fertility and ART in Egypt Suggested strategies included continuousupdating of undergraduate and postgraduate education professionaldevelopment programs and in-service training (Gibreel et al 2015)

South AsiaA survey from this region reported that in the countries for which in-formation was available (Bangladesh India Nepal Pakistan and SriLanka) IVF is available for couples but is not subsidized by the gov-ernment Oocyte donation and surrogacy are available and regulatedin India Nepal and Sri Lanka Of these five countries only Indiareported having a national registry for IVF activities but it is not com-pulsory The typical cost per treatment cycle of IVF was US$2500 orabove in all responding countries and IUI varied widely among theresponding countries from less than US$200 to more than US$2500(Li et al 2018) Of the 11 citations included in the review from thisregion most were from India (Supplementary Table SV) IVFICSIgamete donation and surrogacy are established ART practices in Indiain both the public and private sectors allowing a maximum of threeembryos per transfer (Widge and Cleland 2011) The low cost easyaccess availability and economical prices of IVF drugs along with avail-ability of surrogates and gamete donors have fueled the growth of theART industry in this region Over the last decade there has been aprogressive increase in the number of ART clinics in India with thenumber of voluntary reporting IVF centers increasing However manycenters in India are still not registered with a regulating body and notreporting their ART cycles (Malhotra et al 2015)

Mishra (2013) described the drawback of the growing number ofcenters (now estimated to be over 500 clinics in India) and availabletreatments is that new ART therapies are often introduced directlyfrom the laboratory to clinical practice and (safety) data are collectedas patients are treated with new protocols The options for infertility


Dow


icoupcomhum


treatment in India vary from pharmacotherapy often clomiphene cit-rate as the initial approach for most women to more expensive ARToptions Often patients still turn to alternative systems of medicineand faith healing hoping for a quick and successful outcome (Palattyet al 2012)

Although considered the most important barrier for ART in mostcountries the financial burden was the commonest reason for drop-ping out of IVF cycles in India In spite of the financial constraints themajority of the couples consented to the first IVF cycle but they hadto stop treatment when repeated cycles of IVF were indicated Theauthors did not report on LBR (Kulkarni et al 2014) Efforts havebeen reported to reduce the costs of treatments (to one-third of thecost of conventional ART) by using minimal stimulation protocols andother cost-cutting measures in an attempt to provide more affordabletreatment (Aleyamma et al 2011 Olofsson et al 2013) Mild stimula-tion protocols in use in India have been noted to have a lower preg-nancy rate per cycle compared to conventional IVF protocols (176versus 286) although the cumulative LBR after 1 year of treatmentwas similar (434 versus 447) (Mahajan 2013) Quality manage-ment systems are being implemented in Indian ART clinics and it is ac-knowledged by practitioners that the critical determinants of a high-quality IVF laboratory are the people procedure equipment and thelaboratory design (Olofsson et al 2013)

In Bangladesh 10 tertiary level infertility centers reported 16 700new patients per year but only 5 proceeded to ART mainly due tofinancial constraints (Fatima et al 2015) Some centers in Pakistan of-fer minimal stimulation protocols ICSI at a reduced cost and even freeIVF in some cases to meet the demand (Shah Nawaz and Azhar2014) Infertility and its challenge and barriers to care can be deducedfrom evidence on IUI in a survey from Pakistan 90 of respondentsdeclined IUI because of religious and cultural taboos and if they re-ceived treatment they were not willing to disclose this to their family(Khalid and Qureshi 2012)

Sub-Saharan AfricaIt is reported that lt15 of the population of Africa has access toART (Ombelet and Onofre 2019) This review included 23 citationsfrom this region (Supplementary Table SVI) South Africa (upper MIC)is the most developed and experienced in provision of ART and waspreviously the only country with a published data registry (SouthAfrican registry for assisted reproductive techniques SARA) in this re-gion (SARA report 2014) More recently Dyer et al (2019) publisheddata from the newly developed African Network and Registry forAssisted Reproductive Technology with voluntary reporting from 40centers in 13 countries The Association for Fertility and ReproductiveHealth of Nigeria is active as a regulatory framework and provides eth-ical guidelines for ART (Okonta et al 2018) We found seven studiesexploring the efficacy of ART treatments (Eluga et al 2010 Olukoyaet al 2012 Orhue et al 2012 De Beer et al 2016)

One method to increase efficacy of treatment strongly practiced inSub-Saharan Africa is the transfer of multiple embryos justified as be-ing for economic reasons and the fear of failure (Onah and Okohue2010 Fadare and Adeniyi 2015) In Nigeria the LBR has beenreported as high as 76 but with high multiple pregnancy rates of upto 40 (Olukoya et al 2012) It is reported as common practice totransfer up to five embryos at once in Nigeria Ghana Mali andUganda (Fadare and Adeniyi 2015 Horbst 2016 Horbst and Gerrits

2016) Furthermore limited storage facilities and the quality thereof(power supply access to liquid nitrogen) costs associated with stor-age religious concerns about the fate of additional embryos and thepatientrsquos perspective on multiple pregnancies all support the justifica-tion for transfer of more than two embryos in these countries (Fadareand Adeniyi 2015) African women reportedly wish for and do notmind multiple gestations the complications notwithstanding particu-larly when they are over 35 years old with a long history of infertility(Onah and Okohue 2010) In contrast in South Africa (upper MIC)fewer embryos are transferred (up to three) as they have more expe-rience with ART better technical expertise and legal restrictions(Huyser and Boyd 2012 Fadare and Adeniyi 2015)

ART treatments in Sub-Saharan Africa are largely similar to practicesin high-income countries Owing to the lack of local knowledge guide-lines or legislation clinicians starting an ART clinic often refer toEuropeanAmerican guidelines organize collaborations and training inEuropean centers and even use second-hand equipment fromEuropean laboratories A recent case report showed the feasibility ofknowledge transfer from high- to low-income settings in the set-up ofa fertility clinic in Zimbabwe resulting in safe and affordable ART withsuccessful outcomes (Hammarberg et al 2018) Nevertheless localpractices are also implemented such as extended bed rest and hospi-talization in Ghana after embryo transfers (Gerrits 2016) and eggsharing to reduce costs for patients (Horbst 2016)

