The drospirenone only pill as a contraceptive option for breastfeeding women: First data on users’ acceptability and newborn development

Abstract

Background

Progestin-only pills (POPs) have been used for contraception in breastfeeding women for years. The existing guidelines allow the use of these contraceptives.

Methods

Multicenter study with a single visit and retrospective data review. The study involved 100 women who used a drospirenone-only pill (DRSP) for contraception for at least 5 months during breastfeeding. The study aimed to analyze for those successful users the impact on new-born development, the bleeding profile and evaluate user satisfaction.

Results

Analysis of the newborns showed that their growth parameters length and weight, were within the expected range of standard development. The mean birth weight was 3368 g, with the lowest recorded weight being 2860 g and the highest 5040 g. The median length of the newborns was 55 cm, ranging from 35 to 65 cm. All new-borns demonstrated appropriate growth within the established percentiles. Acceptability with the bleeding profile was rated with a VAS score: the mean acceptability rating was 82.8. Women aged 35 years or older reported significantly higher acceptability compared to younger women (≥35 years: mean = 88.4, SD = 16.5; <35 years: mean = 80.3, SD = 20.2) (p = 0.02). Sixty-one patients (N = 61; 61.0%; 95% CI: 50.7 − 70.4%) expressed willingness to continue using DRSP after breastfeeding.

Conclusion

Among those patients who continued the use of the DRSP only-pill for 5 months, this study shows no negative impact for new-borns, with no clinical influence observed on their growth. Additionally, those users expressed high satisfaction with the bleeding profile of the pill.

Clinical trial registration number: DRKS00028438 

Keywords:

• Drospirenone
• breast feeding
• new-born
• acceptability

Introduction

The benefits of breastfeeding for both women and their infants are considerable [1–3]. The World Health Organization (WHO) recommends exclusive infants breastfeeding during the first six months of life [4]. Although breastfeeding women are unlikely to conceive before six weeks post-partum, many women discontinue exclusive breastfeeding and are at risk of a repeated and unwanted pregnancy [5].

Progestogen-only contraceptives have been used for years; however, their dosages and formulations have changed over time. Methods available include progestogen-only pills (POPs), progestogen implants, injectables, progesterone rings, and progestogen-releasing intrauterine devices (IUDs). They are highly effective when used as directed [6].

A systematic review of Phillips et al. [7], shows that POPs do not adversely affect infant growth, health, or development during the first-year post-partum.

A drospirenone-only pill with 4 mg in a 24/4 dosage was first introduced in 2019 in the USA and 2020 in Europe. Its contraceptive efficacy is comparable to combined oral contraceptives [8], and clinical studies have shown an improvement in the bleeding profile compared to other estrogen-free formulations. Their regimen is 24 consecutive days of tablet intake, followed by four days of placebo, which reduces unscheduled bleeding and spotting [9].

Drospirenone is a synthetic progestogen belonging to the spirorenone group. Unlike other progestogens, this compound has anti-mineralocorticoid, antiestrogenic, antiandrogenic, and antigonadotrophic activities [10]. Its biochemical and pharmacological profile closely matches progesterone [11, 12].

In a study by Melka et al. [13], the transfer after the intake of 4 mg drospirenone per day to breast milk was evaluated. The product was administered daily for seven days to achieve steady-state concentration. The quantity of drospirenone passing to the breast milk was 4478 ng during 24 h, representing 0.11% of the maternal daily dose. This amount has been rated as “negligible” by regulatory agencies who authorized the use of the 4 mg DRSP-only contraceptive during the duration of breastfeeding. This information is documented in the summary of product characteristics of the 4 mg DRSP only contraceptive in the United States, Europe, and rest of the World [14, 15].

The progestin-only contraceptive drospirenone 4 mg offers a high safety profile to women who use it. Preliminary data suggest that under the use of the DRSP-only pill, no additional risks of venous thromboembolic events are expected [16]. It is not associated with any significant change in hemostatic parameters, indicating no effect on hemostasis [17]. These aspects are relevant as the puerperal time, regardless of whether a woman is breastfeeding or not, is associated with a high risk of developing a VTE.

Therefore, the following study was designed to obtain data from a group of breast-feeding patients using the drospirenone-only pill to assess its long-term acceptability, tolerability, and to obtain first data regarding new-borns.

