Prevention and Therapy of Preterm Birth. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/025, September 2022) – Part 1 with Recommendations on the Epidemiology, Etiology, Prediction, Primary and Secondary Prevention of Preterm Birth

Abstract

Aim This revised guideline was coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). It aims to improve the prediction, prevention, and management of preterm birth, based on evidence from the current literature, the experience of members of the guidelines commission, and the viewpoint of self-help organizations.

Methods The members of the contributing professional societies and organizations developed recommendations and statements based on international literature. The recommendations and statements were presented and adopted using a formal process (structured consensus conferences with neutral moderation, written Delphi vote).

Recommendations Part 1 of this short version of the guideline presents statements and recommendations on the epidemiology, etiology, prediction, and primary and secondary prevention of preterm birth.

 

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Key words

guideline - preterm birth - preterm labor - cervical insufficiency - preterm premature rupture of membranes

I  Guideline Information

Guidelines program

For information on the guidelines program, please refer to the end of the guideline.

 

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Citation format

Prevention and Therapy of Preterm Birth. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/025, September 2022) – Part 1 with Recommendations on the Epidemiology, Etiology, Prediction, Primary and Secondary Prevention of Preterm Birth. Geburtsh Frauenheilk 2023; 83: 547–568

 

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Guideline documents

The complete long version in German, a short version, and a slide version of this guideline as well as a list of the conflicts of interest of all the authors and a guideline report on the methodological approach including the management of any conflicts of interest are available on the homepage of the AWMF: http://www.awmf.org/leitlinien/detail/ll/015-025.html

 

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Guideline authors

See [Tables 1] and [2].

Table 1 Lead and/or coordinating guideline author.

Auhtor	AWMF professional society
Prof. Dr. Richard Berger	DGGG

Table 2 Contributing guideline authors.

Author Mandate holder	DGGG working group (AG)/AWMF/non-AWMF professional society/organization/association
Prof. Dr. Harald Abele	AGG Section Preterm Birth
Prof. Dr. Franz Bahlmann	DEGUM
Prof. Dr. Richard Berger	DGGG
Dr. Klaus Doubek	BVF
Prof. Dr. Ursula Felderhoff-Müser	GNPI
Prof. Dr. Herbert Fluhr	AGIM
PD Dr. Dr. Yves Garnier	AGG Section Preterm Birth
Prof. Dr. Susanne Grylka-Baeschlin	DGHWi
Aurelia Hayward	DHV
Prof. Dr. Hanns Helmer	OEGGG
Prof. Dr. Egbert Herting	DGKJ
Prof. Dr. Markus Hoopmann	ARGUS
Prof. Dr. Irene Hösli	SGGG
Prof. Dr. Dr. h. c. Udo Hoyme	AGII
Prof. Dr. Ruben-J. Kuon	DGGG
Dr. Wolf Lütje	DGPFG
Silke Mader	EFCNI
Prof. Dr. Holger Maul	DGPM
Prof. Dr. Werner Mendling	AGII
Barbara Mitschdörfer	Federal Association “Das frühgeborene Kind” [The Premature Baby]
PD Dr. Dirk Olbertz	GNPI
Andrea Ramsell	DHV
Prof. Dr. Werner Rath	DGPGM
Prof. Dr. Claudia Roll	DGPM
PD Dr. Dietmar Schlembach	AGG Section Hypertensive Disorders of Pregnancy and Fetal Growth Restriction
Prof. Dr. Ekkehard Schleußner	DGPFG
Prof. Dr. Florian Schütz	AGIM
Prof. Dr. Vanadin Seifert-Klauss	DGGEF
Prof. Dr. Daniel Surbek	SGGG

The following professional societies/working groups/organizations/associations stated that they wished to contribute to the guideline text and participate in the consensus conference and nominated representatives to contribute and attend the conference ([Table 2]).

Additional authors involved in the revision of the guideline were PD Dr. Mirjam Kunze, Prof. Dr. Jannis Kyvernitakis and Prof. Dr. Johannes Stubert. They did not participate in the voting on recommendations and statements.

 

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II  Guideline Application

Purpose and objectives

The guideline aims to optimize the inpatient and outpatient care given to patients with threatened preterm birth and thereby aims to reduce the rate of preterm births. If a preterm birth cannot be delayed or prevented any longer, the goal must be to reduce perinatal and neonatal morbidity and mortality. This should also contribute to improving the psychomotor and cognitive development of children born prematurely.

