Infertility Nursing - Omnia Education

the 

Omniacme 

journaltm 

special edition: 

Infertility 

Nursing 

1 FREE Contact Hour/CME Credit 

www.OmniaEducation.com 

special 

edition 

september 

2011 

Beyond First Line Therapy: Maximizing 

Outcomes and Minimizing Risks 

Beyond Clomiphene – What’s Next? 

MOnica R. BEnsOn, Rnc, Bsn 

Elective Single Embryo Transfer 

and the Patient Demands 

adRiEnnE KRaMER, Rn, Rnc 

The Patient and Multiple Births: 

Blessing or Burden 

MaRgaREt MaRnEll, FnP

cOntEnts 

Beyond clomiphene – What’s next?....2 

monica r. benson, rnc, bsn 

Elective single Embryo transfer 

and the Patient demands......................7 

adrienne kramer rn, rnc 

the Patient and Multiple Births: 

Blessing or Burden...............................12 

margaret marnell, fnp 

Post-test...............................................16 

activity Evaluation..............................17 

cover image: © gary cornhouse/getty images 

r e l e a s e date 9.19.2011 | expira t i o n date 9.19.2012 

instructions for credit 

Read the three articles included and complete the post-test and activity evaluation on page 16. Fax or mail the completed 

form as indicated on the form instructions. You must answer 70% of the questions correctly in order to receive your 

certificate. Your certificate will be sent via email. If an email address is not provided, your certificate will be sent via mail. 

If you do not receive a passing score, you will be contacted via email and will be given the opportunity to retake the test. 

course description 

This activity is designed to cover a spectrum of “hot” topics that are critical to today’s practice of reproductive 

endocrinology and infertility and will be presented from medical, nursing, psychological, and ethical perspectives. This 

issue includes three articles. The first article will review indications for the use of gonadotropins along with risks and 

potential adverse outcomes for couples with unexplained infertility or anovulation who have failed to conceive or respond 

to clomiphene. The second article assesses the critical subject of elective single embryo transfer, which has generated 

much discussion over the last several years. The third article is a stimulating manuscript that will provide critical tips to aid 

in counseling patients regarding the risks of multiple pregnancy. 

learning Objectives 

At the conclusion of this activity, participants should be able to: 

• Identify clinical guidelines for the appropriate referral, diagnosis, treatment and collaborative management of patients 

and couples affected by subfertility and infertility 

• Evaluate current ovarian stimulation protocols for use during IVF and non-IVF interventions for all patients types 

• Assess emerging assisted reproductive technologies and their implications for clinical practice, at all levels, to improve 

treatment approaches 

• Develop strategies to improve patient education and counseling of infertility therapies to optimize decision-making and 

clinical outcomes 

target audience 

These articles are designed to meet the Continuing Medical Education needs of the IVF and infertility nursing 

professional. 

accreditations and credit designations 

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation 

Council for Continuing Medical Education (ACCME) through the joint sponsorship of The Omnia- 

Prova Education Collaborative, Inc. (TOPEC) and Omnia Education. TOPEC is accredited by the 

ACCME to provide continuing medical education for physicians. 

The Omnia-Prova Education Collaborative, Inc. designates this enduring material for a maximum 

of 1.0 AMA PRA Category 1 Credit(s) TM . Physicians should claim only the credit commensurate with the extent of their 

participation in the activity. 

This continuing nursing education activity was approved by the Pennsylvania State Nurses Association, an accredited 

approver by the American Nurses Credentialing Center’s Commission on Accreditation. 

This activity is designated by the Pennsylvania State Nurses Association for a maximum of 1 Contact Hour. 

acknowledgement of commercial support 

This activity is supported by an independent educational grant from Merck. 

disclosure of conflicts of interest 

To provide the highest quality of CME programming in compliance with the ACCME Standards for Commercial Support, 

The Omnia-Prova Education Collaborative (TOPEC) and Omnia Education require that all faculty and planning 

committee members disclose relevant financial relationships with any commercial interest that produces healthcare goods 

or services. TOPEC and Omnia Education assess conflict of interest with its faculty, planners, authors and reviewers of 

CME activities. Identified conflicts of interest are thoroughly reviewed and resolved by independent reviewers for fair 

balance, scientific objectivity of studies utilized in the activity and patient care recommendations. TOPEC and Omnia 

Education are committed to providing its learners with high quality, unbiased and state-of-the-art education. 

FaCuLTy 

Monica R. Benson, RNC, BSN, has nothing to disclose. 

Adrienne Kramer, RN, RNC, has nothing to disclose. 

Margaret Marnell, FNP, has nothing to disclose. 

REvIEWERS 

Sanjay K. Agarwal, MD, FACOG, has nothing to disclose. 

Adrienne Kramer, RN, RNC, has nothing to disclose. 

Eric S. Surrey, MD, FACOG, has disclosed affiliations with Abbott Laboratories and EMD Serono, Inc. 

MEDICaL EDITOR 

Erem Latif, MS, Medical Physiology, has nothing to disclose. 

PLaNNERS 

Theresa Logan, CCMEP, has nothing to disclose. 

Sean T. Saunders, CCMEP, has nothing to disclose. 

Erica Spengler has nothing to disclose. 

Eric. S, Surrey, MD, FACOG, has disclosed affiliations with Abbott Laboratories and EMD Serono, Inc. 

disclaimer 

The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent 

the views of The Omnia-Prova Education Collaborative or Omnia Education. These articles are not intended to define 

an exclusive course of patient management; the participant should use his/her clinical judgment, knowledge, experience 

and diagnostic skills in applying or adopting for professional use any of the information provided herein. Any procedures, 

medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by 

clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any 

applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Beyond Clomiphene – What’s Next? 

When a woman is having trouble 

conceiving, her first medical 

contact is generally with 

her primary obstetrician/gynecologist 

(OB/gYn). Many patients will initiate 

fertility treatment with their OB/ 

gYn using clomiphene citrate (cc or 

clomid). cc is used as a treatment for 

unexplained infertility or WHO (World 

Health Organization) type 2 anovulation. 

the OB/gYn should begin with a 

basic infertility evaluation including a 

hysterosalpingogram (Hsg), semen 

analysis and a simple day-3 follicle 

stimulation hormone (FsH) level (basic 

assessment of ovarian reserve screening) 

prior to prescribing cc to assure the 

patient is a reasonable candidate for 

this treatment. this basic evaluation is 

necessary to establish that clomid is the 

appropriate initial treatment. if a patient’s 

fallopian tubes are obstructed or if the 

male partner’s sperm count is low, in-vitro 

fertilization should be considered as a 

more effective option. an elevated day-3 

FsH level may identify a diminished 

ovarian reserve, which would also be an 

impetus for more aggressive treatment. 

it is also helpful to know whether there 

are signs of ovulation including regular 

menstrual cycles, positive ovulation 

predictor kits, an elevated luteal 

progesterone or appropriate basal body 

temperature charting. 

in other cases, the initial treatment with 

cc may be prescribed by a reproductive 

endocrinologist (RE). Regardless of how 

clomid was initiated, if pregnancy does 

not occur within the first 3-6 cycles, more 

aggressive treatment is likely warranted. 

luckily, there are several treatment 

options in the reproductive endocrinology 

realm. if the patient was prescribed cc 

by her OB/gYn, it is time to set up an 

appointment with a board certified RE. 

a quick review of why cc did not work 

may be helpful in the development of an 

effective treatment strategy. did the patient 

ovulate in response to cc? if ovulation 

occurs, and there is no conception after 

3-6 cycles, it may be time to move on. 

Many patients will not want to wait until 

6 failed cycles and choose to change 

therapies after 2 or 3 attempts with cc. 

some patients may experience headaches 

or visual disturbances. Furthermore, the 

anti-estrogen effects of cc can sometimes 

cause thickened cervical mucus or a thin 

endometrium which may be more harmful 

than helpful. 

Further treatment choices need to be 

based on a comprehensive and timely 

work-up typically followed by an indepth 

discussion between the patient 

and the RE. the main objective of the 

basic infertility evaluation is to determine 

the etiology of the infertility, then to 

determine the prognosis for live birth. 

it can include but is not limited to: a 

thorough history and physical exam, 

evaluation of ovulatory function as well as 

ovarian reserve screening, evaluation of 

the uterine cavity along with assessment 

of possible tubal factors. it is essential to 

include the male partner in the complete 

history as a semen analysis may uncover 

a low sperm count or other issue. there 

are several tests that may be helpful in 

predicting patient response to treatment. 

