Clinical trial NCT02866643
Conditions: Postpartum Contraception Family Planning
Keywords: contraceptive implant postpartum contraception breastfeeding and contraception
Sponsor: Stanford University
Start date: 2016-10-28; Completion date: 2021-07-31
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A barrier to initiating progestin contraceptives in the early postpartum period is the concern of interference with breastfeeding, specifically lactogenesis. In this trial, the investigators aim to describe the effects of immediate insertion of the contraceptive implant on breastfeeding. The investigators seek to examine the time to lactogenesis with immediate post-delivery insertion in delivery room versus insertion of a contraceptive implant in the postpartum ward prior to medical discharge. For this study, 82 consenting women will be randomized to immediate implant insertion (0-2 hours following delivery) in the delivery room or insertion of the implant following delivery in postpartum room and prior to medical discharge (24-48 hours following delivery).

Participants complete a questionnaire that asks questions about breastfeeding continuation, supplementation, duration, and exclusivity. This questionnaire also includes questions about contraceptive continuation, patient satisfaction with implant, pregnancy, and postpartum care visits.

Detailed description:

Arms: arm 1: Participants who randomize to this arm will receive the contraceptive implant in the Labor and Delivery room (0-2 hours following delivery). arm 2: Participants who randomize to this arm will receive the contraceptive implant in the postpartum ward room before discharge (24-48 hours following delivery).
Interventions: intervention 1: Etonogestrel-Immediate intervention 2: Etonogestrel-Delayed
Intervention descriptions: intervention 1: The investigational intervention will be to insert the contraceptive implant immediately postpartum in the delivery room insertion (0-2 hours following delivery). intervention 2: The investigational intervention will be to insert the contraceptive implant 24-48 hours following delivery.

Protocol documents:
Prot_SAP_000.pdf: 
NCT02866643 
 
December, 27 2016 
 
 
 
 
 
 
 
 
 
 
Labor and Delivery Implant Insertion (LADII)  
 
Griselda Velasquez 
, MPH  
Kate A. Shaw, MD, MS 
Stanford University  
 
 
 
 
 
Phone: 
 
Email: 
 
 
 
 
 


Project Summary:  
 
Investigating the timing to lactogenesis stage II (defined as the initiation of copious 
milk secretion) in women who obtain the contraceptive implant in delivery room versus 
the postpartum ward will add important data to the literature. If insertion in this time 
period is found to be without negative effects on breastfeeding the study findings 
would facilitate earlier insertion of the contraceptive implant, in the delivery room. 
Gurtcheff et al. recently analyzed time to lactogenesis in women initiating the 
contraceptive implant prior to medical discharge following delivery and 4-8 week 
postpartum and found no difference. In the proposed study, we seek to add to the 
literature by investigating immediate post-delivery insertion in the delivery room of the 
contraceptive implant versus insertion prior to medical discharge in the postpartum 
ward.  
 
We propose a non-inferiority randomized controlled trial comparing time to 
lactogenesis stage II in healthy women with immediate insertion (0-2 hours following 
delivery) of the contraceptive implant in the delivery room versus in women with 
insertion of the contraceptive implant following delivery in the postpartum room and 
prior to medical discharge (24-48 hours following delivery). We hypothesize there will 
be no significant difference in time to lactogenesis with immediate delivery room (0-2 
hours following delivery) vs. postpartum ward insertion (24-48 hours). In addition, we 
plan to follow women postpartum to evaluate breastfeeding continuation and 
exclusivity, discontinuation of the implant and any adverse events.  
 
Description of the Project: 
 
1.1 Rationale:   
Over half of the 6.1 million pregnancies each year in the United States are reported as 
unintended. [1] More interventions are needed to prevent unintended pregnancies, as 
they are associated with higher maternal and child morbidity and mortality. [2] Infants 
conceived by women less than six months postpartum are at increased risk of poor 
perinatal outcomes such as being small for gestational age and being born preterm. [3] 
Additionally, both unintended pregnancy and a short inter-pregnancy interval are 
associated with delayed and insufficient prenatal care. [4] Gemmill et al. (2013) 
investigated the prevalence and correlates of short inter-pregnancy intervals in the 
United States. These authors documented that one third of pregnancies conceived in a 
nationally representative sample were within 18 months of a previous birth (n=2253). 
After adjusting for sociodemographic and childbearing characteristics, women were 
significantly more likely to have a short inter pregnancy interval if they were ages 15-19 
years old. [5] 
 