 

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Targeted areas of care

Outpatient and/or inpatient care.

 

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Target user groups/target audience

The recommendations in this guideline are aimed at gynecologists in private practice, hospital-based gynecologists, hospital-based pediatricians, midwives in private practice and hospital-based midwives. Others groups this guideline wishes to address are advocacy groups for affected women and children, nursing staff (obstetrics/puerperium, pediatric intensive care unit), medical-scientific professional associations and organizations, quality assurance institutions (e.g., IQTIG), healthcare policy institutions and decision-makers at federal and state level, and funding bodies.

 

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Adoption and period of validity

The validity of this guideline was confirmed by the executive boards/representatives of the participating medical professional societies, working groups, organizations, and associations as well as by the boards of the DGGG, SGGG and OEGGG and the DGGG/OEGGG/SGGG Guidelines Commission in September 2022 and was thereby approved in its entirety. This guideline is valid from 1 October 2022 through to 30 September 2025. Because of the contents of this guideline, this period of validity is only an estimate. The guideline can be reviewed and updated earlier if necessary. If the guideline still reflects the current state of knowledge, its period of validity can be extended.

 

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III  Methodology

Basic principles

The method used to prepare this guideline was determined by the class to which this guideline was assigned. The AWMF Guidance Manual (version 2.0) has set out the respective rules and requirements for different classes of guidelines. Guidelines are differentiated into lowest (S1), intermediate (S2), and highest (S3) class. The lowest class is defined as consisting of a set of recommendations for action compiled by a non-representative group of experts. In 2004, the S2 class was divided into two subclasses: a systematic evidence-based subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches. This guideline was classifed as: S2k

 

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Grading of recommendations

The grading of evidence based on the systematic search, selection, evaluation, and synthesis of an evidence base which is then used to grade the recommendations is not envisaged for S2k guidelines. The individual statements and recommendations are only differentiated by syntax, not by symbols ([Table 3]).

Table 3 Grading of recommendations (based on Lomotan et al., Qual Saf Health Care 2010).

Description of binding character	Expression
Strong recommendation with highly binding character	must/must not
Regular recommendation with moderately binding character	should/should not
Open recommendation with limited binding character	may/may not

 

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Statements

Expositions or explanations of specific facts, circumstances, or problems without any direct recommendations for action included in this guideline are referred to as “statements.” It is not possible to provide any information about the level of evidence for these statements.

 

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Achieving consensus and level of consensus

At structured NIH-type consensus-based conferences (S2k/S3 level), authorized participants attending the session vote on draft statements and recommendations. The process is as follows. A recommendation is presented, its contents are discussed, proposed changes are put forward, and all proposed changes are voted on. If a consensus (> 75% of votes) is not achieved, there is another round of discussions, followed by a repeat vote. Finally, the extent of consensus is determined, based on the number of participants ([Table 4]).

Table 4 Level of consensus based on extent of agreement.

Symbol	Level of consensus	Extent of agreement in percent
+++	Strong consensus	> 95% of participants agree
++	Consensus	> 75 – 95% of participants agree
+	Majority agreement	> 50 – 75% of participants agree
–	No consensus	< 50% of participants agree

 

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Expert consensus

As the term already indicates, this refers to consensus decisions taken relating specifically to recommendations/statements issued without a prior systematic search of the literature (S2k) or where evidence is lacking (S2e/S3). The term “expert consensus” (EC) used here is synonymous with terms used in other guidelines such as “good clinical practice” (GCP) or “clinical consensus point” (CCP). The strength of the recommendation is graded as previously described in the chapter Grading of recommendations but without the use of symbols; it is only expressed semantically (“must”/“must not” or “should”/“should not” or “may”/“may not”).

 

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Dissenting opinion of the SGGG

Re 1 Definition and Epidemiology

As regards the care provided at the limits of viability, the SGGG would like to refer to the recommendation for Switzerland which was developed together with neonatologists. Rationale: The recommendation for Switzerland diverges in several aspects from the recommendation for Germany. The Swiss recommendation is currently being revised [1].

 

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Re 3.2.3 Indication for cervical length measurement

In individual cases, an examination may also be carried out in asymptomatic women. The Swiss approach for the section “Asymptomatic patients” is as follows: “Transvaginal ultrasound to measure cervical length may be carried out in asymptomatic pregnant women with no risk factors for spontaneous preterm birth.” Rationale: The emphasis on this circumstance is important for Switzerland, as transvaginal ultrasound measurement is routinely carried out in many gynecological practices in Switzerland as part of regular pregnancy screening in the second trimester of pregnancy.