Regarding feasibility and accessibility most studies focused on costsaccessibility of clinicsservices public awareness and acceptability oftreatment There were no reports of state-funded ART treatments inthis region but affordable ART services have been introduced in somecountries (South Africa Uganda and Nigeria) (Eluga et al 2010Orhue et al 2012 De Beer et al 2016) Such affordable alternativesare reported to have an out-of-pocket cost of around US$200 per IVFcycle (Eluga et al 2010) while other studies quoted costs of up toUS$2700 per IVF cycle in Ghana up to US$4500 in Kenya and up toUS$10 000 in Nigeria (Fadare and Adeniyi 2015 Gerrits 2016Ndegwa 2016) These costs are to be seen in relation to the nationalmonthly minimum wage which is approximately US$110 in Nigeria(Fadare and Adeniyi 2015) One in five couples (22) in South Africa(upper MIC) incurred catastrophic expenditure defined as an out-of-pocket cost gt40 of annual non-food expenditure and reported cop-ing by reducing expenditure on clothing and food using of savings bor-rowing money and taking on extra work (Dyer et al 2013) Almost4 years after ART couples had not recovered financially from thetreatment (Dyer et al 2017) Costs are considered to be a factor inthe low utilization rates of ART services (Omokanye et al 2017Botha et al 2018 Dyer et al 2019 Ombelet and Onofre 2019)The accessibility of clinics is another barrier to ART treatment forpatients with only a few clinics reported in Kenya (Murage et al2011) Transnational ART is becoming common with people crossingborders to access treatment in South Africa and Ghana (Gerrits2016)

Public awareness and acceptability of ART treatments were studiedby surveys in Nigeria which reported several cultural concerns (eg le-gitimacy of children born patriarchy polygyny and value of children)and ethical issues (eg decision-making about the use of technologiesdiscrimination against children born psychological problems and lossof self-esteem side effects and costs) related to ART These issuesare largely dependent on the local context (urban and rural) and

222 Chiware et al

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icoupcomhum


religion (Catholic Muslim Anglican and traditional religions) (Fabamwoand Akinola 2013 Iliyasu et al 2013 Bello et al 2014 Menuba et al2014 Fadare and Adeniyi 2015 Omokanye et al 2017 Botha et al2018 Dyer et al 2019 Ombelet and Onofre 2019) We found nostudies exploring the acceptability of ART treatment in other Africancountries

Cost-limiting initiatives aiming at affordableARTSeveral options for lowering the cost of ART have been described in14 citations and compared to conventional ART although mostly insmall feasibility trials or pilot studies (Table I)

In India low-cost ART was evaluated in 143 carefully selectedpatients A mild stimulation protocol with several cost-cutting meas-ures (eg eliminating superfluous investigations) resulted in an LBR perstarted cycle of 14 at an average direct cost of US$675 for IVF(Aleyamma et al 2011) In South Africa a clinical pregnancy rate of163 per embryo transfer was reported with a low-cost protocol(mild ovarian stimulation optimum utilization of trained personnel andadapted laboratory procedures) (conference abstract) (De Beer et al2016) In another study low-cost ART using minimal ovarian stimula-tion the local laboratory and a locally trained embryologist wasassessed in 15 patients in Uganda All patients proceeded to oocyteretrieval but pregnancy outcomes were not reported (conference ab-stract) (Eluga et al 2010)

Minimal stimulation compared to conventional stimulation wasassessed in Turkey (upper MIC) and showed that minimal stimulationresulted in similar clinical pregnancy rates while being more cost effec-tive (Ozornek et al 2013) A study comparing two minimal stimula-tion protocols in normal responders with tubal factor infertilityreported improved outcomes with clomiphene citrate as compared toletrozole and concluded that such stimulation is feasible in the Indiancontext (Nagulapally et al 2012) Other studies evaluated minorchanges to the stimulation drugs to reduce costs In India women un-dergoing treatment for severe male factor infertility with letrozole re-duced the total dose of GnRH agonist required and reduced the costby 34 while pregnancy rates were comparable with conventionalGnRH agonist protocols (Mukherjee et al 2012) A randomized con-trolled trial from Pakistan only accessible as an abstract comparedstimulation with aromatase inhibitors gonadotrophins and indometha-cin to standard stimulation with GnRH analogs and reported similarpregnancy and LBR (Shah Nawaz and Azhar 2014)

In addition to minimal stimulation protocols and changes in stimula-tion drugs novel simplified culture systems have been tested A studyfrom Colombia assessed the INVOcellVR device for intravaginal cultureA mean of 42 oocytes was inseminated and cultured in theINVOcellVR device resulting in on average 26 embryos and a clinicalpregnancy rate of 40 per cycle (Lucena et al 2013) In another studyfrom the same research group good quality embryos higher implanta-tion and pregnancy rates were obtained using INVOcellVR compared toconventional IVFICSI (Navarro-Carbonell et al 2012 Lucena et al2013) A case report from Pakistan reported that using intravaginal cul-ture with the INVOcellVR device was successful and accep to the pa-tient (Khan et al 2013)

International initiatives have been focusing on bringing ART to low-resource settings The Walking Egg project aims to reach the goal of

lsquoglobal access to infertility carersquo (Dhont 2011) As part of the projectfeasibility and pilot studies on low-cost ART have been published In aprospective non-inferiority study IVF with the simplified culture sys-tem without the need for specialized medical-grade gases or equip-ment was evaluated against the routine culture system in 40 patientsof whom 35 reached embryo transfer (Day 3) Fertilization ratescleavage rates and clinical pregnancy rates (812 with simplified versus212 with standard culture) were similar (Van Blerkom et al 2014)In a next step a feasibility study of the simplified (t)WE lab system aclosed [same tube] system for fertilization and development until Day3 resulted in three pregnancies and four live births (Ombelet et al2014) All these studies were performed in Belgium Recently thesame research group published a study on how to implement thesesystems in low-resource settings (Ombelet and Goossens 2016) andthey reported the birth of the first baby in Ghana (Ombelet andOnofre 2019)

