Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
1
Infertility: Protocols and Patient Management
Module 3
Ann Scalia, BSN, RN, CNORManager‐Clinical Education Specialists
Mary Vietzke, BSN, RNSenior Clinical Educational Specialist
Walgreens
Faculty
Ann Scalia, BSN, RN, CNORManager‐Clinical Education Specialists
Mary Vietzke, BSN, RNSenior Clinical Educational Specialist
It is the policy of ProCE, Inc. and NASP to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation.
Disclosure: Ann Scalia and Mary Vietzke are employees of Walgreens.There will be discussion regarding off‐label use of medications during this activity.
2
Objectives
• Discuss recommended appropriate non‐pharmacologic and pharmacologic plans to address infertility
• Identify monitoring parameters for a patient undergoing treatment for infertility
• Discuss the different commonly used medication protocols used in an ART cycle
Infertility Treatments
Varies depending on:• Evaluation outcomes• Day of cycle• Goals of treatment
3
Surgical Pretreatments
• Transvaginal cyst removal
– Rescued corpus luteum
– Large anovulatory follicle(s)
– Endometrioma (“Chocolate cyst”)
• Laparoscopy
– Fibroids
– Adhesions
– Endometriosis
– Hydrosalpinx
Song Xm, et al. Journal of Obstetrics and Gynaecology Research. 2017;43(1):122‐127.Karasu T, Ola B. Reproductive Surgery in Assisted Conception: Springer; 2015:37‐41.
Menstrual Cycle
Luteal PhaseFollicular Phase
Day 1 Day 28Day 14 Day 20‐24
FollicularRecruitment LH Surge
Day 7
Selection ofDominant Follicle
Window of Receptivity for implantation
Speroff , Fritz . Clinical Gynecologic Endocrinology and Infertility. 2005:188.Stauss, Barbieri. Yen & Jaffe’s Reproductive Endocrinology: physiology, pathophysiology, and clinical management. 2014: 159‐160.
4
Non‐Pharmacologic Treatment Cycles
• Natural cycle + timed intercourse
• Natural cycle + Intrauterine insemination (IUI)
Non‐pharmacologic
Biological Markers
• Menstrual cycle
• Cervical mucus
• Basal Body Temperature (BBT)
• Urinary hormones
Pasha H, et al. Iranian journal of reproductive medicine. 2013;11(6):495Martin PL. American journal of obstetrics and gynecology. 2016;46:53‐62
5
Luteinizing Hormone (LH) Levels
• One‐step urinary kits that measure LH
• Easy to use at home
• Used clinically for timing for intercourse or intrauterine inseminations
Martin PL. American journal of obstetrics and gynecology. 2016;46:53‐62
Intrauterine Insemination
• Treatment and monitoring is similar to timed intercourse
• Sperm sample is specially prepared
• Sperm are introduced into the uterine cavity via a catheter
• Used to help overcome negative cervical mucus environments or mild male factor
Martin PL. American journal of obstetrics and gynecology. 2016;46:53‐62
6
Cervical Mucus Changes During Ovulation Phase
BeginningEstrogen causes cervical mucus production
GrowthDominant follicle maturation and estrogen production increases
PeakThe corpus luteum produces progesterone which dries up the mucus and causes the temperature rise
EndThis is the after window of receptivity
Martin PL. American journal of obstetrics and gynecology. 2016;46:53‐62
Non‐IVF Ovulation Induction and
Controlled Ovarian Stimulation(COS)
7
Controlled Ovarian Stimulation (COS)
• Carefully monitored stimulation of ovaries to produce multiple follicles (which contain eggs)
• First step in IVF process
• Protocols designed to decrease risk of OHSS
• Generally involve 3 classes of medications
– GnRH analogs (agonist or antagonist)
– FSH or FSH containing LH gonadotropin
– hCG final maturation of eggs inside the follicle
Assisted reproductive technologies: a guide for patients. American Society for Reproductive Medicine Web site.http://www.asrm.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_Info_Booklets/ART.pdf