Recommendation 4.E12: Prophylactic cerclage may be offered to women with a prior history of preterm birth before 34 weeks of gestation or to women who have had several previous late-term miscarriages. There is no evidence supporting the recommendation to place a cerclage if the previous preterm birth occurred after 34 weeks of gestation.

Table 5 Risk factors for preterm birth (data from [3], [9], [10], [11], [12], [13], [14], [15]).

Risk factor	OR	95% CI
SARS-CoV-2: severe acute respiratory syndrome coronavirus type 2
Status post spontaneous preterm birth	3.6	3.2 – 4.0
Status post medically indicated preterm birth	1.6	1.3 – 2.1
Status post conization	1.7	1.24 – 2.35
Inter-pregnancy interval < 12 months after previous preterm birth	4.2	3.0 – 6.0
Pregnant woman is aged < 18 years	1.7	1.02 – 3.08
Unfavorable socio-economic living conditions	1.75	1.65 – 1.86
Single mother	1.61	1.26 – 2.07
Bacterial vaginosis	1.4	1.1 – 1.8
Asymptomatic bacteriuria	1.5	1.2 – 1.9
Vaginal bleeding in early pregnancy	2.0	1.7 – 2.3
Vaginal bleeding in late pregnancy	5.9	5.1 – 6.9
Twin pregnancy	about 6
Smoking	1.7	1.3 – 2.2
Periodontitis	2.0	1.2 – 3.2
Anemia	1.5	1.1 – 2.2
Subclinical hypothyroidism	1.29	1.01 – 1.64
SARS-CoV-2	1.2 (D) [16] 1.47 (China) [17] 1.6 (Sweden) [18] 2.17 (England) [19] 1.82 (meta-analysis) [20]	1.38 – 2.39

 

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IV  Guideline

1  Definition

Consensus-based statement 1.S1
Expert consensus	Level of consensus +++
Preterm birth is defined as delivery of an infant before 37 + 0 weeks of gestation. Preterm birth contributes significantly to perinatal morbidity and mortality.

Preterm birth is defined as a birth which occurs before the 37th week of gestation has been completed. The agreement on what constitutes the limit of viability differs between countries and cultures. For Germany, we refer readers to the guideline “Preterm-born infants at the limit of viability 024-019”. Preterm birth contributes significantly to perinatal morbidity and mortality. Globally, around 965 000 preterm infants die every year during the neonatal period, and a further 125 000 infants die in the first 5 years of life due to preterm birth. Preterm birth is one of the most important risk factors for disability-adjusted life years (years of life lost due to disease, disability, or early death) [2].

Consensus-based statement 1.S2
Expert consensus	Level of consensus +++
In 2020, the preterm birth rate in Germany was 8.0%. In Europe, the preterm birth rate ranges from 5.4 to 12.0%.

In Germany, the preterm birth rate before the 37th week of gestation is around 8% and has remained about the same since 2008. In 2020 it was 8.0% [3]. In Austria, the rate in 2020 was 7.2% [4] and in Switzerland the rate was 6.4% in 2020 [5]. Cyprus has the highest preterm birth rate in Europe with 12.0%. Lithuania has the lowest preterm birth rate with 5.4% [6].

 

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2  Etiology

Consensus-based statement 2.S3
Expert consensus	Level of consensus +++
Reference: [7]
Around two thirds of all preterm births occur as a result of premature labor with or without premature rupture of membranes (spontaneous preterm birth).

Consensus-based statement 2.S4
Expert consensus	Level of consensus +++
Reference: [7]
The etiology of spontaneous preterm birth is multifactorial. Different pathophysiological signaling pathways activate a common pathway, which manifests clinically as preterm labor and cervical opening.

Consensus-based statement 2.S5
Expert consensus	Level of consensus +++
Reference: [7]
Preterm birth may be associated with bacterially or virally induced inflammation, decidual bleeding, vascular disease, decidual senescence, disordered maternal-fetal immune tolerance, “functional progesterone withdrawal” or uterine overdistension.

 

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3  Prediction

3.1  Risk factors

Consensus-based recommendation 3.E1
Expert consensus	Level of consensus +++
Potential risk factors must be recorded during the periconceptional period, at the latest at the start of prenatal care. Special attention must be paid to risk factors which can be influenced. The intervals between examinations must be adjusted to the individual risk of preterm birth to facilitate prevention strategies.