Methods and patients

Multicenter, observational study with a single visit and retrospective data review from routine clinical practice, with a drug used under authorized conditions. Women > 18 years who requested contraception and used the contraceptive drospirenone 4 mg in a 24/4 regime for five cycles during breastfeeding before the study visit; all women had started the first drug dose between 4 and 12 weeks post-partum. The total duration of treatment was five cycles (from 2 to 8 months post-partum). Breastfeeding women who may have started DRSP at the appropriate time but had discontinued its use before they completed 5 cycles of use were not included. Women were allowed to add nutrition to the newborns during the observational study period.

Objectives

Four objectives were evaluated.

(1) The infant outcome using the control of the growth. (2) The acceptability of the bleeding pattern. (3) The breastfeeding mother’s satisfaction, and (4) The tolerability during the 5 cycles of intake of the 4 mg drospirenone.

The enrolled women were breastfeeding between 1- and 8-months post-partum, and the first drug dose was started between 4 and12 weeks post-partum with a total duration of treatment of at least five cycles (from 1 to 8 months post-partum).

Ethical vote

This study was carried out following all applicable ethical and legal regulations. Thus, the Declaration of Helsinki was respected (revised version of Fortaleza, 2013).

The study was approved by the "Commission of Ethics and Supervision of Research on Human and Animal Research at the Central Clinical Hospital of the Ministry of Internal Affairs and Administration in Warsaw” on 16.02.2022 with the number 8/2022.

Patients were included, and the study activity was carried out once written informed consent was obtained.

Clinical trial registry number: DRKS00028438

Sample size and measurements

Sixteen centers in Poland evaluated one hundred (100) women after at least five (5) cycles of using the progestin-only contraceptive. Acceptability was assessed according to how satisfied they were with the use of the contraceptive, with the options ‘very good’ or ‘good’ considered satisfactory by the patients and ‘different’, ‘bad’ or ‘very bad’ as unsatisfactory.

A VAS score with a 100-point scale to assess the bleeding acceptability was used for all the patients, and the data were obtained using a questionnaire composed of 10 questions.

Study medication

The study medication was one tablet containing 4 mg non-micronized DRSP per day via the oral route, with consecutive administration of 24 active and four placebo tablets with no tablet-free interval between two packs.

Safety

Adverse events (AEs), any untoward medical occurrence in a patient reported by the patient or observed by the investigator, was registered using the case report form (CRF), including duration, causality assessed by the investigator, seriousness, severity, frequency, treatment, action is taken and outcome. Only the AEs that might have been occurred during the study and were documented at the time of the visit were recorded in the CRF as AEs.

Statistical methods

The statistical significance level was equal to 0.05. p-values ≥0.001 were reported to 3 decimal places; p-values less than 0.001 were reported as "<0.001". The mean, standard deviation, and statistics other than quantiles were written to one decimal place, more significant than the original data. Quantiles, such as median or minimum and maximum, used the same decimal places as the original data.

For numerical variables, selection of statistical tests (parametric vs. non-parametric) was based on the assessment made with a quantile-quantile (Q-Q) plot.

A 95% confidence interval (CI) for proportions was calculated using the Wilson method with Yeats continuity correction as implemented in prop—the test function of R statistical software. A 95% confidence interval for the proportions of adverse events was calculated using the Clopper-Pearson approach. For numeric variables, depending on the normality of variable distribution, either the student’s t-test approach to confidence intervals was used (for normally distributed variables) or the bootstrap approach was used.

Results

Among all subjects, the median age was 33; the youngest participant was 20, and the oldest was 44. More than two-thirds (N = 69; 69.0%) of patients were under 35, while women aged 35 or more comprised 31% of the population (Full Analyses Set = FAS) (N = 31). Mother’s weight, height, and BMI data were collected for 94 subjects. Median weight was 66 kg (lowest 45 kg, highest 114 kg), and median height was 166 cm (range 152–180 cm). The mean BMI value was 24.3 (± 4.8) kg/m², while the categorization highlights that more than half of the subjects were of average weight (BMI < 25; N = 53; 56.4%), seven patients (7.4%) were underweight, while almost ¼ (N = 23; 24.5%) was overweight and 11.7% (N = 11) was obese. Systolic and diastolic blood pressure was collected for 87 subjects, with a median SBP value of 120 mmHg (min 89 – max 139) mmHg, while DBP ranged from 58 to 89 mmHg, with a median value of 71 mmHg. The heart rate was investigated in the case of ¾ of the FAS population subjects – with a median HR of 78 (min 62 – max 92) BPM (see Table 1).

Table 1. Women’s characteristics and infant outcome (FAS) and mother BMI.