Ovarian reserve screening should be 

based on a woman’s age along with tests 

including a day-3 FsH level, Basal antral 

Follicle count (BaFc), clomiphene 

challenge test (ccct) and aMH (antimullerian 

hormone). in a meta-analysis 

of 11 studies, “the BaFc was shown to 

author 

Monica R. Benson, rnc, bsn 

Clinical Research Nurse Administrator 

Reproductive Medicine Associates of 

New Jersey 

morristown, nj 

peer reviewers 

Adrienne Kramer, rn, rnc 

Senior Nurse Coordinator 

Reproductive Medical Associates of 

New Jersey 


Eric S. Surrey, md, facog 

Medical Director 

Colorado Center for Reproductive Medicine 

lone tree, co 

medical editor 

Erem Latif, ms, medical physiology 

Medical Editor 

chantilly, va 

be as accurate as multivariate markers.” 1 

“aMH is a serum marker of ovarian 

response that has been shown to be the 

best predictor of response in assisted 

Reproductive technology.” 2 Up to 30% 

of couples have normal infertility testing 

resulting in the diagnosis of unexplained 

infertility. 3 this is a frustrating diagnosis 

that should not give the perception that 

there is not a cause for their inability 

to conceive but that reflects the poor 

sensitivity of the current evaluation of the 

infertile couple. 

the RE will generally discuss their 

findings with the patient and direct 

further work-up and treatment options. 

the diagnostic work-up will help in 

setting basic expectations for prognosis. 

the goal is to develop a treatment 

strategy which best meets the patients’ 

overall needs while decreasing the 

health risks for the patient and future 

baby. setting the stage with appropriate 

expectations for success is an integral 

component of the treatment planning. 

2

tHE OMnia cME JOURnal tm | sEPtEMBER 2011 

Treatment Strategy 

Beyond clomid, infertility treatment 

focuses on improving the quantity 

and quality of eggs ovulated as well as 

improving the opportunity for sperm to 

fertilize an oocyte (egg). the principle 

component of improving ovulation 

is controlled ovarian hypersimulation 

(cOH) or ovulation induction (Oi) 

with injectable gonadotropins. When 

ovulation occurs, it is common for the RE 

to utilize intrauterine insemination (iUi) 

to improve the chances for fertilization 

and pregnancy to occur. alternatively, 

if the evaluation reveals a more serious 

issue, the treatment may turn to anatomic 

evaluation and correction via laparoscopic 

surgery or assisted reproductive 

technologies (aRt), which includes in 

vitro fertilization. For most patients, the 

next step after cc is cOH/iUi and thus 

it will be the focus of this article. 

ovulation induction/ 

intrauterine insemination (oi/iui) 

in women who do not ovulate on their 

own, gonadotropins (gnd) are used 

to induce ovulation, thus the term 

ovulation induction. in women who do 

ovulate on their own, these drugs are 

used to produce more follicles from 

the ovaries in a controlled fashion, 

thus the expression controlled ovarian 

hyperstimulation (cOH) sometimes 

referred to as controlled ovarian 

stimulation (cOs). these terms may be 

used interchangeably. gonadotropins 

are a first line drug for WHO group 1 

anovulatory women who typically have 

normal to low FsH and lH levels. they 

are a second line drug for women who 

fail to ovulate or conceive after optimal 

clomiphene citrate therapy. intrauterine 

insemination (iUi) is often combined 

with cOH to maximize the chances of 

conception. iUi is a procedure in which 

laboratory-prepared sperm are inserted 

into the uterine cavity through a cervical 

catheter. cOH/iUi may also be a first or 

second line of treatment for ovulatory 

women with unexplained infertility or 

endometriosis. 4 

the medications and timeline 

the medications used in Oi are referred 

to as gonadotropins. some common 

drugs used are Gonal F and Follistim 

which are made by recombinant 

dna technology and result in a pure 

preparation. there are also highly 

purified pure preparations of FsH, such 

as Bravelle, Menopur and Serophene, 

which are isolated from the urine of 

menopausal women and freeze dried 

into a powder that be reconstituted. the 

principle protein component of these 

preparations is FsH which stimulates the 

growth of ovarian follicles, the tiny sacs 

that each contain an oocyte (egg). some 

preparations contain lutenizing Hormone 

(lH) for additional activity to stimulate 

androgen and estrogen production from 

the theca and granulosa cells within 

the follicles. the decision regarding 

which product to utilize is made by the 

RE based on the patient’s underlying 

diagnosis, previous stimulations and of 

course by insurance formulary guidelines. 

during an un-stimulated menstrual 

cycle, the pituitary gland produces 

FsH and lH to stimulate the group of 

ovarian follicles that are available for 

use that month. as a result, one follicle 

emerges as the dominant follicle and is 

ovulated. By administering exogenous 

gonadotropins, the RE is able to promote 

the maturation of several follicles, 

allowing a woman to ovulate two, three 

or four eggs in a successful cOH cycle. 

these preparations have been carefully 

processed to ensure maximum safety 

and potency. it is important to note that 

there has been no compelling evidence 

that one gonadotropin preparation is 

better than another. although FsH is 

the hormone primarily responsible for 

follicular development, both FsH and lH 

play a role in the normal development 

and ovulation of ovarian follicles. lH 

is normally responsible for triggering 

ovulation when a mature follicle is 

present. Each of these drugs acts directly 

on the ovaries and do not have activities 

elsewhere in the body. 

close monitoring with transvaginal 

ultrasound and blood tests are an 

important component of the process 

to reduce the chances of adverse 

consequences and to increase 

the chances of success. typically, 

gonadotropins are started on day 3 of 

bleeding during the menstrual cycle, 

although they can be started anytime 

between days 2-5 after review of 

baseline studies. at the baseline visit, 

an ultrasound is performed to ensure 

that the uterus and ovaries are ready 

for stimulation and that the hormones 

such as estradiol and progesterone are at 

their normal basal levels. the patient will 

perform the subcutaneous injection at 

home nightly. Many of the recombinant 

preparations are given using a penlike 

device that improves the accuracy 

of dosing and makes it easier for the 

patients. after several days, another 

transvaginal ultrasound will be performed 

to measure the growth of the follicles. 

Blood tests are repeated, including 

estrogen and progesterone to help 

determine the speed at which the follicles 

are growing. Patients are called the same 

day and medication dosages are adjusted. 

the patient is usually instructed to 

return after one to three more nights 

of injections. Once the follicles reach 

the goal (generally, 1-3 follicles greater 

than 16-18 mm diameter, estragen 

between 300-900 pg/ml; note that the 

goals may vary for each individual and 

practice preference), human chorionic 

gonadatopin (hcg) will be given to 

induce the final maturation of the egg 

and ovulation. an iUi is preformed 

approximately 36 hours later, some

centers may perform 2 iUis once at 12 

hours and one at 36 hours in attempt to 

increase the chances of conception. some 

patients may choose timed intercourse 

pending the results of sperm testing and 

after a review of outcome data with their 

physicians. 

ovulatory dysfuntion 

the WHO describes 3 groups of 

ovulatory dysfunction: group 1: 

hypothalamic-pituitary failure (these are 

women who are anovulatory), group 

2: hypothalamic-pituitary dysfunction 

(polycystic ovarian syndrome- PcOs) 

and group 3: ovarian failure. 4 

in hypothalamic-pituitary failure or 

hypogonadotropic hypogonadism (HH) 

a patient is lacking in endogenous 

gonadatropins and therefore does not 

ovulate on her own. the treatment 

protocol to obtain optimal results needs 

to include FsH and lH. the lH is 

required for estrogen production and 

endometrial proliferation. lH results 

in larger follicles and perhaps better 

fertilization rates, although there are 

no prospective studies of dosages and 

treatment outcomes. 5 

in WHO group 2: Hypothalamic- 

Pituitary dysfunction, a great majority 

will have PcOs which is an ovarian and/ 

or metabolic disorder. First line of therapy 

in obese PcOs patients is ovulation 

induction with cc along with weight loss 

and possibly an insulin sensitizing agent 

as appropriate. data shows that even 

a 5-10% weight loss results in regular 

menses in 80% of obese PcOs. Weight 

loss may improve response to medical 

therapy, reduce pregnancy loss and 

pregnancy complications. 6 

gonadotropins (gnd) in PcOs can be 

tricky as these patients are prone to a 

hyper-response and are at increased risk 

for Ovarian Hyper stimulation syndrome 

(OHss). “the gonadatropin dose should 

start low and slowly be stepped up 

according to patient response. Using low 

dose gnd, 95% of patients will ovulate 

with a cumulative conception rate of 55% 

in 6 cycles and a 6% multiple live birth 

rate. Furthermore, using cc followed 

by low dose gnd results in a cumulative 

singleton live-birth rate of 72%.” 6 

WHO group 3: Hypergonadotropic 

hypogonadism or premature ovarian 

failure is defined as cessation of menses 

before the age of 40. “Ovulation 

may occur in 11-46% in 2-6 months of 

follow-up. there is about a 5% chance 

of conception, most within one year 

after diagnosis. no therapy increases 

pregnancy rates above the background 

of 5% and the only effective therapy is 

oocyte donation.” 7 

adverse effects 

the most common side effects to 

gonadatropins are local irritation at 

injection site and symptoms of estrogen 

excess such as: 