Consensus-based recommendation 3.E2
Expert consensus	Level of consensus +++
For patients with a higher risk, educational material such as the patient guideline “Preterm birth: What you need to know as expectant parents” may be used as a basis for counseling.

The patient guideline “Preterm birth: What you need to know as expectant parents” may be very helpful as a basis for counseling in cases with a higher risk profile [8].

3.1.1  SARS-CoV-2 infection

Consensus-based statement 3.S6
Expert consensus	Level of consensus +++
Reference: [16]
Infection with SARS-CoV-2 leads to an increased risk of preterm birth, the extent of which depends on the severity of the infection.

Consensus-based statement 3.S7
Expert consensus	Level of consensus +++
Reference: [21]
Vaccination against SARS-CoV-2 does not increase the risk of preterm birth.

Consensus-based statement 3.S8
Expert consensus	Level of consensus +++
Vaccination against SARS-CoV-2 protects against severe symptomatic disease and thereby presumably prevents an increased risk of preterm birth due to SARS-CoV-2.

 

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3.2  Cervical length

3.2.1  Measurement technique

Consensus-based recommendation 3.E3
Expert consensus	Level of consensus +++
If transvaginal ultrasound is used to measure cervical length to predict preterm birth, the technique used for measurement must be followed exactly.

Kagan and Sonek have provided a detailed description of an approach that can be used to ensure that measurements are standardized as much as possible [22].

 

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3.2.2  Normal and short uterine cervix

Consensus-based statement 3.S9
Expert consensus	Level of consensus +++
Reference: [23]
In singleton pregnancies, the median cervical length measured before 22 weeks of gestation using transvaginal ultrasound is > 40 mm; between weeks 22 and 32 of gestation it is around 40 mm and after 32 weeks of gestation it is around 35 mm.

Consensus-based statement 3.S10
Expert consensus	Level of consensus +++
Reference: [24]
A cervical length of ≤ 25 mm measured using transvaginal ultrasound is considered short if it is measured before 34 + 0 weeks of gestation.

 

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3.2.3  Indications for cervical length measurement

Consensus-based recommendation 3.E4
Expert consensus	Level of consensus +++
General screening to detect short cervical length with transvaginal ultrasound should not be carried out in asymptomatic patients with no risk factors for preterm birth.

According to one large cohort study, universal screening of singleton pregnancies in women without a prior preterm birth is associated with a small but significant reduction of preterm birth rates before 37, 34 and 32 weeks of gestation (preterm birth before 37 weeks of gestation: 6.7 vs. 6.0%; adjusted odds ratio [AOR] 0.82 [95% CI: 0.76 – 0.88]), before 34 weeks of gestation (1.9 vs. 1.7%; AOR 0.74 [95% CI: 0.64 – 0.85]) and before 32 weeks of gestation (1.1 vs. 1.0%; AOR 0.74 [95% CI: 0.62 – 0.90]) [25]. Whether this study changes the result of the Cochrane Review from 2013, according to which routine screening of cervical length in all (asymptomatic and even symptomatic) pregnant women is not recommended because knowing the cervical findings leads to a non-significant reduction of the preterm birth rate before 37 weeks of gestation [26], remains to be seen but is very unlikely. What is clear is that there are no data which can confirm the influence of cervical length measurement on the parameters considered essential for perinatal mortality in perinatology. Insofar as any data on this issue was even available, the Cochrane review of 2013 was unable to find any differences with regards to parameters of perinatal mortality, preterm birth before 34 or 28 weeks of gestation, birthweight < 2500 g, maternal hospitalization, tocolysis, or the administration of antenatal steroids [26].

Consensus-based recommendation 3.E5
Expert consensus	Level of consensus +++
Transvaginal ultrasound measurement of cervical length should be incorporated into the therapeutic concept for symptomatic pregnant women (spontaneous regularly occurring premature labor) and/or pregnant women with risk factors for spontaneous preterm birth.

Consensus-based statement 3.S11
Expert consensus	Level of consensus +++
Reference: [27], [28], [29], [30], [31]
The benefit of carrying out serial transvaginal ultrasound measurements to determine cervical length has not been confirmed by prospective randomized trials in either asymptomatic or symptomatic pregnant women.

