In sub-Saharan Africa, ~3.35 million infants were born preterm in 2020. In South Africa, ~15% of births are preterm, translating to around 84 000 infants each year. About 10% of these infants face increased risks of mortality and complications such as respiratory, neurological, and eye disorders compared to infants born at full-term.^1,2

The risks of mortality and morbidity increase with the degree of prematurity. Extremely preterm infants (born <28-weeks of gestation) face the highest risks, followed by very preterm infants (born between 28- and <32-weeks), and then moderate to late preterm infants (born between 32 and <37-weeks).¹ 

What causes preterm birth, and can it be prevented?  

According to the International Federation of Gynecology and Obstetrics' (FIGO) Working Group for Preterm Birth, progesterone is crucial for maintaining pregnancy, and a decline in levels is thought to contribute to labour induction.³ 

 The corpus luteum is the primary source of progesterone. In early pregnancy, serum progesterone levels start to decline after gestation week five (75nmol/l), reaching a low at week seven (63.4nmol/l). After week eight, the placenta becomes the primary source of progesterone and levels increase six- to eight-fold - known as the luteal-placental shift.^4,5,6  

However, in some women, progesterone levels do not increase. In their study, Ku et al identified three maternal characteristics associated with declining progesterone levels during the first trimester:⁶ 

1. Maternal age: Progesterone levels decrease with increasing age. 
2. Obesity (≥27.5kg/m2) may lead to biochemical changes that lower progesterone, including reduced luteinizing hormone amplitude and lower urine progesterone metabolites. Women living with obesity had significantly lower serum progesterone levels as compared to those with normal body mass index (mean serum progesterone difference of −1.64nmol/l) 
3. Parity, defined as either nulliparous women who have never given birth, or parous women who have at least one full-term pregnancy previously. Nulliparous women have higher serum progesterone levels as compared to parous women (−7.54nmol/l). 

Other risk factors are poor nutrition and malnutrition, multiple pregnancy, unfavourable living situation/social disadvantage, prior preterm births or miscarriages, smoking, maternal depression, pre-pregnancy stress, assisted fertility treatment, and periodontal disease.⁵ 

How does progesterone support pregnancy? 

A key mechanism through which progesterone supports pregnancy is by inhibiting uterine contractions. Research has shown that progesterone has a relaxing effect on myometrial strips in the latter half of pregnancy by limiting the production of stimulatory prostaglandins and inhibiting the expression of contraction- associated protein genes (ion channels, oxytocin and prostaglandin receptors, and gap junctions) within the myometrium.^3,4,5 

It is now clear that, although levels of progesterone in the maternal circulation do not change significantly in the weeks preceding labour, the onset of labour both at term and preterm is associated with a functional withdrawal of progesterone activity at the level of the uterus. It is data such as these that provide the rationale behind the use of progesterone supplementation to prevent preterm labour and birth.⁷ 

Romero et al conducted a systemic review and meta-analysis of the efficacy of vaginal progesterone for preventing preterm birth and perinatal morbidity and mortality in asymptomatic women with a singleton gestation and a mid-trimester sonographic cervical length ≤25mm.⁸ 

The analysis included five trails (n=974). The primary outcome measure was preterm birth ≤34-weeks of gestation or foetal death. The team reported that vaginal progesterone (27.5%) decreased the risk of preterm birth ≤34-weeks of gestation or foetal death compared to placebo (18.1%).⁸  

Meta-analyses of data from four trials (n=723) showed that vaginal progesterone was associated with a statistically significant reduction in the risk of preterm birth occurring at <28- to <36-weeks, respiratory distress syndrome (53%), composite neonatal morbidity and mortality (41%), birth weight <1500g (48%) and admission to the neonatal intensive care unit (33%). In terms of safety, the team reported that there were no significant differences in neurodevelopmental outcomes at two years of age between the vaginal progesterone and placebo groups.⁸ 

Similarly, the Evaluating Progestogens for Preventing Preterm birth International Collaborative meta-analysis included individual patient data from randomised trials of progestogens to prevent preterm birth, including 31 trials and 11 644 participants.⁹  

It demonstrated that vaginal progesterone reduced the risk of preterm birth <34-weeks for a high-risk population with singleton gestations. In addition, a benefit was seen among included participants who were only eligible for the original trials due to short cervical length (defined by different thresholds in different trials) or history of preterm birth (vaginal progesterone: nine trials, 3769 women, relative risk [RR] 0.78, 95% CI 0.68–0.90, 17-hydroxyprogesterone caproate [17-OHPC]: five trials, 3053 women, RR 0.83, 95% CI 0.68–1.01).⁹  

Vaginal progesterone reduced risk of low birthweight (<2500g, 0.82, 0.74-0.91), very low birthweight (<1500g, 0.70, 0.49-0.99), neonatal intensive care unit admission (0.78, 0.68-0.90), respiratory distress syndrome (0.73,  0.58-0.93), and respiratory support (0.77, 0.61–0.99).⁹ 

What do guidelines recommend? 

