I Guideline Information
Guidelines program
For information on the guidelines program, please refer to the end of the guideline.
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
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
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
|
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Prof. Dr. Ursula Felderhoff-Müser
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GNPI
|
|
Prof. Dr. Herbert Fluhr
|
AGIM
|
|
PD Dr. Dr. Yves Garnier
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AGG Section Preterm Birth
|
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Prof. Dr. Susanne Grylka-Baeschlin
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DGHWi
|
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Aurelia Hayward
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DHV
|
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Prof. Dr. Hanns Helmer
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OEGGG
|
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Prof. Dr. Egbert Herting
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DGKJ
|
|
Prof. Dr. Markus Hoopmann
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ARGUS
|
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Prof. Dr. Irene Hösli
|
SGGG
|
|
Prof. Dr. Dr. h. c. Udo Hoyme
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AGII
|
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Prof. Dr. Ruben-J. Kuon
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DGGG
|
|
Dr. Wolf Lütje
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DGPFG
|
|
Silke Mader
|
EFCNI
|
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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.
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.
Targeted areas of care
Outpatient and/or inpatient care.
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.
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.
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
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
|
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.
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
|
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”).
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].
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
|
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].
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.
|
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.
|
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].
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.
|
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.
|
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).
|
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.
|
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].
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].
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.
|
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.
|
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.
|
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.
|
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].
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].
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].
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.
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.
|