Asymptomatic patients

Consensus-based recommendation 3.E6
Expert consensus	Level of consensus ++
* In contrast to Recommendation 3.E4, this refers to transvaginal ultrasound measurements performed outside a screening program.
Transvaginal ultrasound measurement of cervical length may be considered in asymptomatic pregnant women without risk factors for spontaneous preterm birth.*

Consensus-based recommendation 3.E7
Expert consensus	Level of consensus +++
References: [32], [33]
Cervical length measurement using transvaginal ultrasound should be carried out in asymptomatic women with singleton pregnancy and a history of spontaneous preterm birth or late-term miscarriage from week 16 of gestation.

Consensus-based recommendation 3.E8
Expert consensus	Level of consensus +++
References: [34], [35], [36], [37]
Cervical length measurement using transvaginal ultrasound should be carried out in asymptomatic women with twin pregnancy from week 16 of gestation.

 

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Symptomatic patients

Consensus-based recommendation 3.E9
Expert consensus	Level of consensus +++
References: [38], [39], [40], [41]
Cervical length measurement using transvaginal ultrasound must be carried out in symptomatic women (contractions, preterm cervical shortening, or premature cervical opening on palpation).

 

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3.3  Biomarkers

Consensus-based statement 3.S12
Expert consensus	Level of consensus +++
Reference: [42]
Currently available biomarkers are unable to predict the risk of preterm birth in asymptomatic pregnant women who show no signs of cervical shortening measured with transvaginal ultrasound.

Consensus-based recommendation 3.E10
Expert consensus	Level of consensus +++
References: [43], [44]
No biomarkers should be used to estimate the risk of preterm birth in asymptomatic pregnant women with risk factors for spontaneous preterm birth. No biomarkers must be used to estimate the risk of preterm birth in asymptomatic pregnant women with no risk factors for spontaneous preterm birth.

Consensus-based statement 3.S13
Expert consensus	Level of consensus +++
* negative predictive value References: [45], [46], [47], [48], [49], [50]
The negative predictive value* of biomarkers obtained from cervicovaginal secretions may be used in symptomatic pregnant woman in addition to transvaginal ultrasound measurement of cervical length showing a cervical length of between 15 and 30 mm to help estimate the risk of preterm birth in the next 7 days.

 

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4  Primary prevention

4.1  Progesterone

Consensus-based recommendation 4.E11
Expert consensus	Level of consensus +++
References: [51], [52], [53], [54], [55]
Starting from week 16 + 0 of gestation up until week 36 + 0 of gestation, the administration of progesterone may be considered for women with singleton pregnancies and a previous spontaneous preterm birth.

Dosage: 17-OHPC (17 α-hydroxyprogesterone caproate) is administered IM in a weekly dosage of 250 mg [51]. In the studies, progesterone was sometimes administered orally (200 – 400 mg daily), and sometimes administered vaginally (90 mg gel, 100 – 200 mg capsule daily) [52], [53], [56], [57], [58].

 

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4.2  Cerclage/total closure of the cervix

Consensus-based recommendation 4.E12
Expert consensus	Level of consensus +++
The placement of a primary (prophylactic) cerclage may be considered in women with singleton pregnancy and a previous spontaneous preterm birth or late-term miscarriage(s). Placement should be carried out from the early part of the 2nd trimester of pregnancy.

It is now clear that secondary cerclage in women with a history of preterm birth and who present with a shortened cervical length of ≤ 25 mm before week 24 + 0 of gestation is beneficial. When counseling women with a history of preterm birth, the question is often asked whether early placement of a cerclage before any cervical shortening occurs could be effective. No disadvantages with regards to the prevalence of preterm birth or perinatal mortality have been reported for this approach compared to placement of a secondary cerclage [59]. However, expectant management can reduce the number of surgical interventions by 58%.

Consensus-based statement 4.S14
Expert consensus	Level of consensus +++
In women with singleton pregnancy and previous spontaneous preterm birth or late-term miscarriage(s) there are some indications that total cervical closure may reduce the rate of preterm births. The procedure should be carried out in the early part of the 2nd trimester of pregnancy.

The results of total cervical closure carried out in 11 German hospitals are discussed in an article published in 1996 [60]. These retrospective studies showed a significant prolongation of pregnancy after total cervical closure in women with a history of preterm birth. To date, there are no randomized prospective studies which confirm the benefit of total cervical closure in cases with shortening of the cervix to less than 15 mm. The surgical technique used for total cervical closure differs significantly between international centers, making it difficult to compare the outcomes.