• dizziness 

• nausea 

• Headaches 

• Mood swings/irritability 

• Hot flashes 

• Breast fullness or tenderness 

the primary risks of cOH/iUi 

include multiple births and ovarian 

hyperstimulation syndrome. 

multiple pregnancies 

Multiple pregnancies are more common 

with gonadotropins than with clomiphene 

citrate (clomid, serophene). the risk 

is directly proportional to the number 

of mature follicles. “Overall, multiple 

pregnancies represent approximately 

15-20% of the gonadotropin induced 

pregnancies with 2-5% of all pregnancies 

being high order multiple pregnancies 

(e.g., triplets or more). cOH does have 

slightly higher risks of multiple births than 

iVF as the number of embryos can be 

controlled with transfer. Of all multiple 

births multiple births from aRt was 

17% (24,165) estimated multiple births 

from non-aRt ovulation treatments 

23% (31,900) and 60% of multiple births 

conceived naturally.” 8 

ovarian hyperstimulation 

syndrome (ohss) 

the most serious side effect of ovarian 

stimulation is ovarian hyperstimulation 

syndrome (OHss). its symptoms can 

include increased ovarian size, nausea 

and vomiting, accumulation of fluid in 

the abdomen, breathing difficulties, an 

increased concentration of red blood 

cells, kidney and liver problems, and in 

the most severe cases, blood clots, kidney 

failure, or death. 

OHss is an exaggerated response 

to ovulation induction therapy. With 

OHss there is an enlargement of the 

ovaries and accumulation of fluid in the 

abdomen. the etiology is unknown, but 

it is associated with high estradiol levels. 

Pregnancy increases the likelihood, the 

duration and the severity of OHss. 

Milder forms of OHss occur in 5-10% 

of gonadotropin cycles. severe forms 

are less common. the risk factors for 

hyperstimulation include: young age, low 

body weight, PcOs, increased BaFc, 

patient with history of OHss, higher 

doses of exogenous gonadotropins, high 

absolute or rapidly rising estradiol levels 

(asRM practice guidelines). 

the severe cases affect only a very small 

percentage of women who undergo 

iVF—0.2 percent or less of all treatment 

cycles—and the very severe are an even 

smaller percentage. Only about 1.4 in 

100,000 cycles has lead to kidney failure, 

for example. OHss occurs at two stages: 

early, 1 to 5 days after egg retrieval (as a 

result of the hcg trigger); and late, 10 

4


to 15 days after retrieval (as a result of 

the hcg if pregnancy occurs). the risk 

of severe complications is about 4 to 12 

times higher if pregnancy occurs, which 

is why sometimes no embryo transfer is 

performed to reduce the possibility of 

this occurring. 9 

Early signs and symptoms of OHss 

include abdominal bloating, pelvic pain, 

weight gain of 1-2 pounds, nausea and/ 

or vomiting, decreased urine output, and 

shortness of breath. Patients who are 

considered at risk need to be educated 

on the signs and symptoms as well as 

the potential severity of OHss. Patients 

should be instructed to notify their nurse 

or physician immediately with onset 

of any of these signs and symptoms. 

Patients at risk should be cautioned to 

limit their activities and increase PO 

fluids. Physicians, working with patients 

at risk for OHss, should consider low 

gonadotropin dose initially as well as 

frequent monitoring and adjustment 

of dosage during cycle if needed. 

cancelation of the insemination is 

sometimes the best prevention of OHss 

as well multiple pregnancies. iVF patients 

may benefit from having egg retrieval 

and cryopreservation of embryos. 

figure 1 

Indication for Ovulation Induction or COH 

WHO type I- anovulation 

(Hypogonadotropic hypogonadism) 

WHO type II - (hyperandrogenic-PCOS/ 

Oligomenorrheic) 

unexplained infertility including 

Endometriosis I & II (no iUi) 

unexplained Infertility including 

Endometriosis I & II (with iUi) 

% Pregnant 

(per cycle) 

Total % Pregnant 

after 4 cycles 

29% 67% 

18-19% 30-58% 

7.7-8% 19% 

17.1-18% 33% 

Fluker et al. 1994 

guzick et al. 1998 &1999 

reassuring for patients 

no increased risks 

Miscarriage Rate: 20-25%, about equal 

to the general population and is age 

dependent. 

Ectopic Pregnancy Rate: 2-5%, equal 

to or slightly higher than the general 

population. 

congenital anomalies: the risk is equal 

to the general population. 10 

Ovarian cancer: “no convincing 

association was found between use of 

fertility drugs and risk of ovarian cancer. 

Furthermore, no associations were found 

between all four groups of fertility drugs 

and number of cycles of use, length of 

follow-up, or parity.” 11 

results of ovulation induction/ 

controlled ovarian hyperstimulation 

with gonadotropins 

the results of Oi/cOH presented in 

figure 1 are dependant upon many 

factors including primary diagnosis, 

the woman’s age, quality of sperm, and 

quality of pelvic anatomy, as well as 

other diagnoses that may be present. 

the results presented below are from the 

literature. they are listed to provide you 

with an overall perspective regarding the 

general effectiveness of this therapy. 

in a retrospective review of over 450 

treatment cycles, Fluker et al., examines 

the cumulative pregnancy rates in cOH 

cycles in WHO group i & WHO group 

ii patients. 12 in another retrospective 

analysis of 45 published reports, guzick 

et al. suggests that empiric gonadotropin 

therapy is an effective therapy for 

unexplained infertility, especially when 

combined with iUi. 13 guzick then showed 

in a large randomized multicenter trial 

that FsH combined with iUi yielded 

higher cumulative pregnancy rates than 

FsH alone. 14 it should be noted that 

maternal age was a significant predictor 

of conception in all of these studies. 12-14 

Each patient should discuss their specific 

case with their doctor in order to 

determine their prognosis and potential 

success rates. 

assisted reproductive 

technologies (art) 

although, cOH/iUi results can be 

promising, some patients may choose to 

go directly to iVF following failed cc 

treatment to optimize their outcome. 

this has been demonstrated as a rational 

and cost effective approach by Fastt—a 

randomized clinical trial comparing two 

groups of treatment regimens, one with 

a “faster” approach. the first treatment 

group has a more traditional approach of 

following clomiphene/iUi treatment by 

cOH/iUi before moving on to iVF which 

is compared to a second more aggressive 

approach of clomiphene/iUi followed 

by moving directly on to iVF. the main 

outcome measure was the time it took to 

establish a pregnancy that led to a live 

birth and cost-effectiveness. Reindollar et 

al. results demonstrated an increased rate 

of pregnancy observed in the accelerated 

arm compared with the conventional arm. 15

conclusion 

Beyond clomid, infertility treatment 

focuses on improving the quantity 

and quality of eggs ovulated as well as 

improving the opportunity for sperm 

to fertilize an oocyte(egg). controlled 

ovarian hyperstimulation combined with 

iUi is a viable treatment option for many 

patients. some patients may find that 

the time commitment and emotional 

investment of protracted treatment too 

great and choose to move directly to iVF. 

Either way, the goal of fertility treatment 

remains the same, to optimize the 

outcome by providing the most effective 

means to achieve a healthy singleton 

pregnancy. 

r e f e r e n c e s 

1. Verhagen, t.E.M., Hendriks,d.J., Bancsi, l.F., 

Mol, B.W.J., Broekmans, F.J.M. Update (2008). the 

accuracy of multivariate models predicting ovarian 

reserve and pregnancy after in vitro fertilization: a 

meta-analysis, Hum. Reprod. 14 (2): 95-100. 

2. la Marca a., sighinolfi g., Radi d., argento 

c., Baraldi E., artenisio a.c., stabile g., Volpe a. 

(Update 2010). anti-Mullerian hormone (aMH) 

as a predictive marker in assisted reproductive 

technology (aRt). Hum Reprod. Mar-apr; 

16(2):113-30. 

3. the Practice committees of the american 

society for Reproductive Medicine. (2006 

november). Effectiveness and treatment for 

unexplained infertility. Fertil Steril; 86 ( 4): ps111. 