Parameter	Overall N = 100
Age (years)
N	100
mean (SD)	32.5 (5.4)
median (min–max)	33.0 (20.0–44.0)
Q1–Q3	29.0–35.0
Age (category)
<35 years	69 (69.0%)
> =35 years	31 (31.0%)
Weight (kg)
N	94
mean (SD)	67.6 (13.6)
median (min–max)	66.0 (45.0–114.0)
Q1–Q3	58.2–76.0
Not collected	6
Height (cm)
N	94
mean (SD)	166.8 (5.7)
median (min–max)	166.0 (152.0–180.0)
Q1–Q3	164.0–170.8
Not collected	6
BMI (kg/m^2)
N	94
mean (SD)	24.3 (4.8)
median (min–max)	23.2 (16.3–41.4)
Q1–Q3	20.9–27.1
Not collected	6
BMI categorization[1]
< 20	7 (7.4%)
20–25	53 (56.4%)
25–30	23 (24.5%)
> 30	11 (11.7%)
Not collected	6
Systolic blood pressure (mmHg)
N	87
mean (SD)	118.5 (9.0)
median (min–max)	120.0 (89.0–139.0)
Q1–Q3	112.0–125.0
Not collected	13
Diastolic blood pressure (mmHg)
N	87
mean (SD)	72.1 (7.2)
median (min–max)	71.0 (58.0–89.0)
Q1–Q3	65.5–78.0
Not collected	13
Heart rate (beats/min)
N	75
mean (SD)	78.6 (5.1)
median (min–max)	78.0 (62.0–92.0)
Q1–Q3	76.0–81.0
Not collected	25
Respiratory rate (breath/min)
N	18
mean (SD)	16.1 (1.5)
median (min–max)	16.5 (14.0–18.0)
Q1–Q3	15.0–17.0
Not collected	82
Body temperature (C)
N	56
mean (SD)	36.5 (0.2)
median (min–max)	36.5 (35.9–36.9)
Q1–Q3	36.4–36.7
Not collected	44

Table

Parameter	Overall, N = 98	95% CI[1]	Underweight N = 6	95% CI	Normal weight, N = 52	95% CI	Overweight N = 23	95% CI	Obese N = 11	95% CI
Growth parameters in line with standards
Yes	98 (100.0%)	95.3 –	6 (100.0%)	51.7 –	52 (100.0%)	91.4 –	23 (100.0%)	82.2 –	11 (100.0%)	67.9 –
		100.0		100.0		100.0		100.0		100.0
No	0 (0.0%)		0 (0.0%)		0 (0.0%)		0 (0.0%)		0 (0.0%)

All women performed breastfeeding during the five months.

No specific records were obtained on the number of women with supplementation on nutrition nor the time nor the reason for doing it.

The analyses of the new-borns showed that growth parameters (size and weight) were in line with the standard developments with two exceptions [18]. The mean birth weight was 3368 g (median 3360 g, lowest noted weight was 2860 g and highest 4040 g), and the median new-born length was 55 cm, with a range of 35–65 cm. All these new-borns develop accordingly to the average growth, and no retardation was recorded (see Table 1).

After using drospirenone for at least five months, 98 of 101 new-borns exhibited size and weight values within the range of regular development. For female new-borns, the weight ranged from 6.2 to 8 kg at the 50th percentile (± 40 percentiles), and the height ranged from 65.5 to 69 cm at the 50th percentile (± 40 percentiles). For male new-borns, the weight ranged from 8 to 8.8 kg at the 50th percentile (± 40 percentiles), and the height ranged from 68 to 71.5 cm at the 50th percentile (± 40 percentiles).

Only 2 cases had different values. One new-born was delivered prematurely at 26 weeks + 6 days with a very low birth weight of 1510 g, and the other delivery involved a twin gestation that concluded at week 34. These twin new-borns had body weights of 2050 and 1720 g and body lengths of 45 and 49 cm, respectively.

Patients bleeding acceptability

Patients were asked to rate their acceptability of the bleeding with DRSP regarding cycle control (experience with bleeding) using a visual analogue scale (VAS), where 0 represented ‘Very unsatisfied’ and 100 represented ‘Very satisfied.’ The median satisfaction rate was 89.5 points, while the mean was 82.8 (95% CI: 79.1 to 86.4 points, estimated using a bootstrap approach). The U-Mann Whitney test was performed to assess the significance of the difference between the mean VAS scores in different age groups. The resulting p-value was 0.02, indicating that women aged 35 years or older reported significantly higher satisfaction than to younger women.

