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 2 with Recommendations on the Tertiary
Prevention of Preterm Birth and on the Management of Preterm Premature Rupture of Membranes. Geburtsh Frauenheilk 2023; 83: 569–601
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.
Author
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 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 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 also contributes 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 OEGGG
Re 6.9.1 Type of delivery according to fetal presentation
The Austrian Society for Gynecology and Obstetrics (OEGGG) is of the opinion that there is no clinical and scientific basis for the recommendation to favor delivery by caesarean section
based on the presumed lower perinatal risk of intraventricular hemorrhage and that the type of delivery in the context of very early preterm birth (weeks 22 + 0 to 24 + 6 of gestation)
must be adapted to take account of the individual maternal and fetal clinical situation. In the context of very early preterm birth of singletons in cephalic presentation, the OEGGG
recommends an individualized management of the birth which takes the maternal and fetal clinical situation into account with the clinical decision-making process also including the option
of vaginal birth [1 ].
Dissenting opinion of the SGGG
Re 1 Definition and Epidemiology (and various other chapters: 6.9.1, 6.9.6, 6.9.7, 8.8, 8.9)
As regards the care of infants at the limits of viability, the SGGG refers to the recommendation for Switzerland developed together with neonatologists. Rationale: The
recommendations for Switzerland differ in several aspects from the recommendations for Germany. The recommendations for Switzerland are currently being revised [2 ].
Re 6.6 Administration of antenatal steroids
With regard to this chapter, see the SGGG Letter by Experts No. 56 Glucocorticoid Therapy to Promote Antenatal Lung Maturation with Threatened Preterm Birth: Indications and Dosages.
Rationale: The evidence-based recommendations in Switzerland differ slightly from those in this guideline, particularly with regards to the administration of antenatal
glucocorticoids in weeks 34 + 0 to 36 + 0 of gestation [3 ].
Re 6.2 Tocolysis
With regards to tocolytic drugs, beta-mimetic drugs have been approved for use as tocolytics in Switzerland and may be used as the first choice tocolytic drug; for further information,
see the SGGG Letter of Experts No. 41 Tocolysis for Preterm Labor. Rationale: The recommendations and practice in Switzerland differ from those in Germany [4 ].
Re 8.8 Clinical management before 22 weeks of gestation
In cases with a poor prognosis, the option to terminate the pregnancy should be mentioned. Rationale: The option of terminating the pregnancy through the induction of labor in
cases where there is a serious danger to the motherʼs physical or psychological health is not mentioned in the guideline, even though it is of clinical importance.
The dissenting opinion of the OEGGG is also adopted by the SGGG.
Recommendation 8.E63: Glucocorticoids should not be administered in the 22nd week of gestation. In special cases, they may be administered in the 23rd week of gestation if a preterm birth
is threatened within the next 7 days and after the obstetricians and neonatologists have discussed this with the patient.
IV Guideline
6 Tertiary prevention
6.1 Bedrest
Consensus-based statement 6.S25
Expert consensus
Level of consensus +++
Reference: [5 ]
There is currently no data available which confirms that bedrest reduces the preterm birth rate. However, bedrest does increase the maternal risk of thrombosis and facilitates
the development of muscle atrophy and osteoporosis.
6.2 Tocolysis
Consensus-based recommendation 6.E22
Expert consensus
Level of consensus +++
The aim of tocolysis must be to prolong the pregnancy by at least 48 hours. This allows
antenatal steroids to be administered,
in-utero transfer to a perinatal center with a neonatal intensive care unit.
6.2.1 Indications
Consensus-based recommendation 6.E23
Expert consensus
Level of consensus +++
Tocolytics to slow or stop contractions should be administered in cases with
spontaneous regular preterm contractions ≥ 4/20 min, combined with
shortening of the functional cervical length (transvaginal measurement) and/or cervical opening.
Consensus-based statement 6.S26
Expert consensus
Level of consensus +++
If tocolysis is indicated and there are no contraindications, tocolysis should be carried out in the period between week 22 + 0 and 33 + 6 of gestation.
Consensus-based statement 6.S27
Expert consensus
Level of consensus +++
References: [6 ], [7 ]
The administration of tocolytics (beta-sympathomimetics, atosiban, nifedipine, indomethacin, NO donors) to women with contractions and cervical opening can postpone the birth
by 48 h in 75 – 93% of cases and by 7 days in 62 – 78% of cases.
6.2.2 Medication
Consensus-based recommendation 6.E24
Expert consensus
Level of consensus +++
Because of their significantly higher rate of maternal side effects compared to other tocolytics (beta-sympathomimetics) and the lack of evidence confirming its tocolytic
efficacy (magnesium sulfate), continuous intravenous administration of beta-sympathomimetics or magnesium sulfate should no longer be used for tocolysis.
Of all the tocolytics, beta-sympathomimetics require the most monitoring as well as having the highest maternal (up to 80% cardiovascular) and fetal side effects [7 ]. This is compounded by an incidence of lung edema of around 1/350 applications [8 ]. They should therefore no longer be used
for tocolysis [9 ]. Bolus tocolysis with fenoterol, which is widely used in Germany, is associated with significantly fewer maternal side effects than
continuous intravenous tocolysis.