Other studies have assessed the efficacy and feasibility of improve-ments to the ART clinic organization Batching treatment cycles isused in Nigeria as a method of reducing the costs with a clinical preg-nancy rate of 30 per embryo transfer (Orhue et al 2012) An inten-sive course with training in hystero-contrast-sonography and one-stepIUI was a possible tool as a first step to introduce basic infertility careinto resource-poor settings like Eritrea before advancing to ART(Gnoth et al 2013) Despite these studies and efforts most of the ini-tiatives come from high-income countries and are still not immediatelytransferable to all LMIC settings (Bahamondes and Makuch 2014)

Risk of bias across studiesRisk of bias of individual studies is recorded in I We found 14 studiesfocusing on efficacy feasibility and acceptability of more affordableART options of which two provided indirect evidence (moderate riskof bias) as they were conducted as pilot studies in high-income coun-tries (Ombelet et al 2014 Van Blerkom et al 2014) Of the remain-ing 12 studies five could be accessed as a (conference) abstract only(Eluga et al 2010 Nagulapally et al 2012 Ozornek et al 2013 ShahNawaz and Azhar 2014 De Beer et al 2016) three were scored asat critical risk of bias (Gnoth et al 2013 Khan et al 2013 Lucenaet al 2013) two at serious risk (Aleyamma et al 2011 Orhue et al2012) and two at moderate risk of bias (Mukherjee et al 2012Navarro-Carbonell et al 2012)

DiscussionThe primary aim of this review was to establish the availability of IVFand other ART services in LMIC focusing on accessibility efficacy fea-sibility and acceptability In addition we summarized citations on thecurrently available affordable ART services or cost-reducing interven-tions While performing the review it was evident from many studiesthat high-cost ART treatments are being offered in LMIC often in pri-vate clinics and with the aim of providing ART access to the moreeconomically affluent population Such ART treatments are not acces-sible to the low- and middle-income people living in urban areas asthe cost is estimated to be up to 50 higher than the gross nationalper capita income in many LMIC (Vayena et al 2009) Affordable


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icoupcomhum


ART was considered to be ART that is not cost prohibitive and is ac-cessible to the general population of an LMIC

There were recurring themes among the citations reviewedReports included national data with regard to number of clinics suc-cess rates costs and drawbacks being faced Several of the includedstudies discussed suggestions for increasing access availability and ac-ceptability of ART within a country Finally studies also reported onattitudes toward infertility and ART and a shift in perception that canbe made through education of health care providers patients andcommunities (Vayena et al 2009)

Very few papers were found specifically discussing low-cost ARToptions and most were small feasibility studies or pilot studies per-formed in developed countries rather than large-scale evaluations ofthe efficacy safety and feasibility of these treatments in LMICAffordable ART initiatives include the Walking Egg project and theINVOcellVR device These projects are integral in bringing adapted ARTservices to LMIC but they should be evaluated through robust re-search for efficacy and safety and further adapted to the local infra-structure Recommendations on how to establish an ART center in alow-resource setting have been published to improve access (Cookeet al 2008)

When bringing ART to LMIC the variation in the etiology of infertil-ity should be taken into consideration Male infertility is more commonin some regions and is managed using various ART (for instance spermextraction along with ICSI) or IUI However local culture and stigmain some regions prevents the man of the infertile couple undergoingfertility testing which significantly affects the female partner but mayalso influence availability and research on treatments for male factor in-fertility (Agarwal et al 2015) Secondary infertility often followingunsafe abortions and complications at childbirth is also frequentlyreported in some LMIC and infertility management should include pre-ventative measures in addition to implementing more affordable ARTstrategies

In addition to the varying composition of infertile populations inLMIC the differences in settings between countries and regions aresignificant LMIC is too wide a category to assess and summarize fertil-ity treatments appropriately There was a vast difference betweenART offered in low-income countries and lower MIC compared toupper MIC The upper MIC such as China implement new cuttingedge treatments and technologies aggressively without technicalrestrictions (Ha 2013) while at the other end of the spectrum low-income countries struggle to introduce fertility assessment and low-cost options (Gnoth et al 2013) The need for ART regulating bodieswithin countries and regions was universally reported by the studies

Another aspect of ART in LMIC that raises concern is cross-borderreproductive care where possibly as a consequence of the lack ofART legislation private clinics offer high-quality ART procedures toforeign infertile couples at a high cost (Abedini et al 2016) Cross-border reproductive care could be beneficial to local residents as itboosts the economy as well as bringing resources technologies andtreatments to their country (Sadeghi 2015) However the local inhab-itants are generally not able to afford the same treatments and arerarely offered cost-saving opportunities such as egg sharing Youngwomen have the potential to be exploited as egg donors or surrogatesfor wealthy foreigners

While performing the review it was noted that there is basic sci-ence and clinical research occurring in LMIC which is helping to inform

and improve outcomes in ART worldwide In addition national andregional registries are attempting to collect data on ART treatmentswith some success in Latin America and Africa (Zegers-Hochschildet al 2013 SARA report 2014 Zegers-Hochschild et al 2014 et al2015 et al 2016) More rigorous data reporting collection and verifi-cation are needed from LMIC to enable a meta-analysis in the future(Kushnir et al 2017)

In conclusion the results of this review demonstrate some degreeof availability of IVF and other ART services in LMIC but highlight aneed for the development of more affordable and accessible ARToverall Infertility continues to be a global health problem that is stillnot being adequately addressed worldwide This review was per-formed to inform the WHO guidelines and to consider ART servicesas an important strategy in the management of men and women withinfertility in LMIC These guidelines will hopefully assist policy makersin including the management of infertility including IVF and other ARTservices in the reproductive health agenda and hence to improveoverall access to reproductive care in LMIC

LimitationsHealth care systems and populations largely vary among differentcountries even within the same geographic region and information onthese variations is not readily available In addition to this regional vari-ation the availability heterogeneity and quality of studies largely influ-enced the conclusions to be drawn for the different regions Theheterogeneity of studies and reports can also be attributed to the lessrestrictive inclusion criteria for outcomes which were set as such toincrease the sensitivity of the search strategy

