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Comparison of pregnancy incidence among African women in a randomized trial of intramuscular depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD), and levonorgestrel (LNG) implant
Dr. Maricianah Onono
Good morning. I will be presenting on behalf of my co-authors on the comparison of pregnancy incidence among African women in a randomised trial of intramuscular depot medroxyprogesterone acetate (DMPA), copper iUD and the levonogesterel implant
@Maricianah
Share your thoughts on this presentation with #IAS2019

3. Co-author acknowledgement
Kavita Nanda
Kate Heller
Doug Taylor
Peter Gichangi
Renee Heffron
Margaret Kasaro
Cheryl Louw
Charles Morrison
Nelly Mugo
Zelda Nhlabatsi
Jenni Smit
Imelda Wakhungu
Irina Yacobson
Jared Baeten 
All authors declare no conflict of interest
On behalf of the ECHO Trial Consortium
The authors declare no conflict of interest

4. Background
Sub-Saharan Africa is disproportionately affected by high rates of unintended pregnancy (16 million annually)
Unintended pregnancy can occur due to:
inconsistent or incorrect use of FP method
method non-use
contraceptive failure
Data comparing pregnancy rates with different contraceptive methods as used by women in Sub-Saharan Africa are limited
-Sub-Saharan Africa is disproportionately affected by high rates of unintended pregnancy-
-As shown in the pie chart, slightly more than half of unintended pregnancies occur among women who use no method of contraception during the month in which they conceived,
-and more than four in 10 occur among women who used a method inconsistently or incorrectly.
=Approximately, 5% are attributable to method failure

5. Objectives
This analysis compared pregnancy incidence among women randomized to DMPA-IM, Copper IUD, or LNG implant, which was a protocol-defined objective of the Evidence for Contraceptive options and HIV Outcomes (ECHO) trial
ECHO trial assessed HIV incidence among 7829 women from 12 sites in Eswatini, Kenya, South Africa and Zambia who were:
Seeking effective contraception
Consented to be randomized to DMPA-IM, Copper IUD, or LNG implant
Read
The objective of this analysis was to compare pregnancy incidence among women randomized to DMPA, copper IUD, or LNG implant, which was a protocol-defined objective of the ECHO Trial
ECHO assessed HIV incidence among 7829 women from 12 sites in Eswatini, Kenya, South Africa, and Zambia
Women seeking effective contraception consented to be randomized to DMPA-IM, copper IUD, or LNG implant

6. Primary Exposure: Contraceptive Use
Only women who initiated their randomized method (RM) were included
Pregnancy analysis was done for perfect use
Perfect use was measured from date women initiated their RM until:
first discontinuation/hold of RM, pregnancy, or last visit with no pregnancy
Only women….
Perfect Use was Measured from date women initiated their randomized method until:
first discontinuation/hold of randomized method, pregnancy, or last visit with no pregnancy
Typical Use was Measured from the date women initiated their randomized method until:
permanent discontinuation, switching to a different method, pregnancy, or last visit with no pregnancy
Temporary time off method for any reason (e.g. late or missed DMPA injection, IUD expulsion, provider “hold”) was considered “typical use”

7. Additional analysis done using typical use
Typical use was measured from date women initiated their RM until:
permanent discontinuation of RM, pregnancy, or last visit with no pregnancy
temporary time off method for any reason (e.g. late or missed DMPA injection, IUD expulsion, clinician-initiated “hold”) counted as typical use

8. Outcome Variable: Incident Pregnancy
Pregnancy testing:
Urine pregnancy test done at first and last visits, and when clinically indicated
Confirmed incident pregnancy: a pregnancy with an estimated date of fertilization after the date of enrollment and on method
Estimated Date of Fertilization
Computed per a standard algorithm, and reviewed by a blinded subcommittee
Calculated as the first day of LMP plus 14 days, or ultrasound date minus gestational age, plus 14 days
The main outcome variable was incident pregnancy
Pregnancy was assessed using a urine pregnancy test at enrollment and final exit visit, and as needed based on clinical judgment.
Clinical judgment included a missed or late period
A pregnancy was included if the estimated date of fertilization was after the date of enrolment and on a method
The estimated date of fertilization was computed per a standard algorithm, and reviewed by a blinded subcommittee. This estimated date of fertilization was calculated as the first day of the LMP plus 14 days or ultrasound date minus gestational age, plus 14 days

9. Results: Demographics and Behavioral Data
Median age 23 (range 16-35)
Previous contraceptive use history:
DMPA-IM: 51.0%
Implant: 6.4%
IUD: 0.8%
Single/ and never married: 79.9%
Some or complete secondary education: 74.9%
Condom use during the last vaginal sex: 48.2%
1-2 living children: 66.2%
STI prevalence:
Chlamydia trachomatis: 18.1%
Gonorrhea: 4.7%
Baseline demographics and behavioral data were similar across randomization groups. In summary, the median age was 23 years with a range of Majority were, single and never married (79.9%), had some or complete secondary education (74.3%), had a BMI <=30kg/m2 (74.1%), and had 1-2 living children (66.2%).
Approximately 48.2% of women had used a condom during the last vaginal sex.
In terms of previous contraceptive use –51% had ever used DMPA, 6.4% Implant and 0.8% had ever used copper IUD.
STI prevalence was high with 18.1% having chlamydia trachomatis and 4.7% with gonorrhea
BMI <=30kg/m2: 74.1%