4. speroff l, Fritz M. induction of Ovulation: 

Programs, results, and complications for 

clomiphene, bromocriptine, gonadotropins, and 

gnRh administration. 7th ed: lippincott Williams & 

Wilkins, (2005): 1175-1214. 


society for Reproductive Medicine. (november 

2008) Use of exogenous gonadotropins in 

anovulatory women: a technical bulletin. Fertil Steril. 

Volume 90, issue 5, supplement, Pages s7-s12. 

6. the thessaloniki EsHRE/asRM-sponsored 

PcOs consensus Workshop group,(March 2008). 

consensus on infertility treatment related to 

polycystic ovary syndrome. Fertil Steril. Volume 89, 

issue 3 , Pages 505-522. 

7. Bidet M, Bachelot a, touraine P. (2008). 

Premature ovarian failure ... ovulation induction 

agents. Curr Opin Obstet Gynecol; 20: 416-20. 

8. schieve la, devine O, Boyle ca, Petrini 

JR, Warner l. (2009 dec ) Estimation of the 

contribution of non-assisted reproductive 

technology ovulation stimulation fertility treatments 

to Us singleton and multiple births, Am J Epidemiol. 

1;170(11):1396-407. 


society for Reproductive Medicine. (2006) . 

Ovarian Hyperstimulation syndrome. Practice 

guidelines. Fertil Steril; 86 (suppl 4): s178-s183. 

10. Filicori, M.,cognigni,g.E., (2001). Roles 

and novel Regimens of luteinizing Hormone 

and Follicle-stimulating Hormone in Ovulation 

induction. JcEM 86 (4): 1437. 

11. allan Jensen, a., sharif,H., Frederiksen, K., 

Krüger Kjær, s., (2009). Use of fertility drugs and 

risk of ovarian cancer: danish population based 

cohort study. BMJ; 338:b249. 

12. Fluker MR, Urman B, Mackinnon M, Barrow 

sR, Pride sM, Yuen BH. (1994 Feb). Exogenous 

gonadotropin therapy in World Health Organization 

groups i and ii ovulatory disorders. Obstet 

Gynecol.;83(2):189-96 

13. guzick ds, sullivan MW, adamson gd, 

cedars Mi, Falk RJ, Peterson EP, steinkampf MP. 

(1998 aug). Efficacy of treatment for unexplained 

infertility. Fertility and Sterility, Volume 70, issue 2 

Pages 207-213. 

14. guzick ds; carson sa; coutifaris c; Overstreet 

JW; Factor-litvak P; steinkampf MP; Hill Ja; 

Mastroianni l; Buster JE; nakajima st; Vogel dl; 

canfield RE. (1999). Efficacy of superovulation 

and intrauterine insemination in the treatment 

of infertility. national cooperative Reproductive 

Medicine network. N Engl J Med.; 340(3):177-83. 

15. Reindollar RH, Regan MM, neumann PJ, levine 

Bs, thornton Kl, alper MM, goldman MB.,(2010 

aug). a randomized clinical trial to evaluate optimal 

treatment for unexplained infertility: the fast track 

and standard treatment (Fastt) trial. Fertility and 

Sterility; 94(3):888-99. 

6



and the Patient Demands 

When discussing the topic of 

elective single embryo transfer 

(esEt) with patients, it is 

extremely important to confirm patient 

expectations and demands. as health 

professionals it is important to educate 

our patients and make certain they have 

realistic expectations. it is also important 

to be aware of the facts about the rising 

number of multiple births and the risks 

which are avoidable in many cases, as well 

as the increasing success rates of esEt. 

deciding whether to offer esEt depends 

on the clinical judgment of the health 

care practitioners involved. the decision 

should be based on an assessment of the 

risk of multiple births to the individual 

patient, taking into account their overall 

prognosis. When a patient is considering 

fertility treatment they will have many 

questions about the potential outcome 

including the risk of multiple births. it is 

important to answer questions about how 

esEt may affect the patient’s chances 

of getting pregnant. in addition patients 

must be informed about what will be 

done with remaining viable embryos 

and how they will be stored, as well as 

cost of cryopreservation and storage of 

remaining embryos. 

Which patients are suitable for 


(eSET)? 

Making the decision about doing an 

esEt depends on a patient’s prognosis 

for getting pregnant after iVF. the 

woman with the best chance of getting 

pregnant after iVF is also at the highest 

risk of conceiving multiples. 

Relevant factors to consider include 

the following: 

• Patient’s age and general medical 

condition 

• Obstetric and gynecological history 

• number of previous failed iVF attempts 

• the patient’s ovarian response 

• the number and quality of embryos 

created 

• the availability of good quality embryos 

including blastocysts 

the importance of the overall prognosis 

cannot be understated. the american 

society for Reproductive Medicine 

(asRM) has identified “favorable 

prognosis patients” as those under 37 

years of age (or using an oocyte donor 

under 37 years of age) without prior failed 

iVF cycles, who have morphologically 

good-quality embryos in sufficient 

number to warrant cryopreservation of 

the non-transferred embryos. 1 

Furthermore, esEt is not just for patients 

under 37 years of age. the Human 

Fertilization and Embryology authority 

(HFEa), an independent regulating 

authority in the United Kingdom that 

oversees the use of gametes and 

embryos both in fertility treatment as 

well as research, has posted success 

rates for esEt for 2004 and 2005. 2,3 

these indicate live birth rates of 23.7% 

and 18% retrospectively for patients 

over the age of 35, compared with the 

figures of 23.8% and 22.4% for the under 

35. the HFEa also suggests that esEt 

can be successfully performed in older 

patients, 35–39 years, with good quality 

embryos. the number of previously 

failed iVF attempts needs to be taken 

author 



Reproductive Medical Associates 

of New Jersey 



Sanjay K. Agarwal, md, facog 

Clinical Professor of Reproductive Medicine 

University of California, San Diego 

la jolla, ca 




lone tree, co 




chantilly, va 

into consideration equally when targeting 

esEt to the right patients. this means 

that esEt is normally restricted to the 

first one to two iVF cycles regardless of 

the age of the patient. 

Recent international studies have been 

carried out using the following criteria: 

• Women under 34 who started their first 

iVF/intra-cytoplasmic sperm injection 

(icsi) cycle and had at least two good 

quality embryos. 

• Women of all ages who had at least 4 

good quality embryos and no more than 

one failed treatment cycle. 

• Women under 36 years of age who had 

at least 2 good quality embryos. 

the asRM developed guidelines 

detailing the number of embryos 

transferred. 1 Multiple-gestation 

pregnancies remain the most significant 

and frequent complication of iVF 

treatment. although national and 

international efforts have focused on 

phasing out protocols that result in

higher order multiples, twin gestations 

continue to be a common accepted and 

surprisingly frequent desired outcome 

of iVF in the U.s. 4,5 twin gestations are 

certainly less risky than those involving 

high order multiples. compared with 

singletons, however, twin pregnancies 

contribute to the epidemic of preterm 

deliveries, have a higher rate of 

spontaneous abortion and intrauterine 

fetal demise and are more likely to 

result in neonatal and infant death, 

cerebral palsy and other congenital birth 

defects. 6-8 

Guidelines on number of 

embryos transferred 

in an effort to reduce the incidence 

of high order multiple gestations, the 

asRM and the society for assisted 

Reproductive technology (saRt) has 

developed the following guidelines to 

assist fertility programs and patients in 

determining the appropriate number of 

embryos—cleavage-stage (day 3 after 

fertilization ) or blastocyst (day 5-6 after 

fertilization), to transfer. these guidelines 

may be modified accordingly to the 

individual clinical conditions including 

patient age, embryo quality and the 

opportunity for cryopreservation. 1 

in the absence of data generated by the 

individual iVF program and based on the 

data generated by all clinics providing 

aRt services, the following guidelines are 

recommended based on data available in 

2009 asRM guidelines. 

a. For patients under the age of 35 

and 37 years who have a favorable 

prognosis, considerations should be 

given to transferring only a single 

embryo. no more than two embryos 

(cleavage stage or blastocysts) should 

be transferred. 

B. For patients between 35 and 37 years 

of age who have a more favorable 

prognosis, no more than two cleavagestage 

embryos should be transferred. all 

others in this age group should have no 

more than three cleavage-stage embryos 

transferred. if extended culture is 

performed, no more than two blastocysts 

should be transferred to women in the 

age group. 

c. For patients between 38 and 40 

years of age who have a more 

favorable prognosis, no more than 

three cleavage-stage embryos or two 

blastocysts should be transferred. 

all others in this age group should 

have no more than four cleavage– 

stage embryos or three blastocysts 

transferred. 

d. For patients 41–42 years of age, no more 

than five cleavage-staged embryos or 

three blastocysts should be transferred. 