The data regarding the use of magnesium sulfate as a tocolytic is still controversial. In meta-analyses [6 ], [7 ], magnesium
sulfate was found to be effective in prolonging the pregnancy by 48 h compared to placebo (OR 2.46; 95% CI: 1.58 – 4.94); these findings contradict the results and statements of a 2014
Cochrane review [10 ] generated from 37 studies which included 3571 pregnant women. According to the Cochrane review, magnesium sulfate is not more
effective at prolonging pregnancy for 48 h than placebo or no therapy and does not lower the preterm birth rate. However, the tocolytic efficacy of magnesium sulfate depends on the
dosage and therefore also on the incidence of maternal side effects. According to a meta-analysis published in 2019, the antenatal administration of magnesium sulfate (for all
indications) was not associated with an increased rate of perinatal deaths compared to placebo/no therapy [11 ]. In international guidelines, magnesium
sulfate is no longer recommended for tocolysis [12 ], [13 ], [14 ].
Consensus-based recommendation 6.E25
Expert consensus
Level of consensus +++
References: [6 ], [7 ]
Given their efficacy and side effects profile, calcium antagonists (nifedipine), oxytocin receptor antagonists (atosiban) and COX inhibitors (indomethacin) should be used
preferably as tocolytics even though not all of them have been officially approved.
6.2.3 Combining several tocolytics
Consensus-based recommendation 6.E26
Expert consensus
Level of consensus +++
References: [8 ], [15 ]
Based on the currently available data, different tocolytics should not be combined because of the significantly higher rate of maternal side effects compared to use of a
single tocolytic and the lack of any confirmed increase in efficacy.
Consensus-based recommendation 6.E27
Expert consensus
Level of consensus +++
Reference: [16 ]
Tocolytic drugs should currently not be combined with oral/vaginal progesterone for adjunctive tocolysis as data from studies is still lacking.
6.2.4 Tocolysis in cases of extreme preterm birth, multiple pregnancy and intrauterine growth restriction
Consensus-based statement 6.S28
Expert consensus
Level of consensus ++
References: [17 ], [18 ]
There is no data from randomized controlled studies on the use of tocolytics to stop or reduce contractions in cases of preterm birth at the limits of viability, multiple
pregnancy, or intrauterine growth restriction. The decision whether or not to use tocolytics must be made on a case-by-case basis after participatory decision-making.
6.2.5 Continuous tocolysis
Consensus-based recommendation 6.E28
Expert consensus
Level of consensus ++
References: [19 ], [20 ], [21 ], [22 ], [23 ]
Based on the current state of knowledge, continuous or maintenance tocolysis (general defined as tocolysis for more than 48 h) to reduce the preterm birth rate and neonatal
morbidity and mortality should not be carried out.
Continuous tocolysis may be considered in individual cases with the consent of the pregnant woman.
6.3 Progesterone for maintenance tocolysis
Consensus-based recommendation 6.E29
Expert consensus
Level of consensus +++
Pregnant women with singleton pregnancies who have had tocolysis should not be given progesterone for maintenance tocolysis to prevent preterm birth.
A meta-analysis published in 2017 which selectively included high-quality studies on this issue showed that the use of progesterone as maintenance tocolysis did not significantly reduce
the rate of preterm births before 37 weeks of gestation (OR 1.23, 95% CI: 0.91 – 1.67) [24 ].
6.5 Administration of antibiotics for preterm contractions
Consensus-based recommendation 6.E30
Expert consensus
Level of consensus ++
Pregnant women experiencing preterm contractions with no rupture of membranes and no signs of locoregional clinical infection must not be treated with antibiotics if the only
aim is to prolong the pregnancy or reduce neonatal morbidity.
There are now many prospective randomized studies which have investigated the effect of administering an antibiotic on the preterm birth rate and perinatal morbidity in women with preterm
labor and an intact amniotic sac. However, a meta-analysis published in 2013 showed that antibiotic intervention does not improve any of the above-mentioned parameters [25 ].
More recent studies have re-examined the value of amniocentesis-guided antibiotic therapy in this context. Until valid results have been published, antibiotics should not be used as, in
addition to possibly reducing the duration of the pregnancy, other serious side effects such as selecting treatment-resistant bacteria, inducing vaginal dysbiosis, gastrointestinal
symptoms, etc. also need to be considered [26 ], [27 ]. Of course, this does not apply to patients who present with clinical
symptoms of infection.
6.6 Administration of antenatal steroids
6.6.1 Administration and dosage
Consensus-based recommendation 6.E31
Expert consensus
Level of consensus +++
Reference: [28 ]
Women with immediately threatened preterm birth before week 34 + 0 of gestation must be administered antenatal steroids consisting of 2 × 12 mg betamethasone delivered
intramuscularly at an interval of 24 h (alternatively dexamethasone, 4 × 6 mg intramuscularly every 12 h).
6.6.2 From which week of gestation?
Consensus-based recommendation 6.E32
Expert consensus
Level of consensus +++
Antenatal steroids should be administered even in cases of threatened preterm birth before 24 + 0 weeks of gestation if neonatal intensive care with maximum medical therapy is
planned.
A recently published meta-analysis found eight non-randomized studies on this issue [29 ]. The effect of a single administration of corticosteroids in
weeks 22 + 0 to 23 + 6 of gestation on neonatal mortality and morbidity is shown in [Tables 5 ] and [6 ].
Table 5 Effects of antenatal steroids on the outcome of infants between 22 + 0 and 22 + 6 weeks of gestation (Data from: [29 ]).
22 + 0 – 22 + 6 weeks of gestation
OR
95% CI
Neonatal mortality
0.58
0.38 – 0.89
Intraventricular hemorrhage (grade III – IV) or periventricular leukomalacia
1.03
0.55 – 1.93
Chronic lung disease
1.19
0.52 – 2.73
Necrotizing enterocolitis (> stage II)
0.59
0.03 – 12.03
Table 6 Effects of antenatal steroids on the outcome of infants between 23 + 0 and 23 + 6 weeks of gestation (Data from: [29 ]).