Consensus-based statement 4.S15
Expert consensus	Level of consensus ++
Primary abdominal cerclage is an option to reduce the risk of preterm birth in women with singleton pregnancy who suffered a late-term miscarriage or a preterm birth before 28 weeks of gestation in a previous pregnancy despite placement of a primary or secondary vaginal cerclage. Cerclage placement must be carried out prior to the pregnancy and performed in a center with the relevant experience.

A prospective randomized study of women who previously had a late-term miscarriage or an extremely preterm birth despite placement of a vaginal cerclage compared the effect of transabdominal (n = 39) cerclage with high (n = 39) or low vaginal cerclage (n = 33). Laparotomy was used to place the transabdominal cerclage. The preterm birth rate before 32 weeks of gestation was significantly lower after abdominal cerclage compared to low vaginal cerclage (8% [3/39] vs. 38% [15/39]; RR 0.23, 95% CI: 0.07 – 0.76). The number needed to treat for the prevention of preterm birth was 3.9 (95% CI: 2.2 – 13.3). There was no difference in the preterm birth rate between high and low vaginal cerclage (38% [15/39] vs. 33% [11/33]; RR 1.15 (95% CI: 0.62 – 2.16) [61], [62].

A systematic review and meta-analysis of 43 studies published in 2022 showed that laparoscopic placement of transabdominal cerclage resulted in an average gain of 14.86 weeks of gestation and placement using laparotomy resulted in a gain of 12.79 weeks of gestation [63].

In a series of 69 patients, Ades et al. reported 4 complications following transabdominal cerclage placed via laparotomy (4/18). Bleeding with a volume loss of 250 – 300 ml occurred in three cases, and wound infection in one case. There was only one complication in the group treated with laparoscopic transabdominal cerclage (1/51). The complication consisted of damage to the bladder and was repaired intraoperatively. None of the patients in the laparoscopy group required conversion to laparotomy [64].

 

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4.3  Bacterial vaginosis

Consensus-based statement 4.S16
Expert consensus	Level of consensus +++
A vaginal microbiota dominated by lactobacilli and a normal pH has a protective effect on the course of pregnancy with regards to preterm birth or late-term miscarriage.

Consensus-based recommendation 4.E13
Expert consensus	Level of consensus +++
Pregnant women with symptomatic bacterial vaginosis should be treated with antibiotics based on their symptoms.

Consensus-based statement 4.S17
Expert consensus	Level of consensus +++
A diagnostic workup (including surrogate parameters such as vaginal pH) and treatment of asymptomatic and symptomatic bacterial vaginosis does not generally reduce the rate of preterm births.

Consensus-based statement 4.S18
Expert consensus	Level of consensus +++
There are some indications that the diagnosis and treatment of asymptomatic and symptomatic bacterial vaginosis before week 23 + 0 of gestation reduces the rate of preterm births before week 37 + 0 of gestation.

Several meta-analyses of case-control and cohort studies have confirmed that there is an association between infections of the genital tract and the occurrence of preterm birth [65], [66]. However, the question whether treatment of an infection, particularly of a subclinical infection, reduces the preterm birth rate [65], [67] has not been clearly answered. Only one study [68] has ever been carried out in which women were screened by Gram stain for asymptomatic bacterial vaginosis at the start of the 2nd trimester pregnancy; the findings were then randomized and the results were either revealed to the patientʼs obstetrician or not. Patients then received the appropriate treatment (if the findings were communicated, patients were treated with clindamycin). The preterm birth rate before 37 weeks of gestation in the arm of the study where the results were communicated was 3.0% vs. 5.3% in the “non-communication” arm and differed significantly. The study is the only one on this highly relevant topic which has been included in a Cochrane review and determined the results of the review. The revision published in 2015 [69] states: “There is evidence from one trial that infection screening and treatment programs for pregnant women before 20 weeksʼ gestation reduce preterm birth and preterm low birthweight.”

The findings of the PREMEVA trial were recently published [70]. More than 84 000 pregnant women were screened for bacterial vaginosis before the end of week 14 of gestation. Bacterial vaginosis, defined as a Nugent score of 7 – 10, was detected in 5360 pregnant women. Pregnant women with bacterial vaginosis and no special risk of preterm birth were randomized 2 : 1 into three groups: single course (n = 943) or three courses (n = 968) of 300 mg clindamycin 2 × daily for four days or placebo (n = 958). Women with a high risk of preterm birth were randomized separately 1 : 1 into two groups: single course (n = 122) or three courses (n = 114) of 300 mg clindamycin 2 × daily. Primary outcome was defined as late-term miscarriage between week 16 and week 21 of gestation or early preterm birth between 22 and 32 weeks of gestation.