Monitoring Methods
• Transvaginal Ultrasound Scans
– Follicular diameter and count
– Endometrial thickness
• Hormone Assay
– Estrogen levels (baseline and during COS)
– LH levels (baseline)
– FSH levels (baseline)
– Progesterone levels (specific days of cycle)
Assisted reproductive technologies: a guide for patients. American Society for Reproductive Medicine Web site.http://www.asrm.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_Info_Booklets/ART.pdf
8
Follicular Ultrasound Monitoring• Follicle growth documentation
• Results plotted to observe progression of growth
• Allows for the most accurate assessment for hCG administration
• Other documentation
– Early signs of OHSS such as abdominal fluid, ovarian enlargement, too many follicles
– Ovarian pathology such as endometriomas or other cyst
Assisted reproductive technologies: a guide for patients. American Society for Reproductive Medicine Web site.http://www.asrm.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_Info_Booklets/ART.pdf
Hormone Assay• Baseline done around cycle‐day 3
– Estrogen, (FSH, LH and progesterone levels may also be evaluated)
– Helps decision of dose and type of gonadotropin
• Throughout ovarian stimulation
– Estrogen levels
• Assess ovarian response
• Dosage adjustments
• hCG Administration
– Based on estrogen levels with ultrasound
Assisted reproductive technologies: a guide for patients. American Society for Reproductive Medicine Web site.http://www.asrm.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_Info_Booklets/ART.pdf
9
Monitoring for COS
• Transvaginal Ultrasound
– Follicle diameter 16‐20mm (typical)
– Follicle count depending on patient
– Endometrial thickness >7mm
• Hormone Assay
– Estrogen (estradiol) levels coincide with follicle diameter and number
ASRM. Fertil Steril. 2015;103(6):1379‐1618.
Protocol Guide
• Various protocols used
• Based on patient, type of cycle (non‐IVF, IVF) and physician preference
• Monitoring is required
• Avoid Ovarian Hyperstimulation Syndrome (OHSS)
• Goal is safe treatment to achieve birth of healthy singleton baby
Alper MM, et al. Reproductive biomedicine online. 2017.
10
Ovarian Reserve
Adapted from: Speroff. Clinical Gynecologic Endocrinology and Infertility. 8th ed.
Describes a woman’s reproductive potential with respect to ovarian follicle
number and oocyte quality
Response TypesNormal Responder
• Typically 10‐20 follicles
• Normal ovarian function
• Good prognosis (but still limited by maternal age)
Poor/Low Responder
• Usually <4 follicles
• Typically related to “ovarian” age factor
• Possible increased chance of poor outcome
Hyper/High Responder
• Typically >20 follicles
• Some women at higher risk
• “Low and Slow” approach
La Marca A, et al Human reproduction update. 2013:037.
11
Oral Contraceptive Pills (OCP)• Oral contraceptive pills, may be prescribed to regulate a
patient’s menstrual cycle
• In an ART cycle:
– Used to “suppress or downregulate” activity in the ovaries in the prestimulation phase
– Allows manipulation of the patient's cycle to fit into a set schedule (Batching)
• Combination hormonal OCP
– Progestin component of a combination pill prevents ovulation by inhibiting gonadotropin secretion of LH; also alters endometrium
– Estrogenic component suppresses FSH
Stauss, Barbieri. Yen & Jaffe’s Reproductive Endocrinology: physiology, pathophysiology, and clinical management. 2014: 895.
GnRH Analogs
GnRH Agonists• Binds to a receptor and exhibits
a desired response
GnRH Antagonists• Binds to a receptor and inhibits
another molecule from binding to the receptor, thus inhibiting the desired response
Leuprolide Acetate Cetrotide®
Ganirelix Acetate
GnRH
Prapas Y, et al. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1):43-46.