23 + 0 – 23 + 6 weeks of gestation
OR
95% CI
Neonatal mortality
0.50
0.42 – 0.58
Intraventricular hemorrhage (grade III – IV) or periventricular leukomalacia
0.75
0.55 – 1.03
Chronic lung disease
0.94
0.59 – 1.51
Necrotizing enterocolitis (> stage II)
0.93
0.66 – 1.32
While neonatal mortality is significantly reduced by a single dose of corticosteroids, it clearly had no effect on neonatal morbidity. In view of the rapid progress currently being made
in neonatal intensive medicine, prospective randomized studies on this issue are urgently required.
6.6.3 Repeat administration of antenatal steroids
Consensus-based recommendation 6.E33
Expert consensus
Level of consensus ++
Reference: [30 ]
Women treated more than 7 days previously with steroids for threatened preterm birth before week 29 + 0 of gestation, may receive a further single dose of steroids after
re-evaluation if they have an increasing risk of immediately threatened preterm birth.
6.6.4 Time when antenatal steroids should be administered
Consensus-based statement 6.S29
Expert consensus
Level of consensus +++
References: [31 ], [32 ], [33 ]
The time and indication to administer antenatal steroids must be carefully considered as neonatal morbidity and mortality is only reduced for a period of between 24 h and 7
days after the first administration. There are some indications that the administration of antenatal steroids is already effective before 24 h.
Consensus-based recommendation 6.E34
Expert consensus
Level of consensus +++
References: [34 ], [35 ]
Patients with preterm contractions and a cervical length of > 30 mm or 15 – 30 mm measured by transvaginal ultrasound and who have additionally tested negative for
fibronectin, phIGFBP-1 or PAMG-1 should not be administered antenatal steroids only because of contractions as there is only a small risk (< 5%) of preterm birth occurring
in the next 7 days.
Consensus-based recommendation 6.E35
Expert consensus
Level of consensus +++
If asymptomatic patients with a cervical length of 5 – 15 mm who have tested negative for fibronectin, phIGFBP-1 or PAMG-1 have no additional risk factors for preterm
birth, they should not be administered antenatal steroids because of the very low probability (< 1%) that they will give birth within 7 days. Nevertheless, the patient
should continue to be monitored closely with regards to her risk of preterm birth.
The preterm birth risk of asymptomatic patients with a short cervical length appears to be even lower. In a retrospective study which included 126 asymptomatic patients with a
cervical length of ≤ 25 mm between week 23 and 28 of gestation, none of the patients gave birth within 7 days and only one gave birth within 14 days. The length of her cervix was less
than 10 mm [36 ]. The respective Kaplan-Meier curves are shown in [Fig. 1 ].
Fig. 1 Probability that asymptomatic patients with a measured cervical length of less than 25 mm between week 23 and week 28 of gestation will give birth [36 ]. [rerif]
These data are supported by a further retrospective study which included 367 largely asymptomatic women (lower abdominal pressure or pain and vaginal spotting were not considered to be
exclusion criteria) with a cervical length of less than 25 mm between week 24 and 34 of gestation. Only two of these patients gave birth within 7 days [37 ].
A retrospective analysis also investigated the benefit of fibronectin tests in asymptomatic patients with a cervical length of less than 10 mm between week 22 and 32 of gestation and
compared them with patients with a cervical length of between 11 and 25 mm. The negative predictive value for a birth within 7 or 14 days was 100% for both groups and was still almost
90% for a preterm birth before week 34 of gestation [38 ]. Another retrospective study came to almost identical results [39 ] ([Table 7 ]).
Table 7 Fetal fibronectin test for the prediction of preterm birth in asymptomatic patients between 22 and 32 weeks of gestation (data from: [38 ]).
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
CL: cervical length; PPV: positive predictive value; NPV: negative predictive value
CL < 10 mm (n = 40)
Birth within < 7 days
100
64.9
18.6
100
Birth within < 14 days
100
66.7
25
100
Birth before 34 weeks of gestation
80
73.9
57.1
89.5
Birth before 37 weeks of gestation
58.8
73.9
62.5
70.8
CL 11 – 25 mm (n = 77)
Birth within < 7 days
100
78
5.8
100
Birth within < 14 days
100
73.2
11.8
100
Birth before 34 weeks of gestation
58.3
84.7
50
88.6
Birth before 37 weeks of gestation
35.7
84.7
58.8
68.4
Consensus-based recommendation 6.E36
Expert consensus
Level of consensus +++
Reference: [40 ]
An attempt to rapidly accelerate maturation by administering the second dose of betamethasone after 12 h instead of after 24 h must not be carried out as it significantly
increases the risk of necrotizing enterocolitis.
6.6.5 Administration of antenatal steroids for late preterm birth
Consensus-based recommendation 6.E37
Expert consensus
Level of consensus +++
Antenatal steroids should currently not be administered to patients with threatened preterm birth between 34 + 0 and 36 + 5 weeks of gestation as there are no studies to date
on psychomotor development in later life.
The ALPS trial showed a significant reduction of respiratory disorders in children born late preterm (between week 34 + 0 and 36 + 5 of gestation) who received 2 × 12 mg betamethasone
antenatally administered intramuscularly to their mothers [41 ]. The ASTECS trial in which mothers with elective caesarean section at term were
administered 2 × 12 mg betamethasone antenatally observed a significant reduction in RDS (respiratory distress syndrome) in the delivered infants [42 ].