Regarding the options for affordable ART in LMIC the most signifi-cant limitation was the lack of high-quality studies Of the 14 studiesincluded in the section lsquoCost limiting initiatives aiming at affordableARTrsquo only four were of moderate risk of bias of which two providedindirect evidence Although attempts were made to contact authorsand to find the published trials of references included as an abstractwe may have missed valuable data from studies not available in the in-cluded databases or retrievable through the English search terms andunpublished data

Supplementary dataSupplementary data are available at Human Reproduction Updateonline

AcknowledgementsWe would like to thank Tomas Allen (WHO) and Nancy Bianchi(University of Vermont) for their advice and assistance with the searchstrategies

Authorsrsquo rolesIT was responsible for the concept of this protocol TMC and KBwrote the protocol and designed the search strategy IT RF and KLreviewed and edited the protocol KB performed the final literature

224 Chiware et al

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icoupcomhum


search TMC and NV extracted the data performed the analysis ofthe articles and wrote the manuscript All the authors contributed tothe design interpretation of the results and critical revision of themanuscript

The authors JK and IT are staff members of the World HealthOrganization The authors alone are responsible for the viewsexpressed in this publication and they do not necessarily represent theviews decisions or policies of the World Health Organization

FundingThis study was supported by the World Health OrganizationDepartment of Reproductive Health and Research This work was alsofunded by the UNDP-UNFPA-UNICEF-WHO-World Bank SpecialProgramme of Research Development and Research Training inHuman Reproduction (HRP) a cosponsored program executed by theWorld Health Organization

Conflict of interestNone declared

ReferencesAbedini M Ghaheri A Omani Samani R Assisted reproductive tech-

nology in Iran the first national report on centers 2011 Int J FertilSteril 201610283ndash289

Abutorabi R Razavi V Baghazade S Sharegh L Mostafavi FSEvaluation of the success rate of assisted reproductive techniques(ART) in Shahid Beheshti infertility center Isfahan Iran J IsfahanMed School 2014321767ndash1781

Agarwal A Mulgund A Hamada A Chyatte MR A unique view onmale infertility around the globe Reprod Biol Endocrinol 20151337

Aleyamma TK Kamath MS Muthukumar K Mangalaraj AM GeorgeK Affordable ART a different perspective Hum Reprod 2011263312ndash3318

Audibert C Glass D A global perspective on assisted reproductivetechnology fertility treatment an 8-country fertility specialist sur-vey Reprod Biol Endocrinol 201513133

Aytoz A Female health care professionals in fertility services inTurkey Hum Reprod 201227 ii18

Bahamondes L Makuch MY Infertility care and the introduction ofnew reproductive technologies in poor resource settings ReprodBiol Endocrinol 20141287

Balabanova E Simonstein F Assisted reproduction a comparative re-view of IVF policies in two pro-natalist countries Health Care Anal201018188ndash202

Balic D How to make assisted reproductive technologies (ART) af-fordable in Bosnia and Herzegovina experience after the first 105cycles Med Arh 201165119ndash121

Banerjee K Singla BAcceptance of donor eggs donor sperms ordonor embryos in Indian infertile couples J Hum Reprod Sci 201811169ndash171

Bello FA Akinajo OR Olayemi O In-vitro fertilization gamete dona-tion and surrogacy perceptions of women attending an infertilityclinic in Ibadan Nigeria Afr J Reprod Health 201418127ndash133

Bennett LR Wiweko B Hinting A Adnyana IB Pangestu MIndonesian infertility patientsrsquo health seeking behaviour and pat-terns of access to biomedical infertility care an interviewer admin-istered survey conducted in three clinics Reprod Health 2012924

Botha B Shamley D Dyer S Availability effectiveness and safety ofART in sub-Saharan Africa a systematic review Hum Reprod Open20182018hoy003

Cooke I Gianaroli L Hovatta O Trounson A Affordable ART andthe Third World difficulties to overcome Hum Reprod 2008200893ndash96

Correa MCDV Loyola MA Tecnologias de reproduc~ao assistida noBrasil opc~oes para ampliar o acesso Physis (Rio J) 201525753ndash777

De Beer MW Matsaseng TC Erasmus EL Nel NA Pillay DNosarka S Affordable ART outcomes at the Tygerberg FertilityClinic Tygerberg Academic Hospital (TBAH) South Africa-specialreference to tubal factor infertility Reprod Biomed Online 201632S3

MdCB de Souza Latin America and access to assisted reproductivetechniques a Brazilian perspective JBRA Assist Reprod 20141847ndash51

Dhont N The Walking Egg non-profit organisation Facts Views VisObgyn 20113253ndash255

Dyer S Archary P de Mouzon J Fiadjoe M Ashiru O Assisted re-productive technologies in Africa first results from the AfricanNetwork and Registry for Assisted Reproductive Technology2013 Reprod Biomed Online 201938216ndash224

Dyer SJ Sherwood K McIntyre D Ataguba JE Catastrophic paymentfor assisted reproduction techniques with conventional ovarianstimulation in the public health sector of South Africa frequencyand coping strategies Hum Reprod 2013282755ndash2764

Dyer SJ Vinoos L Ataguba JE Poor recovery of households fromout-of-pocket payment for assisted reproductive technology HumReprod 2017322431ndash2436

Eluga M Tamale Sali E Desmet B Albano C Devroey P OmbeletW Platteau P Controlled ovarian stimulation for in vitro fertiliza-tion in a low resource setting a pilot study in Kampala-UgandaHum Reprod 201025i21ndashi22

ESHRE special task force on lsquodeveloping countries and infertilityrsquoESHRE Monographs 200820081ndash117

European IVF monitoring Consortium (EIM) for the EuropeanSociety of Human Reproduction and Embryology Calhaz-Jorge CDe Geyter C Kupka MS de Mouzon J Erb K Mocanu EMotrenko T Scaravelli G Wyns C Goossens V et al Assisted re-productive technology in Europe 2013 results generated fromEuropean registers by ESHRE Hum Reprod 2017321957ndash1973

European Policy Audit on Fertility (EPAF) 2017Fabamwo AO Akinola OI The understanding and acceptability of

assisted reproductive technology (ART) among infertile women inurban Lagos Nigeria J Obstet Gynaecol 20133371ndash74