Further, pregnancies of adolescents (ages 10-18) and young women (ages 19-24) are 
very unlikely to be planned pregnancies. In fact, 82% of pregnancies were unplanned in 
the 15-19 age range. Robust data demonstrates that adolescent and young mothers are 
at high risk of becoming pregnant within 12 months of delivery--these mothers have a 


higher risk of preterm birth, low birth weight and neonatal mortality compared to their 
adult counterparts. 
 
There is evidence of adolescents who experience repeat pregnancy have poorer 
educational attainment and lower rates of employment than adolescents that do not 
have a repeat pregnancy. We also have data that young mothers who initiate LARC are 
less likely to have repeat pregnancies than those who decline postpartum 
contraception [6]. 
 
A 2015 survey of postpartum women about future pregnancy intention and 
contraception plans found the majority (n=237, 96.7%) of women did not desire 
pregnancy in the next year.  [7]  
 
Many women have already ovulated and resumed sexual intercourse by 6 weeks 
postpartum [8] and upwards of 40% of women do not return for postpartum care. [9] 
The majority of providers wait until the six week postpartum visit to initiate 
contraception—this delay in contraceptive uptake puts women at risk of an unintended, 
short interval pregnancy.  An opportune time to facilitate contraception initiation is in 
the immediate postpartum period following delivery and prior to hospital discharge. 
Providing women with contraception they need during this time is convenient and cost 
effective for the patient, provider, and health care system. [10] In the 2015 survey of 
postpartum women, 42.8% (n=107) indicated that if the implant or intrauterine device 
could be inserted before they left hospital, they would choose these methods 
(p<0.0001). [7]  
 
A 2009 CDC study analyzed the prevalence and types of contraception used by 43,887 
women 2-9 months postpartum and found that 88% reported use of at least one 
contraceptive method, with 61.7% using a highly effective method, defined as: <10% of 
women experience an unintended pregnancy; includes sterilization, intrauterine device, 
shot, pill, patch, and ring. [11]  
 
This same study demonstrated that women with no prenatal care had the lowest rates 
of using at least one method (76.9%) and had a low rate of using highly effective 
contraceptive methods (54.5%). Based on these data, the promotion of highly effective 
contraception, especially among women with no prenatal care, should be prioritized 
and immediate postpartum initiation of a highly effective method could be the 
solution. [11]  
 
The World Health Organization (WHO) and the CDC have distinct recommendations 
with regard to early administration of the contraceptive implant.  By the CDC Medical 
Eligibility Criteria for Contraceptive Use, the etonogestrel implant is classified as a 
Category 2 method for breastfeeding women at less than 1 month postpartum, 
indicating this is a method for which advantages generally outweigh any theoretical or 
proven risks. [12] However, the 5th edition of the WHO Medical Eligibility Criteria for 
Contraceptive use classifies the implant as category 2, indicating “generally use, some 


follow-up may be needed” for women breastfeeding at less than 1 month postpartum. 
[13] These slightly different recommendations may have an impact on the availability of 
progestin-only methods for women in the postpartum period. More information is 
needed on the impact of the implant on breastfeeding immediately postpartum in 
order to inform improvements in service delivery and family planning interventions, 
both domestically and internationally.  
 
In addition to this, a barrier to initiating progestin contraceptives in the early 
postpartum period is the concern of interference with breastfeeding, specifically 
lactogenesis. A study looking at lactation consultants’ knowledge about postpartum 
contraception and impact on breastfeeding documented disconnect between the 
Centers for Disease Control (CDC) United States Medical Eligibility Criteria for 
Contraceptive Use (US MEC) guidance and lactation consultants' knowledge regarding 
the safety of immediate postpartum contraception. [14] Providing different 
recommendations amongst health care providers and lactation consultants may lead to 
confusion for patients—conflicting opinions regarding their contraceptive method may 
result in less women leaving the hospital without a method of contraception.  
 