However, it was found that when school assessments were performed 10 years later, teachers classified significantly more children from the treatment group in the lower quartile of
academic ability and fewer children in the top quartile of ability [43 ]. To date, no follow-up examinations of children have been carried out in the ALPS
trial. No antenatal corticoids should therefore be administered to this group of patients at present.
6.7 Emergency cerclage
Consensus-based recommendation 6.E38
Expert consensus
Level of consensus +++
References: [44 ], [45 ], [46 ]
Placement of an emergency cerclage may be considered in cases with singleton pregnancies and cervical opening of more than 1 cm before week 24 + 0 of gestation with the aim of
significantly prolonging the pregnancy.
Consensus-based recommendation 6.E39
Expert consensus
Level of consensus +++
Reference: [47 ]
Women who underwent emergency cerclage should receive indomethacin and antibiotics perioperatively.
6.8 Neuroprotection
Consensus-based statement 6.S30
Expert consensus
Level of consensus +++
Reference: [48 ]
Typical brain damage suffered by immature preterm infants is peri-/
6.8.1 Magnesium
Consensus-based recommendation 6.E40
Expert consensus
Level of consensus +++
References: [49 ], [50 ]
Intravenous administration of magnesium for fetal neuroprotection may be considered in patients with imminent preterm birth before 32 weeks of gestation.
Treatment should be initiated with a bolus of 4 – 6 grams within 30 min, followed by a maintenance dose of 1 – 2 grams for 12 h. The aim is to double the magnesium levels in maternal
serum. If the birth does not occur within 12 h, magnesium administration may be recommenced again at a later point in time if preterm birth is still imminent.
6.8.2 Delayed umbilical cord clamping
Consensus-based recommendation 6.E41
Expert consensus
Level of consensus +++
References: [51 ], [52 ]
Umbilical cord clamping should be delayed for preterm born infants. Umbilical cord milking must not be carried out if infants are born before 28 weeks of gestation.
6.9 Delivery
6.9.1 Delivery based on fetal presentation
Consensus-based recommendation 6.E42
Expert consensus
Level of consensus +++
The evidence from prospective randomized studies about the appropriate mode of delivery for preterm birth is inadequate. Caesarean section may be considered for pregnant women
who are < 30 + 0 weeks of gestation in cases of cephalic presentation after weighing up the individual risks and benefits.
Consensus-based statement 6.S31
Expert consensus
Level of consensus +++
References: [53 ], [54 ], [55 ]
There are currently no indications that caesarean section considered solely because of gestational age will reduce neonatal mortality/morbidity in women with singleton
pregnancies in cephalic presentation and threatened preterm birth from week 30 + 0 of gestation.
Consensus-based recommendation 6.E43
Expert consensus
Level of consensus +++
Reference: [56 ]
Depending on the ultrasound-based fetal weight estimation and other influencing factors, a caesarean section should be considered for pregnant women who are < 36 + 0 weeks
of gestation with the fetus in breech presentation to reduce neonatal morbidity and mortality.
6.9.2 Longitudinal uterine incision for caesarean section
Consensus-based recommendation 6.E44
Expert consensus
Level of consensus +++
Uterine longitudinal incision may be beneficial in individual cases, particularly in cases of extreme preterm birth, as it can be the most sparing option to deliver the
child.
Consensus-based recommendation 6.E45
Expert consensus
Level of consensus +++
References: [57 ], [58 ]
For women who are status post caesarean section by longitudinal uterine incision, primary caesarean section must be recommended in all subsequent births because of the
increased risk of uterine rupture.
6.9.3 Vaginal surgical delivery
Consensus-based recommendation 6.E46
Expert consensus
Level of consensus +++
Reference: [59 ]
Delivery by vacuum extraction before week 34 + 0 of gestation should be avoided because of the increased risk of intraventricular hemorrhage.
6.9.4 Fetal blood analysis
Consensus-based recommendation 6.E47
Expert consensus
Level of consensus +++
No fetal blood analysis should be carried out before week 34 + 0 of gestation due to the potential risk of injury.
6.9.5 Antibiotic prophylaxis against group B streptococci
Consensus-based recommendation 6.E48
Expert consensus
Level of consensus +++
Reference: [60 ]
Antibiotic prophylaxis must be administered during labor if the GBS status of a preterm birth is positive or unknown.
6.9.6 Cooperating with the neonatology department
Consensus-based recommendation 6.E49
Expert consensus
Level of consensus +++
References: [61 ], [62 ], [63 ]
A pediatrician/neonatologist must be involved at an early stage of the treatment and counseling of cases with threatened preterm birth.
The treating pediatrician must be provided with all information about the pregnant woman which is important for providing primary care and treatment to the neonate. This may include
medication, HbsAg status, blood group, CMV antibody status (up until week 32 of gestation), any findings of a prenatal diagnostic workup, and the results of microbiological screening of
the pregnant woman with threatened preterm birth for GBS (group B streptococci), MRSA (multi-resistant staphylococcus aureus), MRGN (multi-resistant gram-negative bacteria), as well as
the results of any repeat screening if the pregnancy has been prolonged.
Consensus-based recommendation 6.E50
Expert consensus
Level of consensus ++
Reference: [64 ]
A doctor with neonatology experience must be present in cases of preterm birth (< 35 + 0 weeks of gestation) to provide immediate care to the neonate. A neonatology
specialist must be on call in cases of threatened preterm birth before 32 + 0 weeks of gestation and/or an estimated/birth weight of < 1500 g.