12
Downregulation and Flare Effect• Downregulation
– Process of decreasing cells sensitivity to specific hormones
– Specific drugs “turns off” ovaries temporarily gaining control over ovarian function
• Flare Effect
– Initial "flare‐up" response (FSH and LH release) from pituitary gland occurs first 3 days of agonist administration
– Continuing agonist > 3 days temporarily suppresses pituitary gland
Prapas Y, et al. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1):43-46.
GnRH Agonist
• Loss of response to continued stimulation
• Downregulation of GnRH receptors
• Uncoupling of GnRH receptors from intracellular signaling mechanisms
FollicularLuteal
E 2 , P4 LH, FSH
0
10
20
30
DaysStart Administration
Flare Effect
Prapas Y, et al. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1):43-46.
13
GnRH Antagonist E 2
, P4 LH, FSH
0
10
20
30
Start Administration
Hours
NO Flare Effect
Prapas Y, et al. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1):43-46.
Gonadotropins
FSH and/or LH injectable medications
Two
formulations
Urinary extractsRecombinant
FSH
ASRM. Medications for Inducing Ovulation: Patient Information Series: 2012:1‐10.
14
Human Chorionic Gonadotropin (hCG)
• Pregnyl®
– Urinary derived
• Novarel®
– Urinary derived
• Generic hCG
– Urinary derived
• Ovidrel®
– Recombinant technology
CHORIONIC GONADOTROPIN [prescribing insert]. Fresenius, Kabi, Lake Zurich, IL February 2016.Pregnyl® (chorionic gonadotropin for injection) [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc.; January 2015. OVIDREL® PreFilled Syringe (choriogonadotropin alfa injection) [prescribing information]. Rockland, MA: EMD Serono, Inc., September 2014. NOVAREL® (chorionic gonadotropin for injection) [prescribing information]. Parsippany, NJ: Ferring Pharmaceuticals Inc.; September 2016.
Human Chorionic Gonadotropin (hCG)
• Referred to as a “trigger” shot
• Mimics LH surge for final oocyte (egg) maturation
• Very time‐sensitive medication
• Ovulation occur within 36‐40 hours after injection
• Egg retrieval is scheduled 36 hours after injection
• Too soon or too late will negatively impact cycle
resulting in cancellation
Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.
15
Leuprolide Trigger
• Alternative type of trigger that may be ordered by a fertility office if the patient is responding too well to medications
• May also be referred to as “Lupron” trigger
• Pituitary gland is capable of producing an LH surge sufficient for maturation of follicles in response to a Leuprolide trigger as long as premature ovulation was being prevented by the use of an antagonist like Ganirelix or Cetrotide
Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.
Leuprolide trigger protocol
• Most common dosages in a prefilled syringe or vial
• 1 mg (20 units)
• 2 mg (40 units)
• 4 mg (80 units)
• 5mg (100 units)
• Some physicians in addition may order a small amount of hCG (such as 1000 or 1500 units) along with the Leuprolide injection to reduce the risk of inadequate maturation of follicles and still keep the risk for OHSS low
Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.
16
• May be prescribed for additional support for the uterine lining, embryo implantation and resulting pregnancy
• Used in IVF cycles, before and after a frozen embryo transfer and in pregnancy
• Available formulations:
– Estradiol valerate injection (intramuscular injection)
– Estradiol tablets (oral and occasional inserted vaginally)
– Estradiol patch (Estradiol transdermal system)
Endometrial Support: Estrogen
Role of Progesterone
• Progesterone for luteal phase support of the endometrium is needed in stimulation cycles
• Used to build up lining of endometrium for successful implantation
• Administration begins the day of egg retrieval and continues until pregnancy test
• If pregnancy occurs the patient will continue on progesterone support
Stauss, Barbieri. Yen & Jaffe’s Reproductive Endocrinology: physiology, pathophysiology, and clinical management. 2014: 704‐706Lockwood G, Griesinger G et al. Fertil & Steril. 2014;101(1):112‐113.