Based on these and findings from numerous other studies, FIGO strongly recommends that women at high risk of preterm birth, with a history of spontaneous preterm birth and/or sonographic short cervix (≤25mm), should be offered daily progesterone.³  

The 2023 National Institute of Health and Care Excellence (NICE) guidelines recommend prophylactic vaginal progesterone for women at high risk of preterm birth. This includes women with a history of spontaneous preterm birth or loss, as well as those with a cervical length of ≤25mm identified by a transvaginal ultrasound between 16- and 24-weeks. NICE recommends starting vaginal progesterone treatment between 16- and 24-weeks of pregnancy and continuing until at least 34-weeks.¹⁰ 

Similarly, the South African National Department of Health guidelines recommend vaginal  progesterone for women at high risk of preterm labour, particularly for singleton pregnancies. They suggest administering vaginal progesterone as 200mg daily until 34-weeks.¹¹  

The South African Society of Obstetricians and Gynaecologists supports the use of vaginal micronised progesterone for women with singleton pregnancies, a history of spontaneous preterm birth, and a current cervical length of <25mm.¹²  

What is micronised progesterone? 

Micronised progesterone is a natural form of progesterone that is processed to enhance its absorption and effectiveness. The micronisation process reduces the particle size of the progesterone, increasing its surface area and thus improving gastrointestinal absorption. This allows the hormone to bypass first-pass metabolism in the liver, leading to better bioavailability.¹³ 

Micronised progesterone can be administered orally or vaginally.  Vaginal administration of micronised progesterone offers direct absorption, leading to more consistent plasma levels and fewer systemic side effects compared to oral use.¹⁴ 

Utrogestan® is a body-identical micronised progesterone in soft gelatine capsule for oral and vaginal route of administration depending on the indication. Recently, it has been approved by the South African Health Products Regulatory Authority for prevention of preterm birth in women with a singleton pregnancy who have a short cervix and/or a history of spontaneous preterm birth.¹⁵  

The recommended dosage is 200mg per day in the evening at bedtime from around week 20 to week 34 of pregnancy. It is the only progesterone approved for this indication in South Africa.¹⁵  

Conclusion 

A growing body of evidence underscores the critical role of progesterone in reducing the incidence of preterm births and associated complications. With significant risks tied to preterm deliveries, especially in sub-Saharan Africa and South Africa, interventions aimed at bolstering progesterone levels are vital. Micronised progesterone has shown promise in enhancing pregnancy outcomes for high-risk women. As research continues to validate its efficacy and safety, micronised progesterone remains a key strategy in the fight against preterm births, offering hope for healthier pregnancies and neonatal outcomes. 

  References 

1. Ohuma EO, Moller A-B, Bradley E, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. The Lancet, 2023. 
2. South African Government. Official Information and Services. Health commemorates World Prematurity Awareness Month. 2023. [Internet]. Available at: https://www.gov.za/news/media-advisories/government-activities/health-commemorates-world-prematurity-awareness-month#:~:text=About%2015%20million%20or%201,births%20are%20born%20prematurely%20annually  
3. Shennan A, Suff N, Simpsom JL, et al. FIGO good practice recommendations on progestogens for prevention of preterm delivery. International Journal of Obestetics and Gynecology, 2021. 
4. Norman JE. Progesterone and preterm birth. International Journal of Obestetrics and Gynecology, 2020. 
5. Richard E Behrman, Adrienne Stith Butler. Preterm Birth: Causes, Consequences, and Prevention. Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes Washington (DC): National Academies Press (US), 2007. 
6. Ku CW, Zhang X, Zhang VRY, et al. Gestational age-specific normative values and determinants of serum progesterone through the first trimester of pregnancy. Sci Rep, 2021. 
7. Tal R, Taylor HS. Endocrinology of Pregnancy. [Updated 2021 Mar 18]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278962/  
8. Romero R, Nicolaides KH, Conde-Agudelo A, et al. Vaginal progesterone decreases preterm birth ≤ 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet Gynecol, 2016. 
9. EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet, 2021.   
10. NICE. Preterm labour and birth. Clinical guideline [NG25] Preterm labour and birth. Updated 2023. [Internet]. Available at: https://www.nice.org.uk/guidance/ng25/chapter/Recommendations#care-of-women-at-risk-of-preterm-labour 
11. South African National Department of Health. Adult Hospital Chapter 6 Obstetrics. Updated 2020. [Internet]. Available at:  https://knowledgehub.health.gov.za/system/files/elibdownloads/2024-05/Adult%20Hospital%20Ch6_Obstetrics_2020-3%20with%20supporting%20reviews%20%20NEMLC%20report_v0.2.pdf  
12. SASOG. Risk assessment in pregnancy. 2019. [Internet]. Available at: https://sasog.co.za/wp-content/uploads/2021/10/RISK-ASSESSMENT-IN-PREGNANCY.pdf 
13. Memi E, Pavli P, Papagianni M, et al. Diagnostic and therapeutic use of oral micronized progesterone in endocrinology. Rev Endocr Metab Disord, 2024. 
14. Errol R Norwitz, Louis E, et al. Progesterone Supplementation and the Prevention of Preterm Birth. Rev Obstet Gynecol, 2011. 
15. Professional Information. Utrogestan. Updated 2024. [Internet]. Available at: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2024/07/Utrogestan_Approved-PI_13.06.2024.pdf