In the group of 2869 pregnant women with no special risk of preterm birth, 22 (1.2%) in the clindamycin group and 10 (1.0%) in the placebo group had a late-term miscarriage or an early preterm birth (RR 1.10, 95% CI: 0.53 – 2.32; p = 0.82). In the group of 236 pregnant women with a high risk of preterm birth, five (4.4%) in the group treated with three courses of clindamycin and eight (6.0%) in the group treated with one course suffered a late-term miscarriage or an early preterm birth (RR 0.67, 95% CI: 0.23 – 2.00; p = 0.47). Side effects were observed significantly more often in the group of pregnant women with no special risk treated with clindamycin than in the placebo group (58 [3.0%] out of 1904 vs. 12 [1.3%] out of 956; p = 0.0035). The most common side effects were diarrhea and abdominal pain.

The authors concluded from their results that screening for bacterial vaginosis and treatment with clindamycin where necessary does not reduce the primary outcome in patients with a low risk of preterm birth.

A campaign for the prevention of preterm births, based on pH screening carried out before 14 weeks of gestation was initiated in November 2016 in the Free State of Thuringia by its federal government and the professional association of gynecologists. The campaign led to a continuous reduction in the rate of preterm births (≤ 32 + 0 weeks of gestation) from 1.46% to 1.10% in 2020 [71]. Such a clear decrease was not recorded in any other comparable federal state in Germany, but the figure was comparable with figures from Thuringia recorded in 2000 [72] and figures reported across Germany from 2011 [73]. But it is not possible to deduce from the screening strategy what specifically led to these results.

Consensus-based recommendation 4.E14
Expert consensus	Level of consensus +++
The efficacy of determining the microbiome (e.g., to evaluate the risk of or the impact on preterm birth) has not been proven. This diagnostic workup should therefore only be carried out in the context of controlled studies.

 

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4.4  Prevention programs

Consensus-based statement 4.S19
Expert consensus	Level of consensus +++
Reference: [74]
The evidence confirming the efficacy of multimodal prevention programs and risk scoring systems is insufficient.

 

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4.5  Cessation of smoking

Consensus-based statement 4.S20
Expert consensus	Level of consensus +++
References: [75], [76]
Cessation of smoking lowers the preterm birth rate.

 

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4.6  Asymptomatic bacteriuria

Consensus-based statement 4.S21
Expert consensus	Level of consensus +++
Asymptomatic bacteriuria is a significant risk factor for preterm birth. General screening with the sole aim of reducing the preterm birth rate is currently not recommended due to the lack of data.

Consensus-based recommendation 4.E15
Expert consensus	Level of consensus +++
Reference: [77]
Antibiotic treatment of asymptomatic bacteriuria to reduce the preterm birth rate cannot be currently recommended due to the lack of data.

 

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4.7  Supplementation with omega-3 polyunsaturated fatty acids

Consensus-based statement 4.S22
Expert consensus	Level of consensus +++
The data from studies aiming to reduce the preterm birth rate through supplementation with omega-3 polyunsaturated fatty acids (omega-3 PUFAs) is contradictory.

The most recent meta-analysis published in 2021 (31 RCT, n = 21 458) which compared supplementation with omega-3 PUFAs with placebo/no supplementation showed an 11% reduction in the preterm birth rate before 37 weeks of gestation (RR 0.89; 95% CI: 0.82 – 0.96) and a 27% reduction of the preterm birth rate before 34 weeks of gestation (RR 0.73; 95% CI: 0.58 – 0.92). However, the sensitivity analysis found no significant differences between the two groups, and the authors therefore concluded that the administration of omega-3 PUFAs does not lower the preterm birth rate [78].

 

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5  Secondary prevention

5.1  Progesterone

Consensus-based recommendation 5.E18
Expert consensus	Level of consensus +++
Women with a singleton pregnancy and a cervical length of ≤ 25 mm measured by transvaginal ultrasound before week 24 + 0 of gestation must receive intravaginal progesterone daily up until week 36 + 6 of gestation (200 mg capsule/day or 90 mg gel/day).