17
Non‐IVF Ovulation Induction / Stimulation
Day 1 Day 28
Clomiphene Citrate / Letrozole Non‐IVF
Start eitherClomiphene Citrate/
LetrozoleDays 3‐7. 4‐8, 5‐9
LH monitoring Possible hCGinjection
Menses
IUI / intercourse 36‐40 hrs after positive LH kit or hCG injection
Day 7 Day 14
Follicular Phase
Al‐In any H, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:260.
Luteal Phase
Stimulation 5 Days Progesterone support
Pregnancy test ~14 days after IUI or intercourse
18
Gonadotropin Stimulation~10 Days
Day 1 Day 28
Gonadotropin Protocol Non‐IVF
Start gonadotropin stimulation Cycle Day 3
hCGinjection
Menses
IUI or intercourse 36‐40 hrs after hCG
injection
Luteal Phase
Day 7 Day 14
Follicular Phase
Al‐In any H, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:260.
Progesterone support
Pregnancy test ~14 days after IUI or intercourse
IVF Cycle Protocol Phases
Prestimulation Downregulation Phase
Stimulation Phase
Supportive Phase
• Starts with cycle day one of menses
• Baseline monitoring• Ovarian suppression
• Oral contraceptive pills (OCP)
• GnRH agonist
• Baseline monitoring • Start of gonadotropin
stimulation medications• Development of ovarian
follicles• Control premature LH
surge with GnRH analog• Periodic monitoring with
blood assays and transvaginal ultrasounds for medication adjustments
• “Trigger” shot • Egg retrieval
• Sometimes referred to as “Luteal Phase Support”
• Focused on uterine environment for embryo(s)
• Embryo/Blastocyst Transfer
• Medication support • Progesterone • Estrogen
19
Supportive Phase
Embryo transfer
• The ET procedure is the last one of the IVF process.
• Critically important to choose the best quality embryo.
• Either day 2 or 3 after oocyte retrieval
Blastocyst transfer
• Transferred on day 5 of oocyte retrieval.
• ↑ Chance of selecting best quality embryo for ↑ chance at pregnancy.
• ↑ eSET
Freeze all
• Center preference
• Option for those with OHSS
• Banking embryos for future use
ASRM. Fertil Steril. 2012;97 (4):835‐842.
Ovarian Stimulation Protocols• Most commonly used
– Long Luteal (GnRH Agonist Downregulation)
• Oral Contraceptives optional
– GnRH Antagonist
– Oral Contraceptives optional
• Poor/Low responders/Advanced Maternal Age (AMA)
– Microdose Flare
– GnRH Antagonist
– Luteal Estradiol Protocol (Estrogen Priming)
– Mild Stimulation Protocol (Clomiphene Citrate Priming)
• Hyper/High responders
– Long Luteal (GnRH Downregulation)
20
Long Luteal Protocol
Leuprolide Acetate0.5 (10U) or 1.0 (20U) mg/day
Leuprolide Acetate0.25 (5U) or 0.5 (10U) mg/day
Progesterone Hormone Assay ~Cycle Day 21
Day 21
Menses
Gonadotropin stimulation~10 Days hCG
Injection
Egg Retrieval 36 hrs after hCG injection
Prestimulation Downregulation Phase Stimulation Phase
Alper MM, et al. Reproductive biomedicine online. 2017.Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.Fukuda A. Ovarian Stimulation Protocols: Springer; 2016:113‐119.La Marca A, et al. Human reproduction update. 2013:dmt037
Baseline Monitoring
Long Luteal Protocol Using Oral Contraceptive Pills (OCPs)
Leuprolide Acetate0.5 (10U) or 1.0 (20U) mg/day
Leuprolide Acetate 0.25 (5U) or 0.5 (10U) mg/day