Fadare JO Adeniyi AA Ethical issues in newer assisted reproductivetechnologies a view from Nigeria Niger J Clin Pract 201518 SupplS57ndashS61


Dow


icoupcomhum


Fatima P Ishrat S Rahman D Banu J Deeba F Begum N AnwarySA Hossain HB Quality and quantity of infertility care inBangladesh Mymensingh Med J 20152470ndash73

Fertility Europe European Society of Human Reproduction andEmbryology (ESHRE) A Policy Audit on Fertility Analysis of 9 EUCountries 2017 httpwwwfertilityeuropeeuour-projectspolicy-audit (5 October 2020 date last accessed)

Garcia S Bellamy M Assisted conception services and regulationwithin the Brazilian context JBRA Assist Reprod 201519198ndash203

Gerrits T Assisted reproductive technologies in Ghana transnationalundertakings local practices and lsquomore affordablersquo IVF ReprodBiomed Soc Online 2016232ndash38

Gibreel A Eladawi N El-Gilany AH Allakkany N Shams M How doEgyptian gynecologists manage infertility Cross-sectional study JObstet Gynaecol Res 2015411067ndash1073

Gnoth C Kaulhausen H Marzolf S First steps into gynaecological en-docrinology and reproductive medicine in resource-poor countriesan eritrean experience J Reprod Med Endokrinol 20131044ndash48

Gonzalez-Santos SP From esterilologıa to reproductive biology thestory of the Mexican assisted reproduction business ReprodBiomed Soc Online 20162116ndash127

Ha JO Risk disparities in the globalisation of assisted reproductivetechnology the case of Asia Glob Public Health 20138904ndash925

Hammarberg K Kirkman M Infertility in resource-constrained set-tings moving towards amelioration Reprod Biomed Online 201326189ndash195

Hammarberg K Trounson A McBain J Matthews P Robertson TRobertson F Magli C Mhlanga T Makurumure T Marechera FImproving access to ART in low-income settings through knowl-edge transfer a case study from Zimbabwe Hum Reprod Open20182018hoy017

Horbst V lsquoYou cannot do IVF in Africa as in Europersquo the making ofIVF in Mali and Uganda Reprod Biomed Soc Online 20162108ndash115

Horbst V Gerrits T Transnational connections of health professio-nals medicoscapes and assisted reproduction in Ghana andUganda Ethn Health 201621357ndash374

Huyser C Boyd L Assisted reproduction laboratory cost-drivers inSouth Africa value virtue and validity Obstet Gynaecol Forum20122215ndash21

Iliyasu Z Galadanci HS Abubakar IS Bashir FM Salihu HM AliyuMH Perception of infertility and acceptability of assisted reproduc-tion technology in northern Nigeria Niger J Med 201322341ndash347

Inhorn MC Patrizio P Infertility around the globe new thinking ongender reproductive technologies and global movements in the21st century Hum Reprod Update 201521411ndash426

Khalid SN Qureshi IZ Perceptions of infertile couples regarding in-fertility and intrauterine insemination (IUI) in a rural populationand services at government hospitals in Punjab Pakistan HumReprod 201227 ii7-8

Khamoshina MB Arkhipova MP Rudneva OD Vostrikova TVRadzinskaya EV The level of awareness of ART and the attitudeto it of medical students and workers without work experience inIVF clinics Reprod Biomed Online 201020S89

Khan M Zafar S Syed S Successful intravaginal culture of human em-bryos for the first time in Pakistanmdashan experience at the Sindh

Institute of Reproductive Medicine Karachi J Pak Med Assoc 201363630ndash632

Kulkarni G Mohanty NC Mohanty IR Jadhav P Boricha BG Surveyof reasons for discontinuation from in vitro fertilization treatmentamong couples attending infertility clinic J Hum Reprod Sci 20147249ndash254

Kushnir VA Barad DH Albertini DF Darmon SK Gleicher NSystematic review of worldwide trends in assisted reproductivetechnology 2004-2013 Reprod Biol Endocrinol 2017156

Kwek LK Saffari SE Tan HH Chan JK Nada SComparison betweensingle and double cleavage-stage embryo transfers single and dou-ble blastocyst transfers in a South East Asian In Vitro FertilisationCentre Ann Acad Med Singapore 201847451

Li HWR Tank J Haththotuwa R Asia and Oceania Federation ofObstetrics and Gynaecology Updated status of assisted reproduc-tive technology activities in the Asia-Oceania region J ObstetGynaecol Res 2018441667ndash1672

Lucena EE Moran AA Saa AA Pulido CC Lombana OO BonillaEE Invovagina complex replaces conventional incubators FertilSteril 2013100S527

Mahajan N Should mild stimulation be the order of the day J HumReprod Sci 20136220ndash226

Makuch MY Bahamondes L Barriers to access to infertility care andassisted reproductive technology within the public health sector inBrazil Facts Views Vis Obgyn 20124221ndash226

Malhotra J Malhotra N Pai HD Goswami D Retrospective six yearanalysis of ART directory of India Hum Reprod 201530i442ndashi443

Mascarenhas MN Flaxman SR Boerma T Vanderpoel S StevensGA National regional and global trends in infertility prevalencesince 1990 a systematic analysis of 277 health surveys PLoS Med20129e1001356

Menuba IE Ugwu EO Obi SN Lawani LO Onwuka CI Clinicalmanagement and therapeutic outcome of infertile couples insoutheast Nigeria Ther Clin Risk Manag 201410763ndash768

Mishra V IVF scenario in India Int J Fertil Steril 2013720ndash21Mitic D Kopitovic V Popovic J Milatovic S Basic M Milojevic M

[Results of in vitro fertilization cycles at the Clinic for Gynecologyand Obstetrics Clinical Center of Nis] Med Pregl 201265315ndash318

Moher D Liberati A Tetzlaff J Altman DG Group P Preferredreporting items for systematic reviews and meta-analyses thePRISMA statement BMJ 2009339b2535