E. in each of the above age groups for 

patients with two or more previous 

failed, fresh iVF cycles or a less 

favorable prognosis, one additional 

embryo may be transferred according 

to the individual circumstances. 1 the 

patient must be counseled regarding 

the risks of multifetal pregnancy. Both 

the counseling and the justification for 

exceeding the recommended limits 

must be documented in the patient’s 

permanent medical record. 

F. in women 43 years of age or older there 

is insufficient data to recommend a limit 

on the number of embryos to transfer. 

g. in donor egg cycles, the age of the 

donor should be used to determine 

the appropriate number of embryos 

to transfer. 

H. in frozen transfer cycles, the number of 

good-quality, thawed embryos transferred 

should not exceed the recommended 

limit on the number of fresh embryos 

transferred for each age group. 1 

Most professional societies have issued 

guidelines to decrease the number of 

embryos transferred during assisted 

reproductive techniques. despite this, the 

incidence of multiple pregnancies remains 

high. although triplet pregnancies have 

been reduced dramatically in the United 

states by limiting the number of embryos 

transferred, twin pregnancies still make 

up roughtly one third of all births from 

assisted reproductive technology. 9 

despite recent guidelines from the 

asRM, which suggest consideration of 

single embryo transfer in patients with the 

most favorable prognosis, there has been 

considerable resistance in the U.s. 7 Many 

physicians and patients fear that elective 

single embryo transfer may reduce overall 

pregnancy rates. 7 

Multiple births are hailed by many as a 

miracle and the novelty of high order 

multiples has been a source of fascination 

if not entertainment since the 1930s. the 

medical community however is not so 

emamored by these “multiple multiples.” 

Multiple births present potiential acute 

and long-term medical risks to the 

pregnant woman and to the children. 8-10 

Risks to the children include prematurity, 

which can contribute to the high 

incidence of low birth weight among 

multiples. low birth weight significantly 

impacts infant morbidity and mortality. 

Multiples may also suffer long term 

medical and developmental problems. 9 

Multiple births also pose long term and 

short term medical risks to a woman 

including premature labor and delivery, 

pregnancy-induced hypertension, 

gestational diabetes and increased risk 

of hemmorhage. these women may 

require extended periods of time on 

bedrest, be hospitalized and often require 

administration of medication to prevent 

preterm labor. 10 

8


the challenge is in preventing the 

conception of multiples by couples 

undergoing infertility treatment 

while maintaining success rates. the 

american college of Obstetricians 

and gynecologists committee on 

Ethics asserts that the first approach 

to the problem of multiple gestation is 

prevention. 11 

the introduction of a standard called 

“birth per embryo transferred” has been 

suggested to evaluate the efficiency of 

iVF programs and to rank fertility centers, 

and can promote a structural change in 

practice. 11,12 For many years standards 

have been used which encouraged the 

generation of multiple pregnancies. 5,6 

the ideal treatment procedure for in 

vitro patients should combine quantity 

(rate of pregnancy) with quality (healthy 

singletons). it is a challenge to develop 

a procedure that walks the line between 

low pregnancy rates and multiple 

pregnancies. 

Pressure on infertility centers to increase 

iVF success rates is very strong and may 

be a factor as to why multiple embryo 

transfers are being done as often as they 

have been. Often patients are attracted 

to fertility centers based on the success 

rates, which has a strong influence on 

the realization that of two major selfserving 

goals of infertility practitioners, 

namely professional status and profit. 13 

several authors have suggested that the 

commercialization of iVF is the cause of 

multiple embryo transfer. 13,14 

the question is often raised, who should 

decide how many embryos should be 

replaced? For an infertile couple, the 

strength of the desire to have a child can 

be reinforced by financial considerations 

based on limit of iVF cycles they can 

afford. Often patients feel that two 

is surely better than none. after the 

accumulation and publication of the 

consequences of multiple pregnancies, 

they can no longer believe that even 

twins are a happy or acceptable outcome 

of an iVF cycle. 15 

a variety of randomized clinical 

trials have demonstrated that esEt 

(particularly with blastocyst stage 

embryos) can result in high ongoing 

pregnancy rates while virtually eliminating 

multiple pregnancy. 16-21 in an article in 

Health Day News on december, 22 2010, 

the headline read: Single Embryo Beat 

Double Embryo Transfer in IVF Study. 

this finding comes from an analysis of 

data involving nearly 1,400 women who 

participated in one of eight different 

embryo transfer studies. Overall, the 

study authors noted that relative to a 

double embryo transfer, single embryo 

transfer significantly increases the 

chances of carrying a baby to full term. 28 

there are many ongoing studies being 

done in and around the United states 

on esEt including one specific study 

at the University of iowa, to evaluate 

if a mandatory esEt policy with an 

educational campaign in a U.s. iVF 

program reduces multiple gestation rates 

without sacrificing pregnancy rates. the 

objective of the study was to reduce the 

twin rate in the practice. Patients involved 

in the study were given a one page 

educational summary of comparative risks 

of twin versus singletons to maternal and 

fetal health. this data was abstracted 

from published studies current at the time 

of the study development. in this study, 

couples identified as being at high risk 

for twins, based on data from the iVF 

program, underwent single blastocyst 

transfer. High risk couples included those 

in which the woman was under 38 years 

of age with > 7 embryos, no previous 

“failed” (anything other than live birth 

outcome) iVF cycles and at least one 

good quality blastocyst. all patients were 

informed of the policy and informed that 

there were no exceptions to be made. 

the conclusion of the study showed that 

simple educational materials can improve 

knowledge of twin pregnancy rates and 

affect decision making. in this study the 

high risk for multiple patients, who had 

single blastocyst transfer, resulted in 

pregnancy rates similar to two-blastocyst 

transfer with decreased twin pregnancy 

rates. 21 

Educational programs geared for 

infertility patients can improve patients’ 

knowledge of multiple gestation and its 

risks. this may help patients make an 

informed decision about esEt. Physicians 

have been slow to embrace the esEt 

despite their understanding of multiple 

pregnancy and its risks. this may be a 

result of the fact that the data available 

regarding esEt have come largely from 

Europe and involve cleavage-stage 

embryos and historically lower pregnancy 

rates than those from the United states. 

this may be a concern when the cost 

of an iVF cycle averages almost 30% of 

the per-capita gross national income. 22 

Results from the present study using 

blastocysts as well as other recent studies 

of elective sEt should be reassuring. 16-20 

Can the use of 24 Chromosome 

Preimplantation Genetic screening 

improve success rates with elective 

single embryo transfer? 

the 24 chromosome Preimplantation 

genetic screening also called 

comprehensive chromosome screening 

(ccs) is a screening test using a PcRbased 

assay that utilizes choromosome– 

specific primers to integrate the 

chromosome copy number state of 

all 24 chromosomes. Homosapians 

have 46 chromosomes, 22 pair of 

autosomes (chromosomes 1–22) and 

two sex chromosomes, XX (female) 

or XY (male); ccs is done on preembryos 

for the presence of the correct 

number of chromosomes. an embryo is

considered normal only if it has 2 (a pair) 

of each autosome and one esEt of sex 

chromosomes. 23 

Researches are presently doing studies 

to look at the potential of the impact of 

screening an embryo prior to doing an 

elective single embryo transfer to see 

if it can improve pregnancy rates. 24,25 

studies have shown that elective single 

embryo transfer provides the most 

certain means to reduce aRt’s principal 

complication, which is multiple gestation. 

Regrettably, every prospective trial 

comparing esEt to multiple embryo 

transfer has demonstrated reductions in 

per cycle delivery rates. Key to esEt’s 

failure to attain equivilent outcomes is 

the inablility to assess the reproductive 

potential of a given embryo. 26 Many 

recent randomized controlled trials 

recently concluded (or currently 

underway) demonstrate that ccs can 

dramatically increase implantation and 

delivery rates, suggesting that the use of 

ccs might improve esEt outcomes. in 

one particular study out of the colorado 

center for Reproductive Medicine, 

indications for ccs included recurrent 

pregnancy loss, prior implantation failure 

or aneuploid gestation. Preliminary results 

showed that “the aneuploidy rate was 

51.3%. the probability of an individual 

transferred embryo forming a pregnancy 

reaching the third trimester/birth was 

68.9%.” Overall, the pregnancy rate was 

estimated at 82.2%. 27 

ccs with esEt may provide a practical 

way to eliminate risk of multiple 

pregnancy without comprimising clinical 

outcomes. However, the completion of 

appropriately designed randomized trials 

is required before this approach can be 

considered to be a standard option. 