Menses
Start OCPs first week mensesminimum of ~14 days
Prestimulation Downregulation Phase
Menses
Stimulation Phase
Gonadotropin stimulation~10 Days
Egg Retrieval 36 hrs after hCG injection
Start Leuprolide Acetate Overlap OCPs for 3 days
Alper MM, et al. Reproductive biomedicine online. 2017.Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.Fukuda A. Ovarian Stimulation Protocols: Springer; 2016:113‐119.La Marca A, et al. Human reproduction update. 2013:dmt037
Baseline Monitoring
hCG
21
GnRH Antagonist Protocol
GnRH Antagonist start when
dominant follicle ~12‐14 mm
hCG
~Stimulation Day 5 First monitoring check
GnRH Antagonist continued daily
Menses
Egg Retrieval 36 hrs after hCG injection
Stimulation Phase
Alper MM, et al. Reproductive biomedicine online. 2017.Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.Fukuda A. Ovarian Stimulation Protocols: Springer; 2016:113‐119.La Marca A, et al. Human reproduction update. 2013:dmt037
Start gonadotropin stimulation Cycle Day 3
Gonadotropin stimulation ~10 Days
Baseline Monitoring
GnRH Antagonist Protocol Using OCPs
hCG
MensesMenses
Egg Retrieval 36 hrs after hCG injection
Prestimulation Downregulation Phase Stimulation Phase
Alper MM, et al. Reproductive biomedicine online. 2017.Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.Fukuda A. Ovarian Stimulation Protocols: Springer; 2016:113‐119.La Marca A, et al. Human reproduction update. 2013:dmt037
GnRH Antagonist start when
dominant follicle ~12‐14 mm
~Stimulation Day 5 First monitoring check
Start OCPs first week menses~14‐21 days
Baseline Monitoring
GnRH Antagonist continued daily
Gonadotropin stimulation ~10 Days
OCPs Stopped
22
Microdose‐Flare Protocol
Start Microdose Leuprolide Acetate 40 mcg or 50 mcg/10 units twice daily
after 3 days of no OCPshCG
MensesMenses
On third day of microdose Leuprolide acetate Start gonadotropins
Egg Retrieval 36 hrs after hCG injection
Prestimulation Downregulation Phase Stimulation Phase
OCPs Stopped
Alper MM, et al. Reproductive biomedicine online. 2017.Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.Fukuda A. Ovarian Stimulation Protocols: Springer; 2016:113‐119.La Marca A, et al. Human reproduction update. 2013:dmt037
Start OCPs first week menses~14‐21 days
Baseline Monitoring
GnRH Antagonist start when
dominant follicle 12‐15 mm
Stimulation Day 5 First monitoring
check
Luteal Estradiol Protocol
hCG
MensesMenses
Gonadotropin Stimulation
Egg Retrieval 36 hrs after hCG injection
Prestimulation Downregulation Phase Stimulation Phase
Alper MM, et al. Reproductive biomedicine online. 2017.Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.Fukuda A. Ovarian Stimulation Protocols: Springer; 2016:113‐119.La Marca A, et al. Human reproduction update. 2013:dmt037
Estradiol 1mg 2 tablets bid
Cycle Day 21 Start Estradiol
Baseline Monitoring
GnRH Antagonist continued daily
23
Mild Stimulation Protocol
Menses
Stimulation Phase
hCG
Ferraretti AP, et al Mild ovarian stimulation with clomiphene citrate launch is a realistic option for in vitro fertilization. Fertility and sterility. 2015;104(2):333‐338.