Mukherjee S Sharma S Chakravarty BN Letrozole in a low-costin vitro fertilization protocol in intracytoplasmic sperm injectioncycles for male factor infertility a randomized controlled trial JHum Reprod Sci 20125170ndash174

Murage A Muteshi MC Githae F Assisted reproduction servicesprovision in a developing country time to act Fertil Steril 201196966ndash968

Nagulapally S Mittal S Malhotra N A randomized controlled studyof minimal stimulation IVF with two different protocols in normalresponders Hum Reprod 201227 ii7-8

Navarro-Carbonell DE Lucena-Quevedo E Saa-Madri~nan AMComparacion de la calidad embrionaria entre fertilizacion in vitro(FIV) y cultivo intravaginal de ovocitos (INVO) en el CentroColombiano de Fertilidad y EsterilidadmdashCECOLFES BogotaColombia Rev Colomb Obstet Ginecol 201263227ndash233

226 Chiware et al

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icoupcomhum


Ndegwa SW Affordable ART in Kenya the only hope for involun-tary childlessness Facts Views Vis Obgyn 20168128ndash130

Nigam M Nigam R Chaturvedi R Jain A Ethical and legal aspects ofartificial reproductive techniques including surrogacy AnilAggrawalrsquos Internet J Forensic Med Toxicol 2011121ndash21

Okafor NI Joe-Ikechebelu NN Ikechebelu JIPerceptions of infertilityandin vitro fertilization treatment among married couples inAnambra State Nigeria Afr J Reprod Health 20172155

Okonta PI Ajayi R Bamgbopa K Ogbeche R Okeke CCOnwuzurigbo K Ethical issues in the practice of assisted reproduc-tive technologies in Nigeria empirical data from fertility practi-tioners Afr J Reprod Health 20182251ndash58

Olofsson JI Banker MR Sjoblom LP Quality management systemsfor your in vitro fertilization clinicrsquos laboratory why bother J HumReprod Sci 201363ndash8

Olukoya OY Okeke CC Kemi AI Ogbeche RO Adewusi AJAshiru OA Multiple gestationspregnancies from IVF process in afertility center in Nigeria 2009-2011 implementing policy towardsfewer (double and single) embryo transfer Nig Q J Hosp Med20122280ndash84

Ombelet W Reproductive healthcare systems should includeaccessible infertility diagnosis and treatment an important chal-lenge for resource-poor countries Int J Gynaecol Obstet 2009106168ndash171

Ombelet W Campo R Affordable IVF for developing countriesReprod Biomed Online 200715257ndash265

Ombelet W Cooke I Dyer S Serour G Devroey P Infertility andthe provision of infertility medical services in developing countriesHum Reprod Update 200814605ndash621

Ombelet W Goossens J The Walking Egg Project how to start aTWE centre Facts Views Vis Obgyn 20168119ndash124

Ombelet W Onofre J IVF in Africa what is it all about Facts ViewsVis Obgyn 20191165ndash76

Ombelet W Van Blerkom J Klerkx E Janssen M Dhont NMestdagh G Nargund G Campo R The (t)WE lab simplified IVFprocedure first births after freezingthawing Facts Views Vis Obgyn2014645ndash49

Omokanye L Olatinwo A Durowade K Raji H Raji S Biliaminu SGaniyu S Determinants of utilization of assisted reproductive tech-nology services in Ilorin Nigeria J Med Soc 201731109

Onah HE Okohue J Case against single embryo transfer in AfricanIVF clinics Middle East Fertil Soc J 201015296ndash297

Orhue AA Aziken ME Osemwenkha AP Ibadin KO Odoma G Invitro fertilization at a public hospital in Nigeria Int J GynaecolObstet 201211856ndash60

Ozornek H Ozay A Oztel Z Atasever E Turan E Ergin E Minimalstimulation is as effective as classical stimulation in a single embryotransfer program in Turkey Fertil Steril 2013100S277

Palatty PL Kamble PS Shirke M Kamble S Revankar M RevankarVM A clinical round up of the female infertility therapy amongstIndians J Clin Diagn Res 201261343ndash1349

Pottinger AM Everett-Keane D McKenzie C Evolution of in vitrofertilization at the University of the West Indies Jamaica West IndMed J 201261460ndash462

Qiao J Feng HL Assisted reproductive technology in China compli-ance and non-compliance Transl Pediatr 2014391ndash97

Rossi Ada S Amaral E Makuch MY Access of people living with HIVto infertility services perspective of Brazilian healthcare professio-nals AIDS Care 2011231329ndash1335

Sadeghi MR Access to infertility services in middle east J ReprodInfertil 201516179

Sallam H Ezzeldin F Sallam N Agameya A Sallam S Farrag AHMG-only protocol for IVF a practical and more affordable optionfor developing countries Hum Reprod 201328i138

SARA report South African Registry for assisted reproductive techni-ques 2014 report (6th ANNUAL SARA report) 2014 httpanara-africacomwp-contentuploads201709SARA-2014-22052017pdf (5 October 2020 date last accessed)

Shah Nawaz S Azhar A Amazing low cost IVFICSI inductionprotocol in developing countries Hum Reprod 201429 Suppl 1i1ndashi389

Sharma S Mittal S Aggarwal P Management of infertility in low re-source countries BJOG 2009116 Suppl77ndash83

Silva SGD Bertoldi AD Silveira MFD Domingues MR Evenson KRSantos ISD Assisted reproductive technology prevalence and as-sociated factors in Southern Brazil Rev Saude Publica 20195313

Stellar C Garcia-Moreno C Temmerman M van der Poel S A sys-tematic review and narrative report of the relationship between in-fertility subfertility and intimate partner violence Int J GynaecolObstet 20161333ndash8

Sterne JA Hernan MA Reeves BC Savovic J Berkman NDViswanathan M Henry D Altman DG Ansari MT Boutron I et alROBINS-I a tool for assessing risk of bias in non-randomised stud-ies of interventions BMJ 2016355i4919

Stevens GA Alkema L Black RE Boerma JT Collins GS Ezzati MGrove JT Hogan DR Hogan MC Horton R et al Guidelines foraccurate and transparent health estimates reporting the GATHERstatement Lancet 2016388e19ndashe23