Conclusion 

the decision for a woman to undergo 

fertility treatment, in itself is a very 

emotional and difficult decision to make. 

these patients have already learned that 

life often presents unpredicted obstacles. 

Most would prefer to have a healthy 

singleton, however, to a more risky 

multiple pregnancy. they may realize 

that to achieve this, they may well have 

to review their life plans. this is one of 

the reasons why counseling should be 

available in fertility clinics. 

in order to appropriately address these 

patients’ concerns when recommending 

elective single embryo transfer, we 

must properly educate our patients fully 

on the entire process. these patients 

should understand the risks and potential 

benefits so they can make an informed 

decision. it is vital to do a complete 

obstetrical history and discuss prior 

losses and prior infertility issues. the 

importance of informing a patient of their 

overall prognosis is key is dealing with 

their demands. Elective single embryo 

transfer can be a viable option for many 

of our patients and can decrease the 

incidence of multiple births and the 

complications associated with multiple 

gestation. 


1. Practice committee of the asRM and saRt. 

guidelines on number of embryos transferred. 

Fertil&Steril. 2009; 92:1518-9. 

2. Human Fertilisation and Embryology authority. 

1999 HFEA patient guide. london: HFEa; 1999. 

3. Human Fertilisation and Embryology authority. 

a long term analysis of the HFEa data, 1991-2006. 

latest extract date: 01/23/2008. 

4. society for assisted Reproductive technology. 

iVF success Rates: national data summary. 

available @ https//www.sartcorsonline.com/rptcsR_ 

PublicMultYear.aspx?clinicPKid=0. last accessed 

august 2009. 

5. schieve la, Peterson HB, Meikle s Jengg, 

daneli, Burnett nM, et al. an evaluation 

of the multiple-birth risk associated with in 

vitro fertilization in the United states. JAMA 

1999:282:1832-8. 

6. stone J, Eddleman K, lynch l, Berkowitz Rl. 

a single center with 1000 consecutive cases of 

multifetal pregnancy reduction. Am J Obstet Gyn. 

2002; 187:1163-7. 

7. center for disease control. assisted 

Reproductive technology surveillance, 2006. 

Surveillance Summaries. 2009; 58(s s05):1-25. www. 

cdc.gov/mmwr/preview/mmwrhtml/ss5805a1.htm. 

8. Jl Kiely. Epidemiology of perinatal mortality 

in multiple births. Perinatal Mortality. 1990; 66(6): 

618-637. 

9. luke B, Keith lg the contribution of singletons, 

twins and triplets to low birth weight, infant 

mortality and handicap in the Us. J Reprod Med 

1992 aug. 37(8):661-6. 

10. Hazenkamp J, Bergh c, Wennerhold U-B, 

et al. avoiding multiple pregnancies in aRt: 

consideration of new strategies. Hum. Reprod. 2000; 

15:1217-1219. 

11. american college of Obstetrics and gynecology 

committee on Ethics. Multifetal pregnancy 

reduction and selective fetal termination. Opinion 

number 94, april 1991. 

12. EsHRE task Force of ethics and law. Ethical 

issues related to multiple pregnancies in medically 

assisted procreation. Hum Repro 2003:18:1976-9. 

13. Faber, K. iVF in the Us: multiple gestation, 

economic competition, and the necessity of excess. 

Hum. Reprod. 1997; 12:1614-1616. 

14. Jain t, Missmer sa, Hornstein Md. trends in 

embryo-transfer practice and in outcomes of the 

uses of assisted reproductive technology in the Us. 

N Engl J Med 2004:350:1639-45. 

10


15. Pinborg, a. iVF/icsi twin pregnancy: risks and 

prevention. Hum Reprod Update 2005:11: 575-93. 

16. gardner dK, surrey E, Minjarez d, leitz a, 

stevens J and schoolcraft WB. single blastocyst 

transfer: a prospective randomized trial. 

Fertil&Steril. 2004; 81,551–555. 

17. Hunault cc, Eijkemans MJc, Pieters MHEc, 

teVelde ER, Habbema JdF, et al. a prediction 

model for selecting patients undergoing in vitro 

fertilization for elective single embryo transfer. 

Fertil&Steril. 2002; 77(4):725-732. 

18. scotland, g., Mcnamee, P., Peddie, V. and 

Bhattacharya, s. safety versus success in elective 

single embryo transfer: women’s preferences for 

outcomes of in vitro fertilisation. BJOG: Inter J of 

Obstet & Gyn. 2007; 114: 977–983. 

19. thurin a, Hausken J, Hillensjo t, Jablowska B, 

et al. Elective single embryo transfer: the value of 

cryopreservation. N Engl J Med; 2004; 351:2392- 

2402. 

20. templeton, a. avoiding multiple pregnancies in 

aRt: replace as many embryos as you like-one at a 

time. Hum. Reprod. 2000; 15: 1662. 

21. Ryan gl, sparks aEt, sipe cs, et. al. a 

mandatory single blastocyst transfer policy with 

educational campaign in a United states iVF 

program reduces multiple gestation rates without 

sacrificing pregnancy rates. Fert & Steril. 2007; 

88(2):354-360. 

22. Veleva Z, Karinen P, tomas c, tapanainen Js, 

& Martikainen H. Elective single emryo transfer 

with cryopreservation improves the outcome and 

diminishes the costs of iVF/icsi. Hum Reprod. 

2009; 1(1):1-8. 

23. scott Rt,tao X,taylor d,Ferry KM,treff 

nR. a prospective randomized controlled trial 

demonstrating significantly increased clinical 

pregnancy rates following 24 chromosome 

aneuploidy screening: biopsy and analysis on day 5 

with fresh transfer. Fertil & Steril 2011. 94(4): s2. 

24. Findlay i. Pre-implantation genetic diagnosis. Br. 

Med. Bull. 2000; 56(3):672-690. 

25. Harper Jc, Bui tH. Pre-implantation genetic 

diagnosis. Best Prac & Res Clin Obstet Gyn. 2002; 

16(5):659-670. 

26. stern JE, cedars Mi, Jain t, et al. assisted 

reproductive technology practice patterns and the 

impact on embryos transferred guidelines in the 

Us. Fertil & Steril. 2007 aug; 88(2): 275-82. 

27. schoolcraft WB, Fraquoli E, stevens J, et al. 

clinical application of comprehensive chromosomal 

screening at the blastocyst stage. Fertil & Steril. 

2010; 94(5):1700-6. 

28. 2010, december 22. single Embryo Beat double 

Embryo transfer in iVF study. Health Day News. 

http://www.drugs.com/news/single-embryo-beatdouble-embryo-transfer-ivf-study-28537.html.

The Patient and Multiple Births: 

Blessing or Burden 

To many infertile couples, the 

idyllic image of double strollers 

and an instantly complete 

family may sound too good to be true. 

However, the reality of conceiving, 

carrying, delivering, and raising 

multiples is often drastically different 

than the image held strongly in the 

minds of many hopeful patients. the 

very real risks of carrying multiples are 

to be conveyed honestly, clearly, and 

compassionately. the occurrence of 

multiples has drastically increased since 

the advancement of fertility technology, 

and a real assessment of our approach 

to this subject is necessary. 1 assisted 

reproductive technology (aRt) increases 

a woman’s chance of conception by 

hyperstimulating her ovaries, ensuring 

close contact between egg and sperm 

via ovulation induction with timed 

intercourse, intrauterine insemination 

(iUi), or in vitro fertilization (iVF) 

with subsequent embryo transfer (Et). 

Frozen embryo transfers (FEt) are 

another means to conception, with lower 

success rates, compared to its fresh 

counterpart. Patients pursuing these 

avenues of conception have likely faced 

over a year of struggle with infertility. 

their emotional investment and physical 

burden often leave them in a state 

of desiring twins, triplets, or higherorder 

pregnancies in order to achieve a 

complete family in one cycle. Recently, 

a few studies have highlighted the great 

disconnect between dream and reality, 

exhibiting that some infertile couples 

view a multiple fetal pregnancy as the 

ideal outcome. 2 this poses a great risk 

not only to the health of the mother 

and expected children, but also to the 

expectations of parenthood held by the 

infertile couple, as a unit. While there 

are some cases where twins, triplets, and 

even higher-order pregnancies can be 

successfully carried to their respective 

term dates, and may experience a 

complication-free delivery and neonatal 

period, the risk is often too great to 

take. 3 in order to preserve the health and 

wellness of both patient and child(ren) 

while honoring their unique wishes as a 

family, it is important to follow a simple 

yet effective protocol: hold an honest 

conversation to further understand the 

patients’ perspectives, educate them on 

the very real risks and complications of 

carrying multiples, and collaborate to 

create a treatment plan that is both safe 

and realistic. 

taking into consideration the great 

emotional and physical burdens 

experienced by the infertile patient, it 

is not too surprising that they may view 

multiples as a blessing. if the patient is 

uneducated with respect to the very real 

risk and burden associated with twin, 

triplet, and higher-order pregnancy, they 

will likely request a more aggressive and 

risky protocol than may be necessary. in 

the case of conception and successful 

live births of a multiples pregnancy, 

an uneducated patient may not have 

the proper support system in place for 

the challenging neonatal and postpartum 

periods. as practitioners, it is 

our responsibility to fulfill our roles as 

educators, caretakers, and advocates, in 

order to protect our patients and their 

expanding families. 