6.9.7 End-of-life care
Consensus-based statement 6.S32
Expert consensus
Level of consensus +++
References: [65 ], [66 ], [67 ]
In the perinatal phase, specially trained staff must be called in to provide palliative care or end-of-life care for dead or dying neonates and their families. Providing
end-of-life care is an intrinsic part of training in perinatology. According to the principles of the German Medical Association, the provision of dignified end-of-life care is
a key medical task which cannot be delegated.
7 Special features of twin and multiple pregnancies
7.1 Epidemiology and etiology
Consensus-based statement 7.S33
Expert consensus
Level of consensus +++
References: [68 ], [69 ]
Women with multiple pregnancies have a significantly higher risk of preterm birth.
7.2 Prevention
7.2.1 Progesterone
Consensus-based recommendation 7.E51
Expert consensus
Level of consensus +++
References: [70 ], [71 ]
Women must not be administered progesterone to prevent preterm birth only because they have a twin pregnancy.
Consensus-based statement 7.S34
Expert consensus
Level of consensus +++
There is insufficient data to recommend that women with a twin pregnancy and a cervical length of ≤ 25 mm before week 24 + 0 of gestation measured by transvaginal ultrasound
should be administered progesterone.
An individual patient data meta-analysis (IPDMA) by Romero et al. published in 2017 which included six studies and compared the administration of vaginal progesterone with placebo or no
treatment in 303 asymptomatic twin pregnancies with a cervical length of ≤ 25 mm in the second trimester of pregnancy found a significant reduction in preterm births before week 33 of
gestation (31.4% vs. 43.1%; RR 0.69 [95% CI: 0.51 – 0,93]) and better neonatal outcomes (e.g., lower rates of neonatal death [RR 0.53 {95% CI: 0.35 – 0.81}], respiratory distress
syndrome [RR 0.70 {95% CI: 0.56 – 0.89}], birthweight < 1500 g [RR 0.53 {95% CI: 0.35 – 0.80}]) [72 ]. This meta-analysis weighted the study by
El-Refaie, in which progesterone was administered in daily doses of 400 mg, with 70.4% [73 ]. This study has since been retracted by the journal as the
study had no consent from an ethics committee and there are serious reservations about the validity and integrity of the data. Consequently, the statements of the meta-analysis by Romero
et al. must be treated with caution.
7.2.2 Cerclage
Consensus-based recommendation 7.E52
Expert consensus
Level of consensus +++
Primary cerclage should not be placed in women with twin pregnancy.
Consensus-based recommendation 7.E53
Expert consensus
Level of consensus +++
Secondary cerclage may be considered for pregnant women with twin pregnancy and a cervical length of less than 15 mm before week 24 + 0 of gestation.
A meta-analysis published in 2021 which included 1211 women with twin pregnancy from 16 studies showed that placement of a cerclage in patients with twin pregnancy and a cervical length
of less than 15 mm significantly reduced the preterm birth rate before 34 weeks of gestation (RR 0.57; 95% CI: 0.43 – 0.75) and prolonged the pregnancy by almost 4 weeks compared to the
control group (95% CI: 2.19 – 5.59) [74 ].
7.2.3 Cervical pessary for short cervical length
Consensus-based recommendation 7.E54
Expert consensus
Level of consensus +++
References: [75 ], [76 ], [77 ], [78 ], [79 ], [80 ]
Placement of a cervical pessary in women with twin pregnancy and a cervical length of ≤ 25 mm before week 24 + 0 of gestation, measured by transvaginal ultrasound should be
carried out on a case-by-case basis.
7.2.4 Cervical pessary for preterm labor with short cervical length
Consensus-based statement 7.S35
Expert consensus
Level of consensus +++
Reference: [81 ]
A prospective randomized study has indicated that placement of a cervical pessary may reduce the rate of preterm births in women with twin pregnancy who have been treated for
preterm labor and who have a short cervical length, as measured by transvaginal ultrasound (< 20 mm between week 24 + 0 and 29 + 6 of gestation; < 10 mm between week
30 + 0 and 33 + 6 of gestation).
7.2.5 Emergency cerclage
Consensus-based recommendation 7.E55
Expert consensus
Level of consensus +++
Emergency cerclage should be placed in women with twin pregnancy and cervical opening of more than 1 cm before 24 + 0 weeks of gestation with the aim of significantly
prolonging the pregnancy.
A prospective randomized study showed that emergency cerclage in women with twin pregnancy and cervical opening reduced the rate of preterm births before 34 weeks of gestation (RR 0.71;
95% CI: 0.52 – 0.96) and the perinatal mortality rate (6/34 [17.6%] vs. 20/26 [77%]; RR 0.22, 95% CI: 0.1 – 0.5) and significantly prolonged the interval between the diagnosis of
cervical opening and the birth (8.3 ± 5.8 vs. 2.9 ± 3.0 weeks) [82 ].
8 Premature Preterm Rupture of Membranes (PPROM)
8.1 Prevalence and etiology
Consensus-based statement 8.S36
Expert consensus
Level of consensus +++
Reference: [83 ]
Around 3% of pregnant women have a premature preterm rupture of membranes (rupture of membranes before week 37 + 0 of gestation): 0.5% before 27 weeks of gestation, 1% between
27 and 34 weeks of gestation and 1% between 34 and 37 weeks of gestation.