Tremayne S Akhondi MM Conceiving IVF in Iran Reprod Biomed SocOnline 2016262ndash70

Urman B Yakin K New Turkish legislation on assisted reproductivetechniques and centres a step in the right direction ReprodBiomed Online 201021729ndash731

Van Blerkom J Ombelet W Klerkx E Janssen M Dhont N NargundG Campo R First births with a simplified culture system for clini-cal IVF and embryo transfer Reprod Biomed Online 201428310ndash320

van der Poel SZ Historical walk the HRP Special Programme and in-fertility Gynecol Obstet Invest 201274218ndash227

Vayena E Peterson HB Adamson D Nygren K-G Assisted repro-ductive technologies in developing countries are we caring yetFertil Steril 200992413ndash416

Wahlberg A The birth and routinization of IVF in China ReprodBiomed Soc Online 2016297ndash107

Whittaker A From lsquoMung Mingrsquo to lsquoBaby Gammyrsquo a local history ofassisted reproduction in Thailand Reprod Biomed Soc Online 2016271ndash78

Widge A Cleland J Negotiating boundaries accessing donor game-tes in India Facts Views Vis Obgyn 2011353ndash60

World Bank Country and Lending Groups httpsdatahelpdeskworldbankorgknowledgebasearticles906519-world-bank-country-and-lending-groups (30 January 2020 date last accessed)


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icoupcomhum


World Health Organization Preamble to the Constitution of the

World Health Organization as adopted by the International HealthConference New York 19-22 June 1946 signed on 22 July 1946by the representatives of 61 States (Official Records of the WorldHealth Organization no 2 p 100) and entered into force on 7April 1948 httpwww who intgovernanceebwho_constitution_en pdf 1948 (5 October 2020 date last accessed)

Ye H Huang GN Cao YX Zhong Y Huang YH Zhu GJ Zhou LMChen ZJ Shi JZ Zeng Y et al [Effect of domestic highly purifiedurinary follicle stimulating hormone on outcomes of in vitrofertilization-embryo transfer in controlled ovarian stimulation]Zhonghua Fu Chan Ke Za Zhi 201348838ndash842

Zegers-Hochschild F Adamson GD de Mouzon J Ishihara OMansour R Nygren K Sullivan E Van der Poel S The internationalcommittee for monitoring assisted reproductive technology(ICMART) and the world health organization (WHO) revised glos-sary on ART terminology 2009 Hum Reprod 2009242683ndash2687Simultaneously Published in Fertil Steril 200926921520ndash2684

Zegers-Hochschild F Adamson GD Dyer S Racowsky C deMouzon J Sokol R Rienzi L Sunde A Schmidt L Cooke ID et alThe international glossary on infertility and fertility care 2017

Hum Reprod 2017321786ndash1801 Simultaneous Publication in FertilSteril 201711081393ndash1406

Zegers-Hochschild F Dickens BM Dughman-Manzur S Human rightsto in vitro fertilization Int J Gynaecol Obstet 201312386ndash89

Zegers-Hochschild F Schwarze JE Crosby JA Musri C de SouzaMdCB Assisted reproductive technologies (ART) in Latin Americathe Latin American Registry 2011 J Brasil Reprod Assist 201317216ndash221

Zegers-Hochschild F Schwarze JE Crosby JA Musri C de SouzaMdCB Assisted reproductive technologies in Latin America theLatin American Registry 2012 Reprod Biomed Online 20153043ndash51

Zegers-Hochschild F Schwarze JE Crosby JA Musri C de SouzaMdCB Assisted reproductive technologies (ART) in Latin Americathe Latin American Registry 2012 JBRA Assist Reprod 201418127ndash135

Zegers-Hochschild F Schwarze JE Crosby JA Musri C UrbinaMT Latin American Network of Assisted ReproductionAssisted reproductive techniques in Latin America the LatinAmerican Registry 2013 Reprod Biomed Online 201632614ndash625

228 Chiware et al

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icoupcomhum


SEARCH METHODS A systematic literature search was performed of articles and gray literature on IVF and other ART options inLMIC published between January 2010 and January 2020 We selected studies on IVF and other ART treatments for infertile couples ofreproductive age (18ndash44 years) from LMIC The review was limited to articles published after 2010 based on the recent evolution in thefield of ART practices in LMIC over the last decade Citations from high-income countries including data prior to 2010 and focusing onspecialized ART procedures were excluded The literature search included PubMed Popline CINHAL EMBASE and Global IndexMedicus No restrictions were applied with regard to study design or language Two reviewers independently screened the titlesand abstracts and extracted data A search for gray literature was performed using the lsquoGooglersquo search engine and specific databases(worldcatorg greylitorg) In addition the reference lists of included studies were assessed

OUTCOMES The search of the electronic databases yielded 3769 citations After review of the titles and abstracts 283 studies were in-cluded The full texts were reviewed and a further 199 articles were excluded The gray literature search yielded 586 citations most ofwhich were excluded after screening the title and the remaining documents were excluded after full-text assessment due to duplicateentries not from LMIC not relevant or no access to the full document Eighty-four citations were included as part of the review andseparated into regions The majority of the studies were observational and qualitative studies In general ART services are available anddescribed in several LMIC ranging from advanced techniques in China to basic introduction of IVF in some African countries Efforts toprovide affordable ART treatments are described in feasibility studies and efficacy studies however most citations were of low to verylow quality We found no studies from LMIC reporting the implementation of low-cost ART that is effective accessible and affordable tomost of those in need of the services

WIDER IMPLICATIONS The World Health Organization is in a unique position to provide much needed guidance for infertility man-agement in LMIC This review provides insight into the landscape of ART in LMIC in various regions worldwide which will guide efforts toimprove the availability quality accessibility and acceptability of biomedical infertility care including ART in these countries

Key words infertility low- and middle-income countries IVF ART fertility care fertility coverage affordable ART accessible ART

