Vaginal progesterone in risk reduction of preterm birth in women with short cervix in the midtrimester of pregnancy

Figures & data

Table 1 Levels of prevention

Level of prevention	Stage of disease	Goal of therapy^Citation64
Primary	Pre-disease	Health promotion (reduce incidence of the disorder or number of new cases)
Secondary	Latent disease	Early identification and effective treatment (lower disease prevalence)
Tertiary	Symptomatic disease	Disease limitation for early symptomatic disease; Rehabilitation for late disease (reducing severity of impairment associated with disease)

Table 2 Clinically identifiable risk factors for spontaneous preterm birth

	Sensitivity (%)	PPV (%)	False positive rate (%)	Relative risk or odds ratio
Short cervix	35–40
(<35 weeks)^Citation8,Citation10,Citation11	34		5
(<32 weeks)^Citation52	48 (55)		5 (10)
Short cervix + vaginal bleeding				4.6 (2.7–8.0)^Citation65
Prior sPTB				2.0 (1.6–2.5)^Citation66
Fetal loss < 16 weeks				1.4^Citation8
Fetal loss 16–24 weeks				1.7^Citation79
sPTB 24–32 weeks				5.49^Citation8
Short cervix + vaginal bleeding + Prior sPTB				4.84 (1.89–12.4)^Citation65
Risk scoring system (<37 weeks)^Citation67	38		17
Multiparous; Nulliparous^Citation66	24.2; 18.2	28.6; 33.3
Maternal factors (Age + Ob Hx) (<32 weeks)^Citation52	29 (38)		5 (10)
Maternal factors + cervix length (<32 weeks)^Citation52	57 (69)		5 (10)
FFN+ (<34 weeks)^Citation68	61 (33–89)	9–46
Vaginal bleeding				1.3 (1.1–1.6)^Citation69
(1st or 2nd trimester)				1.58 (1.27–1.96)^Citation65 1.6 (1.1–2.3)^Citation66
Bacterial vaginosis		6–49		1.5–3-fold^Citation70
Smoking				1.48^Citation8
Illicit drug use/heavy alcohol use				1.0^Citation8
Maternal age < 20 years				1.42^Citation8
>35 years				1.1
Ethnicity – Black				1.89 (1.1–3.27)^Citation66 1.66^Citation8
Prior cervical surgery				1.0^Citation8
Body mass index < 19.8				2.3 (1.37–3.92)^Citation66
>32.2 ± 2.2 kg/m^2 (<34 weeks)				2.23 (1.19–4.18)^Citation71
Clinical depression				<2-fold^Citation70
Socioeconomic status				2.0 (1.19–3.44)^Citation66
Single marital status				1.4–1.8^Citation66
Long work hours/hard physical labor; stress				<2-fold^Citation70
Interpregnancy interval < 6 months				2.2^Citation72
Multiple gestation	(60)^Citation70
Polyhydramnios/oligohydramnios				1.8 (1.03–3.15)^Citation73
Maternal medical and surgical disorders				0.7–1.34^Citation66
Uterine anomalies				5.9 (4.3–8.1)^Citation74
Intrauterine; vaginal or maternal systemic infections				Twofold^Citation70
Periodontal disease				2.83 (1.95–4.1)^Citation75
No risk factors (>50% of all PTBs)^Citation29

Abbreviations: FFN, fetal fibronectin; Ob Hx, obstetrical history; sPTB, spontaneous preterm births.