More than half of all patients (N = 61; 61.0%; 95% CI: 50.7–70.4%) expressed willingness to continue using DRSP even after breastfeeding.

Of the 61 patients, 24 had previously used a combined hormonal method before discontinuing contraception, none of whom had used a POP. Therefore, 39% of DRSP users after breastfeeding were willing to switch from CHC to DRSP 4 mg following the breastfeeding period (see Table 2).

Table 2. Acceptability of DRSP only pill in women who breastfed from 2 to 8 months (FAS).

Parameter	Overall, N = 100	95% CI[1]	Underweight, N = 7	95% CI	Normal weight, N = 53	95% CI	Overweight, N = 23	95% CI	Obese, N = 11	95% CI
Very good	46 (46.0%)		2 (28.6%)		26 (49.1%)		9 (39.1%)		6 (54.5%)
Good	38 (38.0%)		5 (71.4%)		15 (28.3%)		11 (47.8%)		5 (45.5%)
Acceptable	15 (15.0%)		0 (0.0%)		11 (20.8%)		3 (13.0%)		0 (0.0%)
Bad	1 (1.0%)		0 (0.0%)		1 (1.9%)		0 (0.0%)		0 (0.0%)
Very bad	0 (0.0%)		0 (0.0%)		0 (0.0%)		0 (0.0%)		0 (0.0%)
Experience rate with Slinda[3]
Satisfied	84 (84.0%)	75.0–90.3	7 (100.0%)	56.1–100.0	41 (77.4%)	63.5–87.3	20 (87.0%)	65.3–96.6	11 (100.0%)	67.9–100.0
Not satisfied	16 (16.0%)		0 (0.0%)		12 (22.6%)		3 (13.0%)		0 (0.0%)

95% CI calculated using Wilson’s method.

Satisfaction with the use of drospirenone-only pill was determined based on answers to a question “How would you rate your experience with Slinda?” (options "Very good" or "Good" were considered as satisfied while "Acceptable," "Bad" or "Very bad" as unsatisfied).

Nearly all patients (N = 94; 94.0%; 95% CI: 86.9 − 97.5%) considered recommending DRSP to other women. There was no statistically significant difference in this aspect between age groups.

When analyzing according to BMI, all patients with a BMI < 20 and > 30 were satisfied (N = 7 and N = 11, respectively, 100% in both cases). Among patients with a BMI between 25 and 30 (N = 20), 87% expressed satisfaction, while among patients with a BMI between 20 and 25 (N = 41), 77% reported satisfaction. These differences were not significant.

Patients’ satisfaction

Satisfaction with using of DRSP was measured by combining patients’ experiences rated as ‘very good’ and ‘good.’ In total, 84% of patients expressed satisfaction with the medication (95% CI: 75.0 − 90.3%). When considering age, more patients in the group aged 35 years or older were satisfied (N = 29; 93.5%) compared to women younger than 35 years (N = 55; 79.7%). However, this difference is not statistically significant based on each group’s overlapping 95% CI. The results are presented in Table 3.

Table 3. Willingness to continue with the DRSP only pill after breastfeeding (FAS) and type of contraceptive methods used before the pregnancy (FAS).

Parameter	Overall N = 100	95% CI[1]	<35 years N = 69	95% CI	> =35 years N = 31	95% CI
Willingness to take DRSP after breastfeeding
Yes	61 (61.0%)	50.7–70.4%	40 (58.0%)	45.5–69.6%	21 (67.7%)	48.5–82.7%
No	39 (39.0%)		29 (42.0%)		10 (32.3%)
Parameter	Overall, N = 61	95% CI [1]	<35 years old, N = 40	95% CI	≥35 years old, N = 21	95% CI
No contraceptive method
Yes	25 (41.0%)	28.8–54.3%	16 (40.0%)	25.3–56.6%	9 (42.9%)	22.6–65.6%
No	36 (59.0%)		24 (60.0%)		12 (57.1%)
Combined oral contraceptives
Yes	22 (36.1%)	24.5–49.4%	14 (35.0%)	21.1–51.7%	8 (38.1%)	19.0–61.3%
No	39 (63.9%)		26 (65.0%)		13 (61.9%)
Condoms
Yes	19 (31.1%)	20.2–44.4%	14 (35.0%)	21.1–51.7%	5 (23.8%)	9.1–47.5%
No	42 (68.9%)		26 (65.0%)		16 (76.2%)
Vaginal ring
Yes	2 (3.3%)	0.6–12.4%	1 (2.5%)	0.1–14.7%	1 (4.8%)	0.2–25.9%
No	59 (96.7%)		39 (97.5%)		20 (95.2%)
IUD
Yes	0 (0.0%)	0.0–7.4%	0 (0.0%)	0.0–10.9%	0 (0.0%)	0.0–19.2%
No	61 (100.0%)		40 (100.0%)		21 (100.0%)