A meta-analysis of individual patient data (individual patient data meta-analysis, IPDMA) published in 2018 which includes the data of the OPPTIMUM trial [52] found that vaginal progesterone was associated with a significant reduction in the preterm birth rate and a better neonatal outcome in pregnant women with asymptomatic cervical shortening (≤ 25 mm) before week 24 + 0 of gestation [79]. The most recent individual patient data meta-analysis on this topic has confirmed this effect [80].

 

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5.2  Cerclage

Consensus-based recommendation 5.E19
Expert consensus	Level of consensus +++
Reference: [81]
Cerclage placement should be done in women with a singleton pregnancy after a previous spontaneous preterm birth or late-term miscarriage if they have a cervical length of ≤ 25 mm before week 24 + 0 of gestation measured by transvaginal ultrasound.

Consensus-based recommendation 5.E20
Expert consensus	Level of consensus +++
Placement of a cerclage may be considered if a cervical length of ≤ 10 mm is measured by transvaginal ultrasound before week 24 + 0 of gestation in women with a singleton pregnancy and no previous spontaneous preterm birth or late-term miscarriage.

There are some indications from a retrospective multicenter study showing that in women without a previous preterm birth and a cervical length in their current pregnancy of less than 10 mm before 24 weeks of gestation, cerclage placement can prolong the pregnancy [82].

 

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5.3  Cervical pessary

Consensus-based recommendation 5.E17
Expert consensus	Level of consensus ++
A cervical pessary may be placed in women with a singleton pregnancy and a cervical length, measured by transvaginal ultrasound, of less than 25 mm before week 24 + 0 of gestation.

A meta-analysis by Perez-Lopez et al. published in 2019 evaluated three RCT (n = 1612) with a defined endpoint (preterm birth rate < 34 + 0 weeks of gestation). The study compared pregnant women (singleton pregnancies) with a shortened cervix of ≤ 25 mm on ultrasound between week 18 + 0 and 22 + 6 of gestation who underwent placement of a cervical pessary with expectant management. In all three RCT, placement of a pessary did not result in a significant reduction of the preterm birth rate before week 34 + 0 of gestation (11.6 vs. 18.4%) but it did reduce the preterm birth rate before week 37 + 0 of gestation (20.8 vs. 47.6%, RR 0.46; 95% CI: 0.28 – 0.77) [83]. This could not be confirmed in another meta-analysis published in 2019 (preterm birth rate before 34 weeks of gestation: OR 0.68, 95% CI: 0.2 – 2.29; preterm birth rate before 37 weeks of gestation: OR 0.36, 95% CI: 0.09 – 1.48) [84].

The heterogeneity of the study results is very surprising. But it can be explained in part by the fact that not all pessaries may have had the right shape and consistency to affect the cervical-uterine angle towards the sacrum, which would have had a preventive effect [85]. Moreover, the reported use of antibiotics in up to 33% of all patients in some of the studies raises significant questions about the obstetric management [86].

Placement of a cervical pessary is an intervention with an extremely low rate of complications. Increased discharge often occurs but this has no pathological importance.

 

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5.4  Workload and avoidance of strenuous physical activity

Consensus-based statement 5.S23
Expert consensus	Level of consensus +++
References: [87], [88]
Long working hours, shift work, standing every day at work or staying in the same position for more than 6 hours, heavy lifting and heavy physical work carried out by working pregnant women are associated with a higher risk of preterm birth. As part of the current individual risk assessment for every pregnant employee, employers must check whether the professional activities carried out by their pregnant employee are associated with an unjustifiable risk for their employee. The order of priority for any protective measures is legally regulated in the MuSchG (Gesetz zum Schutz von Müttern bei der Arbeit = German law protecting working mothers): changes to working conditions, change of work station, and prohibition on working in the company. In addition to employerʼs records and the information provided by the employer, the provision of individualized medical advice which takes account of additional risk factors or obstetric complications is recommended.

Consensus-based statement 5.S24
Expert consensus	Level of consensus +++
The data on whether pregnant women with and without risk factors for preterm birth should limit their domestic physical activities is insufficient to allow a reliable conclusion to be made.

 

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Conflict of Interest/Interessenkonflikt

The statements of all of the authors about their conflicts of interest are available in the long version of the guideline./Die Interessenkonflikterklärungen aller Autoren finden Sie in der Langversion der Leitlinie.

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Publication History

Received: 15 January 2023

Accepted after revision: 22 January 2023

Article published online:
04 May 2023