10. Results 7829 women enrolled and followed-up
33 women excluded from analysis due to pregnancy at time of method initiation (15 DMPA-IM, 3 Copper IUD, 15 LNG implant)
86 women excluded from analysis because they never received method (1 DMPA-IM, 79 Copper IUD, and 6 LNG implant)
7710 women included in pregnancy analysis
2593 DMPA-IM
2525 Copper IUD
2592 LNG implant
A total of 7829 Women were enrolled and followed up in the study. For this pregnancy analysis, 7710 were included.
We excluded 33 women who were retrospectively estimated to be pregnant at time of method initiation (15 DMPA-IM, 3 IUD, 15 LNG implant
We also excluded 86 women who never received the method ((1 DMPA-IM, 79 IUD, and 6 LNG implant))

11. Results: Incident Pregnancy
Median days from randomization to first pregnancy was 96 days for DMPA-IM, 252 days for Copper IUD, and 108 for LNG implant with perfect use
255 pregnancies reported
85 pregnancies in typical use
185 pregnancies (72.5%) occurred after women stopped using their contraceptive method
70 pregnancies occurred during perfect use
In terms of incident pregnancies, a total of 255 pregnancies were reported during the trial
72.5% of those pregnancies occurred after women stopped using their method
Among the pregnancies that occurred while on method, 70 of those occurred during perfect use
The median days from randomization to first pregnancy was 96 days for DMPA-IM, 252 days for copper IUD, and 108 for LNG Implant with perfect use

12. Perfect Use: Cumulative Incidence Curves
Pregnancy incidence per 100 WY
(95% CI); Pregnancies(n)
1.06 (95%CI ); n=31
0.63 (95%CI ); n=21
0.61 (95%CI ); n=18
These curves show the cumulative incidence curves for perfect use. The figures on the right are pregnancy incidence per 100 woman years and the pregnancy counts
The curves show that pregnancy was low across all three methods. However, the Copper IUD appears to have a somewhat different slope—starting lower and rising relatively higher when compared to the other 2 methods
Overall pregnancy incidence per 100 woman years at 18 months was low: per 100 woman-years (wy) for DMPA-IM, 1.06 for copper IUD, and 0.63 for LNG implant

13. Risk of Pregnancy in Perfect Use: Comparisons by Randomized Arm
Method
Adjusted Hazard Ratio*
(95% CI)
p-value
DMPA-IM v. Copper IUD
0.56
0.053
DMPA-IM v. LNG Implant
0.93
0.827
Copper IUD v. LNG Implant
1.65
0.075
In pairwise comparisons -there was no statistically significant difference in terms of the risk of pregnancy incidence between the method pairs
* Adjusted for no condom use with last vaginal sex

14. Typical Use Pregnancy Incidence: Comparisons by Randomized Arm
Method
aHR (95% CI)*
p-value
DMPA-IM v. Copper IUD
0.80
0.375
DMPA-IM v. LNG implant
1.39
0.246
IUD v. LNG implant
1.74
0.044
*Adjusted for no condom use with last vaginal sex
Pregnancy incidence per 100 WY; Pregnancies (n)
1.11 (95%CI ); n=35
0.87 (95%CI ); n=29
0.63 (95%CI ); n=21
This slide presents findings for the typical use analysis.
The figure on the left shows the cumulative incidence curves for typical use which is somewhat similar to what we saw in the perfect use curves
Since typical use incorporates time when women were temporarily off her method, the pregnancy incidence per 100 WY is greater as you can see in the numbers on the right
In adjusted models-typical use of copper IUD was associated with a statistically significant higher risk of pregnancy compared to LNG implants with an aHR of The other comparisons did not reach statistical significance

15. Conclusion
Both perfect and typical use of all three contraceptive methods resulted in very low pregnancy rates
Women using Copper IUD had somewhat higher pregnancy rates than those using LNG implants and DMPA-IM

16. Conclusion
The DMPA-IM pregnancy incidence with typical use is much lower than has been reported in routine settings, which may be attributed to the proactive tracing by research staff
Higher pregnancy rates with copper IUD may be due to
Lack of ascertainment of fundal placement of the IUD, thus increasing risk of expulsion
Partial or complete expulsions are often asymptomatic or unnoticed thus may not trigger action by both providers or clients

17. Conclusion
Our findings provide strong justification to expand access to a range of contraceptive options including LNG implants and Copper IUD for African women at risk of HIV

18. We gratefully acknowledge the echo trial consortium sites, staff and participants.

19. ASANTENI SANA
Contraceptive supplies donated by USAID and the Republic of South Africa
And acknowledge the funding support from our donors without whom this work would not have been possible. Asanteni sana