Start eitherClomiphene Citrate/ Letrozole
Days 3‐7 for 5 Days
Gonadotropin stimulation
Egg Retrieval 36 hrs after hCG injection
GnRH Antagonist start when
dominant follicle ~12‐14 mm
Day 5 of Gonadotropin
First monitoring check
GnRH Antagonist continued daily with IVF Cycle ONLY
Baseline Evaluation Cycle Day 3
Gonadotropin Stimulation Start Check
Supportive Phase: All Fresh IVF Protocols
Embryo/Blastocyst Transfer 3‐6 Days after Retrieval
Supportive Phase
hCG
Egg Retrieval 36 Hours after
hCG
Progesterone support started day of retrieval
Pregnancy Test ~14 Days after Transfer
Possible Estrogen support started day of retrieval
Alper MM, et al. Reproductive biomedicine online. 2017.Costello M, et al. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.Fukuda A. Ovarian Stimulation Protocols: Springer; 2016:113‐119.La Marca A, et al. Human reproduction update. 2013:dmt037
24
Frozen Embryo Transfer Protocol
Leuprolide Acetate0.5 (10U) or 1.0 (20U) mg/day
Leuprolide Acetate 0.25 (5U) or 0.5 (10U) mg/day
Menses
Day 15 of Estradiol Start Progesterone
Day 21
Fukuda A. Ovarian Stimulation Protocols: Springer; 2016:113‐119.La Marca A, et al. Human reproduction update. 2013:dmt037
Progesterone Hormone Assay ~Cycle Day 21
Baseline Monitoring
Estradiol 1mg 2 tablets bid or sliding scale
Endometrium Lining & Estradiol Level
Monitoring
Embryo/Blastocyst Transfer 3‐6 Days after Progesterone Start
In vitro fertilization (IVF)
Ovarian stimulation
(daily injections of fertility hormones) Retrieval of
oocytes/eggs
Eggs and partner or donated sperm
combined (through IVF)
in lab Fresh embryo transfer or freezing of
embryos/oocyte
ICSI to assist in fertilization
2017 Walgreens Co. All Rights Reserved
25
Prevention of Multiple Gestation
• The goal of any infertility treatment is a healthy SINGLE full term birth
• Number of embryos transferred impacts multiple gestation rates
• With non‐IVF treatments no control over how many eggs will fertilize
• IVF use of elective single embryo transfer (eSET) is increasing
Gerris J. Complications and Outcomes of Assisted Reproduction. 2017:33.
Review of Objectives• Discuss recommended appropriate non‐pharmacologic and pharmacologic plans to address infertility
– Thorough evaluation required so the best individualized plans of treatment can be utilized
• Identify monitoring parameters for a patient undergoing treatment for infertility
– Blood assay draws and transvaginal ultrasounds are required for all treatment protocols to minimize risk of developing OHSS
• Discuss the different commonly used medication protocols used in an ART cycle
– Many different protocols used and each protocol is applied individually to optimize positive outcome potentials
26
Thank You
References• Song Xm, Jiang H, Zhang Wx, Zhou Y, Ni F, Wang Xm. Ultrasound sclerotherapy pretreatment
could obtain a similar effect to surgical intervention on improving the outcomes of in vitro fertilization for patients with hydrosalpinx. Journal of Obstetrics and Gynaecology Research. 2017;43(1):122‐127.
• Karasu T, Ola B. Endometrioma and Infertility: Principles and Techniques of Management. Reproductive Surgery in Assisted Conception: Springer; 2015:37‐41.
• Mastroianni L, Jr., Laberge JL, Rock J. Appraisal of the efficacy of artificial insemination with husband's sperm and evaluation of insemination technics. Fertility and Sterility. 1957;8(3):260–26
• Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. 7th ed. Philadelphia, PA : Lippincott Williams & Wilkins; 2005:1143,1147‐1151.
• Stauss, Barbieri. Yen & Jaffe’s Reproductive Endocrinology: physiology, pathophysiology, and clinical management. 2014: 159‐160.
• Pasha H, Faramarzi M, Esmailzadeh S, Kheirkhah F, Salmalian H. Comparison of pharmacological and nonpharmacological treatment strategies in promotion of infertility self‐efficacy scale in infertile women: A randomized controlled trial. Iranian journal of reproductive medicine. 2013;11(6):495
• Martin PL. Detection of ovulation by the basal temperature curve with correlating endometrial studies. American journal of obstetrics and gynecology. 2016;46:53‐62.