Table 3 Frequency of women with short cervix

	GA in weeks at screening	Cervical length (mm)					Percentiles (mm)			Mean/median CL (mm)	Funnel
		≤15	≤20	≤25	≤30	10–20	1	5	10
Fonseca^Citation28	14–24	1.7%		8.3%						34
Heath^Citation15	22–24	1.6%	3.4%	8.1%	18.6%		11	23		38	8%
Hassan*,^Citation76	14–24	0.6%	0.9%	1.7%	9.1%					37.5 ± 6.6
To**,^Citation52	22–24	0.9%								36
Iams^Citation10	22–24		3.0%	7.8%	23.7%		13	22	26	35.2 ± 8.3	6.3%
Moroz^Citation77	21–28			7.27%					25
Hassan^Citation29	19–24					2.3%
Grobman^Citation78	16–22				<30 = 10.3				<30

Notes:

* All were screened by transabdominal ultrasound, followed by TVS only if CL < 30 mm. In all other studies primary transvaginal screening was performed, suggesting greater detection with TVS;

** low-risk population with sPTB ≤ 32 weeks of 0.6% (compared to 1.5% in the Heath cohort¹⁵).

Abbreviations: CL, cervical length; sPTB, spontaneous preterm birth; TVS, transvaginal ultrasound.

Figure 1 Cholesterol is converted to pregnenolone by cytochrome P450_scc inside steroidogenic mitochondria. The transport of cholesterol across the mitochondrial membranes is a limiting step, and it involves the transport protein (TSPO). Ligands of TSPO can stimulate the passage of cholesterol into the mitochondria and, as a consequence, the synthesis of pregnenolone. The conversion of pregnenolone to progesterone by different isoforms of the 3β-hydroxysteroid dehydrogenase (3β-HSD) also takes place inside the mitochondria or within the cytoplasm.

Notes: Progesterone regulates gene transcription by binding to intracellular receptors (PR), which interact as dimers with DNA progesterone-response elements (PREs). In addition, PR can also directly interact with extranuclear signaling proteins of the Src/Ras/Erk pathway. At the level of the plasma membrane, progesterone binds to the recently identified membrane receptors of progesterone (mPR, comprising a, b, and g isoforms), progesterone receptor membrane component 1 (PGRMC1, the former protein 25Dx) and the s1 receptor. Major signal transduction pathways which have been shown to be activated by the mPRs are ERK and p38. The mPRs also inhibit adenylate cyclase (AC), and as a consequence the protein kinase A (PKA) pathway, and they stimulate Ca²⁺ release from internal stores. Likewise, PGRMC1 and s1 receptors increase intracellular Ca²⁺ release. Both receptors are also located on membranes inside the cytoplasm, but they may translocate from them to the plasma membrane. In addition, PGRMC1 has been shown to activate protein kinase G (PKG), and s1 receptors function as amplifiers of ion channels (eg, voltage-gated K+ channels). Progesterone also activates γ-aminobutyric acid type A (GABA_A) receptors via its metabolite allopregnanolone. Copyright © 2008, Elsevier. Reproduced with permission from Schumacher M, Sitruk-Ware R, De Nicola AF. Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol. 2008;8:740–746.³²
Abbreviation: 5αDHP, 5α dihydroprogesterone.

ShamanskySLClausenCLLevels of prevention: examination of the conceptNurs Outlook1980281041086898305

 PubMedGoogle Scholar

HeathVCSouthallTRSoukaAPElisseouANicolaidesKHCervical length at 23 weeks of gestation: prediction of spontaneous preterm deliveryUltrasound Obstet Gynecol1998123123179819868

 PubMed Web of Science ®Google Scholar

IamsJDGoldenbergRLMeisPJThe length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit NetworkN Engl J Med19963345675728569824

 PubMed Web of Science ®Google Scholar

TaipalePHiilesmaaVSonographic measurement of uterine cervix at 18–22 weeks’ gestation and the risk of preterm deliveryObstet Gynecol1998929029079840546

 PubMed Web of Science ®Google Scholar

ToMSSkentouCARoystonPYuCKHNicolaidesKHPrediction of patient-specific risk of early preterm delivery using maternal history and sonographic measurement of cervical length: a population-based prospective studyUltrasound Obstet Gynecol20062736236716565989

 PubMed Web of Science ®Google Scholar

RamaekerDMSimhanHNSonographic cervical length, vaginal bleeding, and the risk of preterm birthAm J Obstet Gynecol2012206224. e1e422133802