Duvan et al. (2010) showed that if women are well-informed regarding the side effects 
of the contraceptive implant, women find that it is an acceptable form of reversible 
contraception in the postpartum period. [15] The pharmacokinetic profile of the 
etonogestrel implant shows a peak serum concentration of approximately 1,000 pg/mL 
on day 4 after insertion. Thus insertion immediately postpartum should not interfere 
with lactogenesis, as there would still be a drop in progesterone that would allow for 
lactation induction to occur following delivery. [16], Appendix A  
 
The initiation of the contraceptive implant at 4-8 weeks postpartum has been studied in 
breastfeeding women; no change in volume or composition of breast milk was found. 
[17] A study looking at growth of breastfed infants found that at three year follow up, 
child growth and development was no different between users of implant and copper 
intrauterine device (IUD). [18] Additionally, Brito et al. (2009) documented no 
diminished weight gain in infants of women who were exclusively breastfeeding and 
obtained a contraceptive implant at 6 weeks postpartum. [19] The literature 
demonstrates immediate contraceptive implant insertion does not alter volume of 
breast milk intake by newborns. Braga et al. (2015) evaluated breast milk volume when 
the ENG implant was inserted immediately postpartum and found no difference in the 
median breast milk intake by newborns between women who were randomized to have 
the implant inserted within 48 hours after delivery and those who obtained no method 
of contraception. The study also documented similar weights of newborns between 
both groups at six weeks following delivery, adding to safety data on effects of 
immediate insertion on breastfeeding. [20] 
 
Objectives and hypotheses:   
 
This is a non-inferiority randomized controlled trial:  


 
Our objective is to determine whether time to lactogenesis stage II differs between 
immediate delivery room insertion (0-2 hours following delivery) and delayed 
postpartum insertion (24-48 hours following delivery) of the contraceptive implant in 
the postpartum ward prior to medical discharge. We hypothesize there will be no 
significant difference in time to lactogenesis stage II between the two groups. 
 
Design & Methodology:  
 
This is a non-inferiority randomized controlled trial.  
 
Peripartum women with healthy, term newborns who plan to use the contraceptive 
implant (etonogestrel implant, Nexplanon) for postpartum contraception and 
intend to breastfeed will be randomized to receive: 
 
• Arm 1: Immediate delivery room insertion (0-2 hours following delivery)  
• Arm 2: postpartum room insertion (24-48 hours following delivery) 
 
The primary outcome is time to lactogenesis stage II (defined as the initiation of 
copious milk secretion) as documented by maternal perception by a validated tool. 
[21]   
 
Secondary outcomes include breastfeeding continuation and exclusivity, contraceptive 
continuation, patient satisfaction, pregnancy rates, timing and number of follow up 
postpartum care visits.  
 
Data will be collected on time of exclusive breastfeeding in days, supplementation 
rates, side effects (irregular menstrual periods, changes in appetite, nausea, acne, 
headache) continuation or change of contraceptive method, dates of follow up 
postpartum care visits, subsequent pregnancies and user satisfaction. These data will 
be collected in the week following insertion, at 4-8 weeks, 3, 6, and 12 months following 
insertion with telephone interviews or online questionnaires.  
 
Recruitment methods will take place in the clinical setting through chart review and 
provider referral. We will also use flyers placed on public announcement boards on 
campus and wherever permitted in the hospital.  
 
Study Procedures:  
 
Eligible women will be screened and identified via chart review, in the pre-natal 
obstetric clinic, and labor and delivery ward (L&D) at Stanford University by research 
study staff.  If patients meet criteria, the treating physician will initially approach and 
inform patients about the study. If a patient is interested, the treating physician will 
notify research staff and the patient will be approached by research personnel to 
discuss participation. If a treating physician has identified a patient who may be eligible 


for study recruitment and physician confirms that patient agrees to be contacted by 
phone, we will call the patient and conduct a telephone screening interview (please see 
attached materials) and will recruit the patient in person at their next prenatal visit or 
when admitted to Labor and delivery, prior to delivery. 
 