The Allure of Multiples 

after what may have been years of 

trying to conceive, financial sacrifice, 

and emotional struggles such as, “… 

distress, loss of control, stigmatization, 

author 

Margaret Marnell, fnp 

Family Nurse Practitioner 

CNY Fertility Center 

syracuse, ny 




Reproductive Medical Associates of 

New Jersey 





lone tree, co 




chantilly, va 

and a disruption in the developmental 

trajectory of adulthood,” 4 the idea of 

achieving a complete family in one 

cycle is going to appear ideal. never 

having to worry about attempting to 

conceive again, ensuring a full house, 

and sense of completion, are just a few 

benefits of having multiples in the eyes 

of the infertile patient. Regardless of 

the risks involved, the idea of a bustling 

home after years of feeling empty is 

a challenging emotion to overcome. 

abandoning the known and unknown 

risks of multiples, many couples 

are choosing to pursue aggressive 

treatments, sometimes even with the 

hope of conceiving twins or triplets. a 

recent study revealed that many women 

pursuing in vitro fertilization (iVF) would 

prefer to deliver a child with severe 

disabilities, as sometimes associated 

with double or multiple embryo transfer, 

than experience an unsuccessful cycle 

resulting in no child. 5 Understanding the 

magnitude of grief, loss, and struggle 

associated with infertility is critical 

12


to compassionate and empathetic 

counseling of the infertile patient. 

as many patients are willing to surmount 

all odds to conceive, it will be challenging 

to convey the importance of proceeding 

conservatively. some patients have gone 

as far as taking out second mortgages 

on their homes, borrowing money from 

family members, changing careers, 

relocating their family, and enduring 

multiple procedures, medication 

protocols, and Eastern medical practices. 

From where many of them are sitting, any 

live birth is a success. two children would 

be ideal, and three is a dream come 

true. the immediate desire and yearning 

outshines the risk and reality that 

eventually will ensue. neonatal intensive 

care Unit stays are a distant worry, and 

multiple late night nursing sessions are 

something to sheepishly look forward to. 

Unfortunately, conceiving twins, triplets, 

or higher-order pregnancies are often 

not a dream, and can sometimes be the 

cause of much grief and struggle. as 

their health care providers, it is our job to 

acknowledge their journey and empathize 

with their pain, but more importantly 

educate them of the real risks of carrying 

multiples, and work towards a happy, 

healthy, singleton pregnancy. 

The Reality of Multiples 

after the initial joy and excitement of the 

first ultrasound subsides, many patients 

begin to realize that carrying multiples 

is not as easy and clear-cut as it seems. 

there are very real and serious risks 

involved. taken lightly, mortality may 

result for not only the fetuses, but for 

the mom as well. according to a study 

featured in Fertility & Sterility, there are 

many risks associated with multiples that 

span beyond the physical health and 

wellbeing of both mom and babies. Many 

of the risks include but are not limited to, 

“…death, low birth 

weight, deformational plagiocephaly, and 

other physical and mental disabilities. 

Risks to the women include premature 

labor, premature delivery, pregnancyinduced 

hypertension, toxemia, 

gestational diabetes, and vaginal-uterine 

hemorrhage. children born in multiples 

face difficulty socializing, developmental 

delays, and behavioral problems, whereas 

their parents risk exhaustion, depression, 

and anxiety. in addition to personal costs 

faced by families, society often bears the 

financial costs of overburdened hospitals, 

caps on insurance and/or inability of 

parents to cover expenses.” 6 

the risks are real, and they are not easy 

to cope with. Many of the conditions 

listed above do not have a quick remedy, 

and often are lifetime struggles. this 

creates a challenge not only in the 

prenatal, neonatal and post partum 

periods, but also for the duration of the 

family’s life. 

Beyond the physical, social, and financial 

issues associated with multiple fetal 

pregnancies, there is a prominent 

emotional factor to consider. Mothers 

of multiples are at a greater risk for 

post-partum depression. specifically, 

“mothers of multiple births had 43% 

greater odds of having moderate/ 

severe, 9-month postpartum, depressive 

symptoms, compared with mothers of 

singletons.” 7 additionally, the family will 

have to cope with the great potential 

for disappointment and grief, if the 

pregnancy does encounter complications. 

a family that has already faced such great 

challenges and turmoil up to this point 

could potentially be faced with continued 

struggle and heartache. a moment that 

had been expected to be fulfilling and 

joyous, suddenly becomes an extension of 

the previous struggle and greater reason 

to question one’s ability to conceive and 

nurture successfully. 

Coping with Multiples 

Once a pregnancy has been established, 

a fair amount of counseling is necessary. 

Whether the patient had been expecting 

to conceive twins, triplets, or beyond 

is not pertinent at this point. From this 

point on, intensive and consistent care 

is most important. Proper hormone 

therapy protocols, if necessary, should 

be followed to support the early stages 

of pregnancy. additionally, diet and 

activity guidelines should be discussed. if 

possible, the patient should be referred 

to a practice specializing in high-risk 

pregnancies. Here, you can be sure that 

she will receive intensive and appropriate 

guidelines for care. 

High order multiple pregnancy (triplets 

or greater) is extremely high risk to 

mother and fetuses and all efforts 

should be made to avoid this outcome. 

in the rare cases when this does occur, 

consultation with a specialist is maternalfetal 

medicine is critical. another option 

is consideration of a multifetal selective 

reduction procedure which is designed 

to reduce the pregnancy to a single or 

twin gestation. this procedure is also not 

without risk or controversy and should 

only be considered after appropriate 

counseling by an experienced physician. 

since the rate of multiples has drastically 

increased over the past few years, new 

and unique support opportunities for 

moms have emerged. Utilizing online 

message boards and social networking 

sites, many moms of multiples have 

connected, shared, and created 

supportive and loving communities for 

each other. these support communities 

are unique, in that they often form 

around the challenges of infertility, and 

provide a caring environment beginning 

with fertility treatment and extending 

into parenthood. Making patients aware 

of various emotional, physical, and

even spiritual support opportunities will 

increase maternal wellbeing and fetal 

outcome. 9 

Approaching the Subject of 

Multiples Prior to Conception 

While there are many therapies available 

to patients carrying multiples to preserve 

the health and wellbeing of mom and 

fetuses, the best therapy is prevention. 

single embryo transfers are the ideal 

solution to the challenge of multiple 

pregnancies. However, this is often 

in direct opposition to the wishes of 

the infertile patient. after what may 

have been years of trying to conceive, 

transferring one embryo at a time often 

just seems too conservative and slow. as 

a result, there has to be a compromise 

between wanting the immediate result 

of pregnancy [however many fetus(es)], 

and balancing the long-term challenges 

of multiples. Engaging the patient in 

an ongoing conversation of potential 

risks and outcomes beginning in the 

early stages of treatment is integral to 

giving them the opportunity to make 

well thought out and informed decisions. 

as the health care practitioner, it is 

important to carefully assess the risk of 

multiples on a case-by-case basis, and 

make recommendations accordingly. 

Our patients look to us to recommend 

in areas that are beyond their scope 

of knowledge, and our diligence will 

contribute to what will be their ideal 

pregnancy and family situation. 