Adverse events

A total of six nonsevere AEs were reported in six patients. Five patients experience bleeding disorders (irregular bleeding/spotting) and one patient abdominal bloating. All were classified as mild and were transient. They were associated with the intake of the DRSP.

Discussion

Previous data have demonstrated that an estrogen-free contraceptive containing 4 mg of drospirenone in a 24/4 regimen provides effective contraception with a favorable safety and tolerability profile across a wide range of women. With only 0.11% of the nominal dose of DRSP transferring to the breast milk of lactating women [13], regulatory agencies, including the US FDA and other regulated countries, have authorized the unrestricted use of the DRSP-only pill in breastfeeding women [14, 15].

In this context, the data presented in this study reinforce the tolerability of the DRSP-only pill.

Among women who did not discontinue their use of DRSP-only pill for the first 5 months no negative impact on the new-born’s development was observed as all infants exhibited growth within established percentiles for weight and height.

Notably, after an average usage of 5 months, 61% of the patients expressed such satisfaction with the DRSP-only pill that they desired to continue its use after breastfeeding, including women who had previously used combined oral contraceptives.

This provides reassurance for patient, as estrogen-free contraceptives have no impact on hemostasis, thus not increasing the risk of venous thromboembolism (VTE) [17].

The limitations of this clinical trial are that it was performed only in one country with 100 patients and without characterizing the milk properties. Only women who fulfilled the inclusion criteria were evaluated so that no data on reasons for possible discontinuation rates during the use of the DRSP only-pill were obtained and on women that may have stopped a DRSP treatment during breast-feeding. Also, only women using the DRSP only pill were evaluated in this trial. No comparator group or placebo group was used for the evaluation. Another limitation is that all adverse events were recorded on the evaluation day. Only the AEs that might have been occurred during the study and were documented at the time of the visit were recorded in the CRF as AEs.

The study was not designed to address the VTE risks.

The strength of this study is the description of the regular development of the new-born under the use of the DRSP pill only. This should reassure users and clinicians that it is safe to use and that the negligible level of progestin is safe.

Future clinical trials should assess the breastmilk quality and quantity as the present trial could show a very high acceptability of the breastfeeding women with no impact on the infant’s development under the use of the DRSP pill during breastfeeding. They also should be prospective and collect more comprehensive information about the use of the DRSP only pill in breastfeeding women.

Authors’ contributions

Artur Jakimiuk: Responsible for the clinical data evaluation. Enrico Colli: Responsible for the scientific design. Pedro Antonio Regidor. Responsible for the study design and writing.

Financial support

Insud Pharma funded the study.

Ethics approval and consent to participate

We performed the study in accordance with Good Clinical Practice (GCP), local requirements, and the Declaration of Helsinki. For each of the investigational centers, ethical approval was obtained. The leading ethical committee was approved on 16th February 2022 by the Commission of Ethics and Supervision of Research on Human and Animal Research at the Central Clinical Hospital of the Ministry of Internal Affairs and Administration in Warsaw. Number 8/2022. Clinical trial register: DRKS-ID: DRKS00028438. Date of registration: May 2021. The date the first subject entered was 14th July 2021. Last patient: 9th February 2022.

Informed consent

Written informed consent was obtained from all participants that were enrolled in the clinical trial.

Acknowledgments

Dr. Bartłomiej Barczyński, Dr. Mariola Stapińska, Dr. Ewa Surynt, Dr. Sylwia Miśta, Dr. Jaromir Sołtysiak, Dr. Arkadiusz Bartkiewicz, Dr. Emilia Tupacz-Mosakowska, Dr. Piotr Pychtin and Dr. Maria Kulbiej. We would like to express our gratitude to Agnieszka Mozdzynska for her valuable support in the implementation of this clinical trial. 

Disclosure statement

E. Colli and P.-A. Regidor are employees of Exeltis Healthcare. Artur J Jakimiuk declares no conflict of interest.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Additional information

Funding

The clinical trial has been funded by Insud Pharma.