IntroductionThe World Health Organization (WHO) defines health as lsquoa state ofcomplete physical mental and social well-being and not merely the ab-sence of disease or infirmityrsquo (World Health Organization 1948) In2010 an estimated 485 million couples worldwide were infertile de-fined at that time as an inability lsquoto have any live birth over a 5-year pe-riodrsquo (Mascarenhas et al 2012) The overall prevalence of infertility isestimated at 35ndash167 in low- and middle-income countries (LMIC)with the prevalence as high as 30ndash40 in some regions of Sub-SaharanAfrica (Ombelet 2009 Inhorn and Patrizio 2015) Infertility in LMICis more than a health problem it is a social issue and a public healthmatter that continues to be neglected (Bahamondes and Makuch2014)

Infertility is known to cause significant psychological and socialeffects such as fear guilt depression self-blame marital stress emo-tional abuse intimate partner violence divorce and abandonment ofthe partner social isolation economic deprivation loss of social statusand in some regions (eg Africa and Asia) even starvation diseaseviolence-induced suicide and loss of dignity in death (Ombelet et al2008 Hammarberg and Kirkman 2013 Stellar et al 2016)

The most common etiologies of infertility in LMIC are male factorand tubal disease secondary to sexually transmitted infections unsafeabortion and complications of childbirth (Ombelet 2009 van derPoel 2012) Tubal factor infertility is reported to be as high as 85 inSub-Saharan Africa compared with 33 worldwide (Ombelet 2009)The most effective treatment is ART (Sharma et al 2009Bahamondes and Makuch 2014)

Infertility and ART are not considered a priority in many LMICThe most often used arguments against the use of ART are overpopu-lation other health priorities (eg family planning vaccinations malariaHIV) limited government budgets and limited experience of providers

with inadequate facilities for performing sophisticated procedures(Ombelet and Campo 2007) Furthermore in some LMIC ART isconsidered to be expensive only moderately effective with risks ofcomplications and unknown effects on women and their offspring(Ombelet and Campo 2007) In 2008 ESHRE published a series ofmonographs by experts from around the world highlighting the impor-tance of infertility its prevalence access to treatment and outcomes indeveloping countries (ESHRE Special Task Force on lsquoDevelopingCountries and Infertilityrsquo 2008) Along with the WHO and ESHREother non-governmental organizations (NGOs) are involved in initia-tives aimed at improving access to ART in LMIC including theAmerican Society for Reproductive Medicine the InternationalFederation of Gynecology and Obstetrics the International Federationof Fertility Societies and the International Committee for MonitoringAssisted Reproductive Technologies

Providing ART services in an LMIC requires an understanding of thecountry-specific magnitude and character of the issue of infertility aswell as identification of pre-existing resources that may be utilized(Sharma et al 2009 Bahamondes and Makuch 2014) WHO is in aunique position with 194 member states worldwide to assist in evalu-ating the burden of disease by the systematic assessment of infertilityand resources available within various regions

There is complete absence of affordable and accessible ART serv-ices in some LMIC possibly due to high costs of IVF and underdevel-oped infrastructure in addition to cultural religious and legal barriersThis deficiency has led to considerable interest by NGOs policymakers and ART specialists in developing more affordable IVF proto-cols such as minimal ovarian stimulation However there is a paucityof evidence and systematic reviews on the safety and efficiency profileof low-cost ART on the ability to replicate various techniques in differ-ent laboratories and under various field conditions and on how to inte-grate ART into existing health systems and infrastructures

214 Chiware et al

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216 Chiware et al

Dow


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Serio

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220 Chiware et al

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222 Chiware et al

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224 Chiware et al

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226 Chiware et al

Dow


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Dow


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228 Chiware et al

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icoupcomhum













Dow


icoupcomhum







(n = 3868)

Screen

ing

Inclu

ded

Eligibility

Iden

ficao

n


(n = 586)





(n = 283)


(n = 199)


(n = 84)




216 Chiware et al

Dow


icoupcomhum









Dow


icoupcomhum


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Full

text

not

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218 Chiware et al

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icoupcomhum


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Serio

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222 Chiware et al

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224 Chiware et al

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(n = 3868)

Screen

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Inclu

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n


(n = 586)





(n = 283)


(n = 199)


(n = 84)




216 Chiware et al

Dow


icoupcomhum









Dow


icoupcomhum


Tab

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US

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162

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514

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Crit

ical

Orh

ueet

al

(201

2)N

iger

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hecy

cles

wer

eca

rrie

dou

tin

batc

hes

with

anav

erag

eof

30co

uple

spe

rba

tch

To

syn-

chro

nize

thei

rm

enst

rual

cycl

est

hew

omen

took

estr

a-di

olva

lera

tean

dno

reth

iste

r-on

eac

etat

e(s

eque

ntia

llyf

orva

ryin

gnu

mbe

rsof

days

over

1or

2m

onth

s)

Non

eC

linic

alpr

egna

ncy

occu

rred

in18

0(3

00

)of5

04w

omen

(84

0)

who

unde

rwen

tem

bryo

tran

sfer

Oft

he18

0pr

egna

ncie

s40

(66

)

ende

din

spon

tane

ous

abor

tion

and

4(0

6

)w

ere

ecto

pic

Of3

6m

ultip

lepr

eg-

nanc

ies

(60

)

8(1

3

)tr

iple

tsan

d28

(46

)

twin

soc

curr

edT

wo

(03

)

ofth

etr

iple

tpre

gnan

cies

ende

din

abor

tion

at16

and

20w

eeks

Oft

he28

twin

preg

nanc

ies

8(1

3

)en

ded

inab

ortio

n8

(13

)

wer

epr

eter

ma

nd12

(20

)

deliv

-er

edat

37w

eeks

OH

SSoc

curr

edin

6(1

0

)of

the

wom

en

The

cost

ofIV

For

ICSI

isab

outU

S$3

000

(for

good

resp

onde

rsp

oor

resp

onde

rsne

eded

mor

edr

ugs

and

ther

efor

epa

idm

ore)

com

pare

dan

aver

age

cost

ofU

S$4

000ndash

5000

for

conv

entio

nalm

etho

dsM

edia

was

used

for

only

1ba

tch

and

ther

ew

aslo

wst

affd

edic

atio

n

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us

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IVF and other ART in low- and middle-income countries

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Transcript of IVF and other ART in low- and middle-income countries