Patients will be counseled about risks and benefits of contraceptive options and will be 
counseled appropriately regarding risks and benefits of subdermal contraception 
implant, as well as the unknown effects of early progestin administration on 
breastfeeding. Patients will not be eligible for the study unless they have been 
consented for a postpartum contraceptive implant prior active labor. If the patients 
meet inclusion criteria they will be invited to participate in the study and consent will be 
obtained. When a study patient is admitted to L&D, they will be met by research 
personnel and be randomized to one of the two arms. Participants will be randomized 
through block randomization—allocation will be sealed in an opaque envelope. The 
patient, provider, and research staff will be aware of arm allocation, this is not a blinded 
study. At this time, baseline data will be collected on patient age, gravidity, parity, 
breastfeeding experience on REDCap with a designated Ipad.  
 
Trained providers will use standard protocol to place the contraceptive implant either in 
delivery room or in postpartum ward after delivery. We will collect information on the 
timing of delivery and the time of implant insertion.  A card indicating date of insertion 
and expiry date will be given together with post insertion instructions on wound care. 
Participants will be monitored daily by the research staff, in the first seven days 
postpartum, or until lactogenesis reported, beginning at 24-hours following delivery, to 
determine time to lactogenesis stage II using a validated tool. [21] Patients will be 
asked: “Has your milk come in yet?” and “When did your milk come in?” If the patient 
answers yes to first question the response will be recorded to the nearest hour. 
Participants will be asked: “How many times have you tried to breastfeed before your 
milk came in? Delayed lactation will be defined as no lactation by 72-hours following 
delivery. Lactation failure will be defined as no lactogenesis by 120-hours following 
delivery. Post-discharge follow-up questionnaires will involve telephone interviews, 
text messaging, electronic communication as needed, until lactogenesis occurs and at 
4-8 weeks, 3, 6, and 12 months.  Participants will be asked about length of exclusive 
breastfeeding, supplementation rates, side effects, continuation or change of 
contraceptive use (including abstinence or withdrawal), dates of postpartum medical 
visits, pregnancy, satisfaction with the contraceptive implant, resumption of vaginal 
intercourse, and infant weight. Once the participant completes the 12 month follow up 
questionnaires, they will have completed the study.  
 
Criteria for selection of subjects:  
 
Exclusion criteria:  
 


Contraindication to implant insertion such as history of breast cancer.  Hypersensitivity 
to any components of implant. Women who are not English or Spanish speakers or 
fluent in either language. Women who delivery infants that are not healthy.  
 
Inclusion criteria: 
 
• Pregnant women who are patients of the Stanford University Obstetrics service 
• Pregnant women who delivery a healthy infant, regardless of gestational age.  
• Intend to breastfeed  
• Desire the contraceptive implant as their method of contraception  
• Agree to be randomized to delivery room vs. postpartum ward insertion  
 
 
 
Description of the drugs & devices to be studied:  
Not applicable.  
 
Follow up procedure: 
Participants will receive brief telephone follow-up, including an interview at 4-8 weeks, 
3, 6, and 12 months from date of delivery.  
 
Criteria for discontinuation: 
Participants who experience complications during labor and delivery or whose infants 
have medical problems will be discontinued. Patients who change their mind about 
contraceptive implant use will be discontinued. Intention to treat analysis will be 
employed.  
 
Lab and other investigations: 
Not applicable.  
 
Data Management  
Data will be collected on REDCap software, will be coded, monitored, and verified.   
 
Data Analysis  
SPSS version 23 will be used for data analysis.  
 
Number of subjects and statistical power: 
Based on previous reports of women with uncomplicated vaginal deliveries, mean time 
to lactogenesis stage II is 54 hours with a standard deviation of 12 hours. [21] If there is 
truly no difference between immediate insertion and delayed insertion of the 
contraceptive implant on time to lactogenesis stage II, then 68 patients are required to 
be 80% sure that the lower limit of a one-sided 95% confidence interval (or equivalently 
a 90% two-sided confidence interval) will be above the non-inferiority limit of a mean 
difference of 12 hours (alpha 5%; SD 18). Sealedenvelope.com was used to calculate 


sample size based on these parameters. A non-inferiority margin of 12 additional hours 
is chosen to be relevant because common medical interventions like epidural 
anesthesia, cesarean section, labor induction, have been to delay stage II lactogenesis 
by up to 12 hours. [22] To account for potential participant dropout, 82 participants will 
be recruited.   
 