When assessing a patient’s risk for 

multiples, there are a few factors to 

consider. the patient’s age, overall health, 

specific detected causes of infertility, 

and personal cycle preference are just 

a few elements of the scenario to take 

into consideration. You will find that 

each patient is different, with unique 

limitations and desires. Essentially, you 

will have to find a balance between 

acting conservatively to try and ensure 

a singleton or twin pregnancy and 

remaining realistic and within the 

patient’s limitations. as you approach 

the conversation, remember to take the 

patient’s entire being and current life 

situation into consideration. some of the 

elements to consider are: 

age | How long has the patient been 

trying to conceive, and what is the 

realistic timeframe for conception before 

risking complications due to advanced 

maternal age, and poor egg quality? 

gamete quality | are gametes (sperm 

and/or egg) of adequate quality? is there 

a concern that acting conservatively 

in regards to follicle stimulation and/ 

or embryo quality would diminish the 

chances of conception? 

gamete availability | When dealing with 

cases of frozen gametes, especially after 

a procedure or scenario rendering one or 

both parties sterile, what is the best use 

of the available gametes? 

overall health | are there any 

limitations in the general health and 

wellbeing of the patient that would 

restrict multiple cycles, or multiple 

gestations? 

donor gametes | if the patient is 

transferring embryos created via donor 

eggs, do they understand that their 

potentially poor egg quality does not 

impact the quality of the donor’s eggs? a 

young and healthy donor’s eggs will likely 

still produce a multiple pregnancy, even 

if transferred into a patient of advanced 

maternal age or poor egg quality. 

support | does that patient have support 

at home, to help them through what 

could be a challenging prenatal, neonatal, 

and post partum period? 

religious/moral views | does the patient 

have a religious or moral objection 

to multiple embryo transfers and/or 

selective reduction? 

financial limitations | does the patient 

have the means to pursue a conservative 

path, potentially resulting in multiple single 

embryo transfers? do they have a cap on 

their insurance allocations, that would dictate 

their tendency to place more pressure on 

one multiple embryo transfer cycle? 

asrm recommended national guidelines 

take into consideration asRM’s 

suggested protocol for embryo transfer, 

to avoid higher-order multiples. 10 For a 

more in-depth explanation, please visit 

the original document, which outlines 

specific parameters to consider, and 

makes suggestions for conservative 

embryo transfer within the scope of a 

realistic cycle. this is a great resource to 

become familiar with. 

While this list of potential factors is 

extensive, it is not exhaustive. Just 

a simple introduction to the various 

elements of counseling an infertility 

client through the process of a safe and 

healthy cycle is clearly challenging. it 

is important to remember that while 

the ideal would be to only transfer one 

or two embryos, this does not always 

coincide with the reality of the patient’s 

health and wishes. there will always be 

multiple pregnancies, and complications 

to remedy. However, what remains 

constant is the vital need for an open 

and honest conversation conveying the 

risks and benefits of any cycle. Meeting 

the patients where they are emotionally 

and empathizing with their journey will 

allow for a greater sense of trust with 

them. this trust will translate into further 

acceptance of your proposed cycle plans, 

and your ability to accurately read their 

emotional and physical response as the 

cycle progresses. conceiving, carrying, 

delivering, and parenting multiples can 

be both a blessing and a burden. it is 

our responsibility to ensure our patients 

that they are informed, supported, and 

appreciated – regardless of the outcome. 

14



1. trends in the occurrence, determinants, and 

consequences of multiple births Béatrice Blondel, 

Monique Kaminski Seminars in Perinatology; 

2002 august;26(4): 239-249; dOi: 10.1053/ 

sper.2002.34775. 

2. Hojgaard a, Ottosen ldM, Kesmodel U, 

ingerslev HJ. Patient attitudes towards twin 

pregnancies and single embryo transfer—a 

questionnaire study. Hum Reprod; 2007; 22:2673- 

2678. 

3. less is more: the risks of multiple births Fertility 

and Sterility; 74 (4):617-623. 

4. Psychological impact of infertility tara M. 

cousineau, alice d. domar Best Practice & Research 

Clinical Obstetrics & Gynaecology ;april 2007; 21(2: 

293-308; dOi: 10.1016/j.bpobgyn.2006.12.003. 

5. scotland gs, Mcnamee P, Peddie Vl, 

Bhattacharya s. safety versus success in elective 

transfer: woman’s preferences for outcomes of in 

vitro fertilization. BJOG. ; 2007 aug; 114(8):977-83. 

Epub 2007 Jun 18. 

6. Elster n. less is more: the risks of multiple births. 

Fertility and Sterility. 2000 October; 74(4):617-623. 

7. Multiple Births are a Risk Factor for Postpartum 

Maternal depressive symptoms. Yoonjoung 

choi, david Bishai, and cynthia s. Minkovitz. 

Pediatrics: 2009 april; 123:4 1147-1154; dOi:10.1542/ 

peds.2008-1619. 

8. Yaron Y, Bryant-greenwood PK, dave n, 

Moldenhauer Js, Kramer Rl, Johnson MP, Evans 

Mi. Multifetal pregnancy reductions of triplets 

to twins: comparison with nonreduced triplets 

and twins. Am J Obstet Gynecol; 1999 May; 

180(5):1268-71. 

9. s. Elsenbruch, s. Benson, M. Rücke, M. Rose, J. 

dudenhausen, M.K. Pincus-Knackstedt, B.F. Klapp, 

and P.c. arck. social support during pregnancy: 

effects on maternal depressive symptoms, smoking 

and pregnancy outcome Hum. Reprod.;2007; 22(3): 

869-877 first published online november 16, 2006 

doi:10.1093/humrep/del432. 

10. american society for Reproductive Medicine 

and the Practice committee of the society for 

assisted Reproductive technology. guidelines 

on number of embryos transferred. Fertility and 

Sterility: 2009 november; 92(5):1518-9.

POst-tEst 

instructions for credit 

Please complete the below posttest 

and evaluation. Fax or mail the 

completed form as indicated on the 

last page. You must answer 70% of the 

questions correctly in order to receive 

your certificate. Your certificate will be 

sent via email. if an email address is not 

provided, your certificate will be sent 

via mail. if you do not receive a passing 

score, you will be contacted and given 

the opportunity to retake the test. 

1. the most appropriate treatment plan to 

minimize the risk of high-order multiple 

gestation in a patient with unexplained 

infertility undergoing gonadotropin 

therapy and planned intrauterine 

insemination (iUi) with 5 follicles > 15 mm 

in mean diameter is to: 

A. administer hcg, cancel the iUi and 

recommend timed intercourse 

B. cancel the cycle and restart with a 

lower dose 

C. administer hcg administration and 

perform intrauterine insemination 

D. cancel the cycle and instruct the 

patient to also avoid intercourse 

E. B and d 

2. Risk factors for ovarian 

hyperstimulation syndrome include all 

of the following, except: 

A. Prior twin pregnancy 

B. High serum aMH level 

C. Polycystic ovary syndrome 

D. antral follicle count greater than 14 

3. Based on current american society 

for Reproductive Medicine (asRM) 

guidelines, how many embryos should 

be transferred into a 33-year-old woman 

undergoing her first iVF cycle who has 

five excellent quality blastocyst stage 

embryos? 

A. One 

B. two 

C. three 

D. the guidelines do not address this 

situation and the decision should be 

based on patient preference. 

4. Which of the following issues should 

be taken into account when counseling 

patients regarding a multiple birth? 

A. age 

B. Quality and availability of gametes 

C. Overall patient health 

D. support system 

E. Patient’s religious and moral views 

F. Ramifications of preterm labor and 

birth 

G. all of the above 

5. Please rate your confidence in the 

following steps in the management of 

couples affected by subfertility and 

infertility. (5 = extremely confident, 

1 = not at all confident, n/a = not 

applicable) 

A. diagnosis 5 4 3 2 1 n/a 

B. coming up with treatment options 

5 4 3 2 1 n/a 

6. How often do you discuss the 

following, with patients who are looking 

to conceive via assisted Reproductive 

technology (aRt)? (5 = always, 

1 = never, n/a = not applicable) 

A. Patient expectations 

5 4 3 2 1 n/a 

B. the risk of multiple births 

5 4 3 2 1 n/a 

C. Reality of emotional investment to 

patient 5 4 3 2 1 n/a 

D. cost to patient 

5 4 3 2 1 n/a 

7. Based on this article, what two new 

patient care strategies do you plan to use 

that you have not used before? 

8. What challenges or barriers might you 

face as you work to implement these 

strategies? 

16

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* your CME certificate will be sent via 

email. If an email address is not provided 

to the right, your certificate will be sent 

via mail. 

r e l e a s e date 9.19.2011 

e x p i r a t i o n date 9.19.2012 

answer each question using a scale of 5-1 

(5 = strongly agree, 3 = agree, 1 = strongly disagree) 

1. the articles met the stated objectives. 5 4 3 2 1 

2. the articles are relevant to my current clinical practice needs. 

5 4 3 2 1 

3. disclosure of faculty relationships with commercial organizations was 

made available to me before the articles. 

true False 

4. the commercial supporters were acknowledged in print. 

true False 

5. the articles were balanced and free of commercial bias. 

true False 

6. if trade names were used, all product trade names were discussed. 

true False 

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by the Fda was disclosed before or during the activity. 

true False 

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details below. 

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Join us for this year ’s Stages in Women’s Health conference! 

This multi-day curriculum will provide healthcare professionals with a robust review 

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