8.2 Risk factors
Consensus-based statement 8.S37
Expert consensus
Level of consensus +++
References: [84 ], [85 ], [86 ], [87 ], [88 ], [89 ], [90 ], [91 ], [92 ]
A previous history of premature preterm rupture of membranes (PPROM) is a significant risk factor for PPROM. Additional risk factors are the same as those for spontaneous
preterm birth.
8.3 Diagnosis
Consensus-based recommendation 8.E56
Expert consensus
Level of consensus +++
References: [93 ], [94 ]
In most cases, PPROM is diagnosed by speculum examination. Biochemical tests must be used if there is any uncertainty.
Consensus-based recommendation 8.E57
Expert consensus
Level of consensus +++
References: [95 ], [96 ]
Digital examinations must not be carried out in patients with PPROM.
8.4 Latency period
Consensus-based statement 8.S38
Expert consensus
Level of consensus +++
References: [97 ], [98 ]
More than 50% of all patients with PPROM give birth after one week.
8.5 Maternal and fetal risks
Consensus-based statement 8.S39
Expert consensus
Level of consensus +++
References: [99 ], [100 ], [101 ], [102 ], [103 ], [104 ]
Patients with PPROM are at risk of clinical infection. Additional risks include placental abruption and umbilical cord prolapse.
8.6 Triple I
Consensus-based statement 8.S40
Expert consensus
Level of consensus ++
Internationally, the term Triple I has replaced the term chorioamnionitis to differentiate maternal fever from infection or inflammation or both ([Table 8 ]).
Table 8 Classification of maternal fever in Triple I*.
Definition
* Triple I: inflammation or infection or both; **amniotic fluid obtained by amniocentesis; ***postpartum histopathology of the placenta [105 ].
Maternal fever
An orally measured temperature of more than 39.0 °C is classified as maternal fever.
If the orally measured temperature is between 38.0 and 38.9 °C, the measurement is repeated after 30 min. If the temperature is again above 38.0 °C, this is classified as
maternal fever.
Suspicion of Triple I
Maternal fever of unknown origin and one of the following characteristics:
fetal tachycardia > 160 beats/min for more than 10 min
maternal leukocytes are > 15 000 µl without using corticosteroids
purulent cervical discharge
Confirmed Triple I
Suspicion of Triple I and objective findings of an infection such as
positive amniotic fluid** Gram stain, low glucose levels (< 14 mg/dL), elevated leukocyte levels (> 30 cells/mm3 ), positive bacterial culture
or
histopathological findings*** of inflammation or infection or both of the placenta, the fetal membranes or the umbilical cord (funisitis)
8.7 Maternal and fetal risks associated with Triple I
Consensus-based statement 8.S41
Expert consensus
Level of consensus +++
References: [106 ], [107 ], [108 ], [109 ], [110 ], [111 ]
Maternal risks associated with Triple I include sepsis, uterine dysfunction with the risk of failure to progress in labor, and postpartum uterine atony. Women who give birth by
caesarean section are at increased risk of wound infection, endometritis, thrombophlebitis, and pelvic abscess formation.
Consensus-based statement 8.S42
Expert consensus
Level of consensus +++
References: [112 ], [113 ]
The fetus may develop inflammatory response syndrome if Triple I is present. Postnatally, affected infants have a high risk of sepsis.
8.8 Clinical management of PPROM before 22 weeks of gestation
Consensus-based recommendation 8.E58
Expert consensus
Level of consensus +++
References: [114 ], [115 ], [116 ]
If PPROM occurs before the fetus reaches viability, the risks of maternal sepsis, fetal pulmonary hypoplasia and fetal skeletal anomalies must be discussed with the expectant
parents.
Consensus-based recommendation 8.E59
Expert consensus
Level of consensus +++
Treatment with antibiotics may be considered for patients with PPROM before the fetus reaches viability.
As almost all studies on antibiotic therapy in cases with rupture of membranes only recruited patients after week 24 + 0 of gestation, there are no reliable data on the administration of
antibiotics before the fetus reaches viability. But the risk that the patient could develop sepsis from ascending infection is sufficient for antibiosis to be advisable [117 ]. The same regimen may be used as reported for cases with PPROM occurring between (22 + 0) 24 + 0 and 33 + 6 weeks of gestation.
Consensus-based recommendation 8.E60
Expert consensus
Level of consensus +++
Antenatal steroids, tocolysis, or neuroprotection with magnesium must not be administered in cases with PPROM before the fetus has reached viability.
8.9 Clinical management of PPROM between (22 + 0) 24 + 0 and 33 + 6 weeks of gestation
Consensus-based recommendation 8.E61
Expert consensus
Level of consensus +++
If PPROM occurs between 22 + 0 and 23 + 6 weeks of gestation, all further actions must be discussed and agreed upon with the parents in accordance with the guideline “Preterm
infants at the limits of viability 024-019”.
8.9.1 Expectant management
Consensus-based recommendation 8.E62
Expert consensus
Level of consensus +++
If the mother or infant are not in immediate danger, expectant management must be initially considered for PPROM between 22 + 0 and 23 + 6 weeks of gestation if maximum
therapy is requested and for PPROM between 24 + 0 and 33 + 6 weeks of gestation.
If PPROM occurs between 24 + 0 and 33 + 6 weeks of gestation or between 22 + 0 und 23 + 6 weeks of gestation and maximum therapy is requested, the risk of ascending infection must be
weighed against the neonatal risks which may result from a preterm birth [118 ]. Ascending infection with chorioamnionitis, preterm placental abruption,
pathological CTG (cardiotocography) trace, a high risk of or the presence of umbilical cord prolapse are all indications for immediate delivery of the infant. Otherwise, the standard
international approach is currently expectant management [119 ].