27
References
• Alper MM, Fauser BC. Ovarian stimulation protocols for IVF: is more better than less? Reproductive biomedicine online. 2017.
• Costello M, Koch J, Ledger W. Recombinant LH, Recombinant hCG and GnRH Agonist to Trigger Ovulation: A Critical Evaluation. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.
• Fukuda A. Ovarian Stimulation for Poor Responders. Ovarian Stimulation Protocols: Springer; 2016:113‐119.
• La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Human reproduction update. 2013:dmt037.
• Prapas Y, Petousis S, Dagklis T, et al. GnRH antagonist versus long GnRH agonist protocol in poor IVF responders: a randomized clinical trial. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2013;166(1):43‐46
• Costello M, Koch J, Ledger W. Recombinant LH, Recombinant hCG and GnRH Agonist to Trigger Ovulation: A Critical Evaluation. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:454.
References• Al‐Inany H, El‐Mazny A. The Efficacy of Clomiphene Citrate in Preventing a Premature LH
Surge during Controlled Ovarian Stimulation with Human Menopausal Gonadotropins. Manual of Ovulation Induction & Ovarian Stimulation Protocols. 2016:260.
• Ferraretti AP, Gianaroli L, Magli MC, Devroey P. Mild ovarian stimulation with clomiphene citrate launch is a realistic option for in vitro fertilization. Fertility and sterility. 2015;104(2):333‐338.
• Gerris J. Minimizing Multiple Pregnancy After Assisted Reproductive Technology. Complications and Outcomes of Assisted Reproduction. 2017:33.
28
References Medications
• Fertility medication information: CLOMIPHENE CITRATE. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=be399623‐6400‐475d‐93d3‐1dedd4d43017. Updated March 2013. Accessed January 19, 2017.
• Fertility medication information: CRINONE®8%. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7def92fe‐d521‐41c0‐b419‐48e028f59f15 . Updated August 2014. Accessed January 19, 2017.
• Fertility medication information: ENDOMETRIN®. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2ba50fa9‐b349‐40cb‐9a4b‐1af8faa4ec09#section‐1 . Updated September 2016. Accessed January 19, 2017.
• Fertility medication information: FEMARA®. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82b77d74‐085f‐45ac‐a7dd‐1f5c038bf406. Updated January 2014. Accessed January 19, 2017.
• Fertility medication information: FOLLISTIM® AQ Cartridge. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=96f11b5d‐cc7b‐48aa‐830a‐a28e1962d871. Updated December 2014. Accessed January 16, 2017.
• Fertility medication information: GANIRELIX ACETATE Injection. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=96118395‐557e‐4998‐842d‐424a59d574b6. Updated March 2016. Accessed January 19, 2017.
References Medications
• Fertility medication information: GONAL‐f®Multi‐Dose. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae85b9c3‐e7eb‐4981‐a5d9‐346050e8f189. Updated April 2013. Accessed January 19, 2017.
• Fertility medication information: GONAL‐f RFF®Redi‐ject. DailyMed Web site. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b6d11c45‐b502‐478e‐bb28‐2ff596ea259c. Accessed January 19, 2017.
• Fertility medication information: LETROZOLE. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4818abc4‐2797‐4248‐b7d7‐5cb4b5cdcf6a#section‐1 . Updated October 2014. Accessed January 19, 2017.
• Fertility medication information: LEUPROLIDE ACETATE. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8bd72c1e‐2751‐4498‐a346‐bc5e3acbba0b. Updated January 18, 2017. Accessed February 10, 2017.
• Fertility medication information: NOVAREL®. DailyMed Web site. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac6918ff‐9dc3‐40d9‐8619‐54b26e4bdfc8 . Updated September 2016. Accessed January 19, 2017.
• Fertility medication information: PREGNYL® (chorionic gonadotropin for injection USP) https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e26b843‐9c7a‐4517‐a1b6‐9362aab0b86c. Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc. Updated January 2015. Accessed January 19, 2017.