 PubMed Web of Science ®Google Scholar

MercerBMGoldenbergRLDasAThe preterm prediction study: a clinical risk assessment systemAm J Obstet Gynecol199617418851893 discussion, 93–958678155

 PubMed Web of Science ®Google Scholar

MercerBMGoldenbergRLMoawadAHThe preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. NICHHD MFMU NetworkAm J Obstet Gynecol19991811216122110561648

 PubMed Web of Science ®Google Scholar

HonestHBachmannLMSundaramRGuptaJKKleijnenJKhanKSThe accuracy of risk scores in predicting preterm birth – a systematic reviewJ Obstet Gynaecol20042434335915203570

 PubMedGoogle Scholar

LeitichHEgarterCKaiderAHohlagschwandtnerMBerghammerPHussleinPCervicovaginal fetal f ibronectin as a marker for preterm delivery: a meta-analysisAm J Obstet Gynecol19991801169117610329873

 PubMed Web of Science ®Google Scholar

YangJHartmannKESavitzDAVaginal bleeding during pregnancy and preterm birthAm J Epidemiol200416011812515234932

 PubMed Web of Science ®Google Scholar

GoldenbergRLCulhaneJFIamsJDRomeroREpidemiology and causes of preterm birthLancet2008371758418177778

 PubMed Web of Science ®Google Scholar

MandalDMandaSRakshiADeyRPBiswasSCBanerjeeAMaternal obesity and pregnancy outcome: a prospective analysisJ Assoc Physicians India20115948648921887903

 PubMedGoogle Scholar

SmithGCSPellJPDobbieRInterpregnancy interval and risk of preterm birth and neonatal death: retrospective cohort study. [Erratum appears in BMJ. 2003;327(7419):851.]BMJ200332731312907483

 PubMed Web of Science ®Google Scholar

OforiBDLe TiecMBerardARisk factors associated with preterm birth according to gestational age at birthPharmacoepidemiol Drug Saf20081755656418327870

 PubMed Web of Science ®Google Scholar

HuaMOdiboAOLongmanREMaconesGARoehlKACahillAGCongenital uterine anomalies and adverse pregnancy outcomesAm J Obstet Gynecol201120522

 Web of Science ®Google Scholar

VergnesJ-NSixouMPreterm low birth weight and maternal periodontal status: a meta-analysisAm J Obstet Gynecol2007196135.e1135e717306654

 PubMedGoogle Scholar

HassanSSRomeroRVidyadhariDVaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trialUltrasound Obstet Gynecol201138183121472815

 PubMed Web of Science ®Google Scholar

da FonsecaEBCelikEParraMSinghMNicolaidesKHProgesterone and the risk of preterm birth among women with a short cervixN Engl J Med200735746246917671254

 PubMed Web of Science ®Google Scholar

HeathVCSouthallTRSoukaAPNovakovANicolaidesKHCervical length at 23 weeks of gestation: relation to demographic characteristics and previous obstetric historyUltrasound Obstet Gynecol1998123043119819867

 PubMed Web of Science ®Google Scholar

HassanSSRomeroRBerrySMPatients with an ultrasonographic cervical length <or=15 mm have nearly a 50% risk of early spontaneous preterm deliveryAm J Obstet Gynecol20001821458146710871466

 PubMed Web of Science ®Google Scholar

MorozLASimhanHNRate of sonographic cervical shortening and the risk of spontaneous preterm birthAm J Obstet Gynecol2012206234. e1e522189048

 PubMed Web of Science ®Google Scholar

GrobmanWAfor the Eunice Kennedy Shriver National Institute of Health and Human DevelopmentRandomized controlled trial of progesterone treatment for preterm birth prevention in nulliparous women with cervical length less than 30 mmAm J Obstet Gynecol2012206S367

 Web of Science ®Google Scholar

SchumacherMSitruk-WareRDe NicolaAFProgesterone and progestins: neuroprotection and myelin repairCurr Opin Pharmacol2008874074618929681

 PubMed Web of Science ®Google Scholar