8.9.2 Administration of antenatal steroids
Consensus-based recommendation 8.E63
Expert consensus
Level of consensus +++
Patients with PPROM between 22 and 23 + 6 weeks of gestation if maximum therapy is requested or between 24 + 0 and 33 + 6 weeks of gestation must be given antenatal steroids
consisting of 2 × 12 mg betamethasone administered intramuscularly at an interval of 24 h (alternatively, dexamethasone, 4 × 6 mg intramuscularly every 12 h).
8.9.3 Administration of antibiotics
Consensus-based recommendation 8.E64
Expert consensus
Level of consensus +++
* The approach followed before week 22 + 0 of gestation and between week 34 + 0 and 36 + 6 of gestation is described in 8.E59 and 8.E70.
Reference: [120 ]
Patients with PPROM between 22 + 0 and 33 + 6 weeks of gestation must be treated with antibiotics.*
Consensus-based recommendation 8.E65
Expert consensus
Level of consensus +++
* There are no clear recommendations for the dosages and duration of azithromycin administration. One commonly used dosage consists of administration of a single dose of 1 g
on the first day. However, the recommended therapy regimen for azithromycin in the specialist information is a total dose of 1.5 g administered over a 3-day period (3 × 500 mg)
or a 5-day regimen to be sufficiently effective. Unfortunately, there are currently no prospective randomized studies on the dosage and duration of azithromycin administration.
A retrospective analysis of 4 different antibiotic regimens (single dose of 1 g azithromycin, azithromycin over a period of 5 days, azithromycin over a period of 7 days and
erythromycin for 7 days) in addition to standard intravenous administration of ampicillin for 2 days, followed by oral amoxicillin for 5 days showed no differences with regard
to latency periods and the chorioamnionitis rate. However, preterm neonates in the 5 days azithromycin group had higher rates of RDS (44%) compared to the group which received
a single dose of azithromycin (29%) and the erythromycin group (29%) [121 ].
References: [97 ], [119 ], [120 ]
The currently available data do not permit any recommendations to made with regards to a specific therapy regimen. One option consists of intravenous ampicillin administration
for 2 days followed by 5 days of oral amoxicillin as well as oral administration of azithromycin* at the start. Amoxicillin must not be combined with clavulanic acid.
8.9.4 Tocolysis
Consensus-based statement 8.S43
Expert consensus
Level of consensus +++
Reference: [122 ]
Tocolysis is not associated with a significant improvement in perinatal morbidity and mortality in cases with PPROM.
Tocolysis may be considered in cases with preterm labor until fetal lung maturation is completed (the decision must be taken on a case-by-case basis).
8.9.5 Neuroprotection
See 6.8.1.
8.9.6 Maternal and fetal monitoring
Consensus-based recommendation 8.E66
Expert consensus
Level of consensus +++
Patients with PPROM must be monitored for Triple I. Clinical signs include maternal fever plus one of the following findings: fetal tachycardia (> 160 beats/min) or
maternal leukocytes > 15000/µl or purulent cervical discharge.
Pregnant women with preterm premature rupture of membranes should be routinely examined for signs of infection. Signs of infection include the above-mentioned clinical parameters as
well as symptoms such as painful uterus, uterine contractions, maternal blood pressure, and heart rate [105 ]. In addition, blood count and CRP
(C-reactive protein) must be checked daily at least once. It should be noted that the benefit of daily laboratory tests is controversial [123 ]. Kunze et
al. reported an AUC (area under the curve) of just 0.66 for a combination of maternal fever, CRP and leukocytes to predict FIRS (fetal inflammatory response syndrome) [124 ]. Musilova et al. reported that a CRP of 17.5 mg/L in maternal serum had a sensitivity of 47%, specificity of 96%, positive predictive value of 42% and
negative predictive value of 96% for the prediction of intraamniotic infection or inflammation [125 ].
Daily CTG monitoring of patients with PPROM is standard clinical practice. But there is currently no fetal monitoring method which reliably indicates whether intrauterine inflammation
or infection is present. Neither CTG trace nor combining CTG with other tests to create a biophysical profile (CTG plus fetal breathing and other movement, fetal tone and amniotic fluid
volume) are suitable as predictors of intrauterine infection (CTG: sensitivity 39%; biophysical profile: 25%) [104 ].
Regular monitoring of amniotic fluid volume is similarly pointless. Although reduced amniotic fluid increases the risk of umbilical cord compression and demonstrably shortens the time
to the start of labor, the value for predicting a negative outcome is low [126 ]. The use of Doppler sonography has no confirmed benefits for preterm
rupture of membranes [127 ].
Consensus-based statement 8.S44
Expert consensus
Level of consensus +++
Reference: [128 ]
Performing amniocentesis to diagnose Triple I is only useful in exceptional cases, e.g., in cases where the source of maternal infection is unclear.
Consensus-based statement 8.S45
Expert consensus
Level of consensus +++
References: [124 ], [129 ]
According to the current state of knowledge, using biochemical parameters measured in vaginal secretions to predict Triple I is not useful.
8.9.7 Amnioitic infusion
Consensus-based statement 8.S46
Expert consensus
Level of consensus +++
References: [130 ], [131 ]
Based on the currently available data, it is not possible to say whether carrying out amniotic infusion in cases with PPROM is beneficial or not.