Study limitations:  
This is not a blinded study; appropriate blinding would require the use of placebo 
implants and additional procedures. We do not anticipate our inability to blind 
participants and providers to impact our primary outcome of time to lactogenesis stage 
II.    
 
Our recruitment will be limited to the Stanford Obstetrics and Gynecology service. 
Thus internal validity will not be a concern, but this clinic’s population is not 
representative of the diversity of the female population in the United States or of 
women giving birth in the United States.    
 
Based on this study’s inclusion and exclusion criteria, results cannot be extrapolated to 
women with some medical conditions, complications, during labor and delivery, or who 
have infants with medical problems.  
 
Duration of project:  
Project completion is expected in 21 months. 9 months for recruitment, enrollment, 
and data collection, 12 months for follow up phone call, data analysis, and manuscript 
writing. Estimated Start and End date: September 2016 – June 2018.  
 
Project management:  
Project will be coordinated, conducted, and monitored by research staff.  The research 
mentors will be: Kate Shaw M.D., M.S, primary mentor, and 
, MPH, 
secondary mentor.  
 
Links with other projects:  
Not applicable.  
 
Main problems anticipated:  
Our recruitment site sometimes experiences low patient volumes that may contribute 
to slow recruitment. It is possible that enrolled patients may experience complications 
during labor and delivery or after delivery in which case, patients will no longer be 
eligible for study. Patients may change their mind and no longer wish to participate in 
study. In order to mitigate these potential challenges, we will chart review in advance 
on a weekly basis in order to approach all eligible patients. We will also counsel and 
explain study thoroughly to ensure patients are able to make informed decisions 
regarding participation.  
 
Expected outcomes of the study and dissemination of findings: 


We expect to find that timing to lactogenesis stage II is not different between women 
who obtain contraceptive implant insertion in the delivery room versus in the 
postpartum ward. We hope to publish these results to contribute to body of literature 
that examines safety of immediate postpartum contraception, allowing for better 
delivery of postpartum contraception without negative effects to breastfeeding in the 
period of 1-2 hours after delivery.  
 
References:  
 
1. Finer LB and Zolna MR, Declines in unintended pregnancy in the United States, 
2008–2011, New England Journal of Medicine, 2016, 374(9):843–
852,http://nejm.org/doi/full/10.1056/NEJMsa1506575. 
 
2. Zhu, B.P: Effect of interpregnancy interval on birth outcomes: findings from 
three recent US studies. Int J Gynecol Obstet, 89 (Suppl. 1) (2005), pp. S25–S33 
 
3. Zhu, B.P, R.T. Rolfs, B.E. Nangle, J.M. Horan. Effect of the interval between 
pregnancies on perinatal outcomes. N Engl J Med, 340 (8) (1999), pp. 589–594 
 
4. Mayer JP1. Unintended childbearing, maternal beliefs, and delay of prenatal 
care. Birth. 1997 Dec;24(4):247-52. 
 
5. Gemmill A, Lindberg LD. Short Interpregnancy Intervals in the United States. 
Obstet Gynecol. 2013 Jul; 122(1): 64-71  
 
 
 
 
 
6. Cohen R, Sheeder J, Arango N, Teal S, Tocce K. Twelve-month contraceptive 
continuation and repeat pregnancy among young mothers choosing 
postdelivery contraceptive implants or postplacental intrauterine devices. 
Contraception. 2016 79(2) pp. 178-183 
 
 
 
 
 
7. Heller R, Cameron S, Briggs R, Forson N, Glasier A. Postpartum contraception: a 
missed opportunity to prevent unintended pregnancy and short inter-pregnancy 
intervals. Fam Plann Reprod Health Care. 2015 Dec 8. pii: jfprhc-2014-101165.  
 
8. L. Speroff, D.R. Mishell Jr. The postpartum visit: it's time for a change in order to 
optimally initiate contraception. Contraception. 2009 78(2) pp. 90–98 
 
9. Centers for Disease Control (CDC). Postpartum care visits–11 states and New 
York City, 2004. MMWR Morb Mortal Wkly Rep 2007;56:1312–6. 
 