8.9.8 Antibiotic prophylaxis against group B streptococci
See the recommendations on GBS prophylaxis.
8.9.9 Delivery
Consensus-based recommendation 8.E67
Expert consensus
Level of consensus +++
References: [118 ], [119 ]
From 34 + 0 weeks of gestation, delivery or expectant management may be considered for patients with PPROM between 22 and 23 + 6 weeks of gestation if maximum therapy is
requested or between 24 + 0 and 33 + 6 weeks of gestation. Indications for an immediate delivery irrespective of gestational age are (suspected or confirmed) Triple I, preterm
placental abruption, pathological CTG trace, or high risk or presence of umbilical cord prolapse.
Consensus-based recommendation 8.E68
Expert consensus
Level of consensus +++
Patients with (suspected or confirmed) Triple I must be treated with antibiotics and the infant must be delivered immediately.
8.10 Clinical management of PPROM between 34 + 0 and 36 + 6 weeks of gestation
Consensus-based recommendation 6.E69
Expert consensus
Level of consensus +++
Unless otherwise contraindicated, women with premature preterm rupture of membranes between 34 + 0 and 36 + 6 weeks of gestation should be offered the option of expectant
management as an alternative to immediate delivery, with the aim of prolonging the pregnancy until week 37 + 0 of gestation.
Between 2004 and 2013, a total of 1839 women between 34 + 0 and 36 + 6 weeks of gestation and premature preterm rupture of membranes (PPROM) were recruited into the PPROMT trial [132 ]. The trial compared immediate induction of labor with expectant management. 21% of infants from the group managed with an expectant approach were born
after 37 weeks of gestation, whereas only 3% of infants from the control group were born after 37 weeks. The prevalence of neonatal sepsis was the same in both groups; however, RDS
occurred significantly less often with expectant management. The birthweight of neonates born after expectant management was also significantly higher and the time spent in the neonatal
intensive care unit or in hospital was shorter. However, as expected, uterine bleeding before or during the birth and maternal fever during the birth was more common in the mothers of
these infants. The caesarean section rate was significantly lower compared to the group which had induction of labor [132 ].
The results of the PPROMT trial are supported by the PPROMEXIL and PPROMEXIL-2 trials [133 ], [134 ]. However, if
colonization with group B streptococci was diagnosed, the prevalence of early onset sepsis in affected neonates increased significantly (15.2 vs. 1.8%; p = 0.04) [135 ]. According to a meta-analysis of 12 studies on this issue, no increased prevalence of neonatal sepsis was observed with expectant management. After
immediate induction of labor, rates of RDS, neonatal mortality, the need for artificial respiration, endometritis, and caesarean section were significantly higher, while the incidence of
chorioamnionitis decreased [118 ]. A patient-level meta-analysis came to similar results [136 ].
Consensus-based recommendation 8.E70
Expert consensus
Level of consensus +++
Clinical monitoring and antibiotic treatment of cases with PPROM between 34 + 0 and 36 + 6 weeks of gestation must be carried out in the same way as described for (22 + 0)
24 + 0 – 33 + 6 weeks of gestation. No antenatal steroids, tocolysis, or neuroprotection with magnesium must be administered.
9 Psychosomatic support and supportive therapies
Consensus-based recommendation 9.E71
Expert consensus
Level of consensus +++
Pregnant women who have been admitted to hospital for preterm labor and women who have had a preterm birth should be offered psychosomatic support and a choice of supportive
therapies.
In addition to worries about the impact of a preterm birth on maternal and infant health, which may be difficult to gauge, therapeutic measures which can include immobilization, tocolysis,
and the administration of cortisone are also experienced as stressful. If additional stresses are present (previous experience of loss, prior psychological illness, relationship problems,
etc.), the incidence of anxiety and depression increases [137 ], [138 ], [139 ].
Hospitalization of the mother puts enormous organizational pressure on the family system, particularly in big families.
Several different psychometric tests are available to detect psychological and social stress factors, for example, HADS, the Babylotse-Plus screening questionnaire, etc. [140 ].
Affected couples should be offered acute psychological crisis intervention to start with followed by the offer of supportive talks and psychotherapy, if required. This approach also
encourages parent-child bonding.
Support from self-help groups such as the federal association “Das Frühgeborene Kind (The preterm-born child)” [141 ] may help affected parents, and
parents should be informed about their options.
Affected families should be actively encouraged to make use of locally and regionally available “Early Support” options which provide coordinated offers of help to parents and children with
the aim of sustainably improving familial and social development opportunities for children and parents very early on [142 ].
The Babylotse program has been proven to be especially helpful, as it aims to systematize the transition of families from the healthcare system to the “Early Support” network and other
social security systems. The key aim of the program is to guide families in such a way that they are able to find, select, and use the most suitable facilities out of the range of locally
available options.
All of these measures should be considered as providing additional support and care to patients and their families by the attending midwife.
10 Counseling after previous spontaneous preterm birth
Consensus-based recommendation 10.E72
Expert consensus
Level of consensus +++
After a spontaneous preterm birth, the affected parents must be advised by the obstetric team caring for them about the risk of recurrence in any subsequent pregnancy and the
primary prevention options.
Consensus-based recommendation 10.E73
Expert consensus
Level of consensus +++
A pregnant woman who has had a previous spontaneous preterm birth must be advised about the options of primary and secondary prevention.
The patient guideline “Preterm birth: what you need to know as expectant parents” may be very useful as a basis for counseling in this context [143 ].