10. Gariepy AM1, Duffy JY, Xu X. Cost-Effectiveness of immediate compared with 
delayed postpartum etonogestrel implant insertion. Obstet Gynecol. 2015 
Jul;126(1):47-55. 
 


11. Centers for Disease Control (CDC). Contraceptive Use Among Postpartum 
Women, 12 States and New York City, 2004-2006. MMWR Morb Mortal Wkly 
Rep 2009;58(30); 821-826 
 
12. Update to CDC's U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: 
Revised Recommendations for the Use of Contraceptive Methods During the 
Postpartum Period Weekly July 8, 2011 / 60(26);878-883 
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6026a3.htm 
 
13. Department of Reproductive Health, World Health Organization: Medical 
Eligibility Criteria for Contraceptive use. Fifth edition – Executive Summary. 
Number of Pages. Publication date: 2015 Who reference number: 
WHO/RHR/15.07.http://apps.who.int/iris/bitstream/10665/172915/1/WH 
O_RHR_15.07_eng.pdf?ua=1 
 
14. Dunn K, Bayer LL, Mody SK. Postpartum contraception: An exploratory study of 
lactation consultants' knowledge and practices. Contraception. 2016 
Jul;94(1):87-92  
 
15. Duvan Cİ1, Gözdemir E1, Kaygusuz I1, Kamalak Z1, Turhan NÖ1. Etonogestrel 
contraceptive implant (Implanon): analysis of patient compliance and adverse 
effects in the breastfeeding period. J Turk Ger Gynecol Assoc. 2010 Sep 
1;11(3):141-4.  
 
16. Merck. Pharmacokinetic Profile of NEXPLANON (etonogestrel implant) Mean 
(+/- SD) Serum concentration-time profile of etonogestrel after insertion of 
Nexplanon during 3 years of use. (See attached graphic below) 
 
17. Gurtcheff, SE; Turok, DK; Stoddard, G; Murphy, PA.; Gibson, M; Jones, KP. MD 
Lactogenesis After Early Postpartum Use of the Contraceptive Implant: A 
Randomized Controlled Trial. Obstetrics and Gynecology 2011; 17: 1114 – 1121  
 
18. Taneepanichskul S, Reinprayoon D, Thaithumyanon P, Praisuwanna P, 
Tosukhowong P, Dieben T. Effects of the etonogestrel-releasing implant 
Implanon and a nonmedicated intrauterine device on the growth of breast-fed 
infants. Contraception 2006;73:368 –71 
 
19. Brito MB, Ferriani RA, Quintana SM, Yazlle ME, Silva de Sá MF, Vieira CS. Safety 
of the etonogestrel-releasing implant during the immediate postpartum period: 
a pilot study. Contraception 2009 Dec; 80 (6)519-26  
 
20. Braga GC, Ferriolli E, Quintana SM, Ferriani RA, Pfrimer K, Vieira CS. Immediate 
postpartum initiation of etonogestrel-releasing implant: A randomized 
controlled trial on breastfeeding impact. Contraception. 2015 Dec;92 (6):536-42. 
 


21. Chapman DJ, Perez-Escamilla R. Maternal perception of the onset of lactation is 
a valid, public health indicator of lactogenesis stage II.  J Nutr 2000;130: 2972–80 
 
22. Sievers E, Haase S, Oldigs HD, Schaub J. The impact of peripartum factors on 
the onset and duration of lactation. Biol Neonate 2003;83:246–52.  
 
 
 
Informed decision-making and confidentiality: 
Please see attached consent form in appendix A.  
 
Budget  & Justification:   
There is no monetary cost for this study. Only human resources are required. Griselda 
Velasquez has a research grant that will fund living costs.  
 
Personnel:   
 
 
 
 
 
  
 
Participant Costs:  
None. Patients will not require additional office visits or expenses. Participants will not 
be compensated for their time.  
 
Appendices:  
A: Consent Form  
B: Redcap Data Collection Tool Script  
 
 
Reference Graphic: