Keywords
cerclage - interpregnancy interval - premature birth - cervical insufficiency - late
miscarriage
Introduction
Late miscarriage or preterm birth is a significant emotional and physical burden for
affected women [1]
[2].
The wish to have another pregnancy, especially after suffering the loss of a child,
is often very strong. For many women, the previous pregnancy shows them just how strong
their wish is to have a child [3].
Counseling patients after late miscarriage or preterm birth is important but often
challenging, as the wish to quickly start a subsequent pregnancy can be very strong.
Recommendations on the optimal interval until starting a subsequent pregnancy are
inconsistent and depend on the treating physician or the patient’s individual situation.
After a live birth, the WHO recommends leaving an interval of at least 24 months before
the next conception to reduce the risk of maternal and neonatal complications. In
contrast, the American College of Obstetricians and Gynecologists (ACOG) considers
an interval of at least six months to be sufficient but advises against an interpregnancy
interval of less than six months. The ACOG also emphasizes the importance of individual
counseling about the risk of having another pregnancy before 18 months have expired
since the last pregnancy. Several studies and meta-analyses have reported a correlation
between a short interpregnancy interval of less than 6 months and a higher risk of
low birth weight, preterm birth and intrauterine or neonatal death [4]
[5]
[6].
When treating high-risk pregnant women with a medical history of preterm birth, the
main aim is to increase the probability of a birth at term. Prophylactic (primary)
cerclage with or without additional TCC may be considered for patients with a prior
history of late miscarriage or preterm birth. If the cervical length late in the first
trimester or early in the second trimester of pregnancy is unremarkable, a surgical
procedure can be carried out to mechanically stabilize the cervix. This is an effective
established approach. Several studies and meta-analyses have shown that cerclage can
significantly reduce the risk of repeat late miscarriage or preterm birth [7]
[8].
The most common surgical cerclage techniques are McDonald cerclage and Shirodkar cerclage.
It is not clear which of these surgical techniques is more effective [9]
[10]
[11].
A secondary cerclage may be considered in addition to primary cerclage in high-risk
patients if the cervix decreases to less than 25 mm.
According to the S2k-guideline “Prevention and Therapy of Preterm Birth” issued by
the DGGG (2022), vaginal microbiological diagnostic tests are recommended for pregnant
women with a relevant medical history to identify asymptomatic bacterial or mycotic
infections at an early stage and prevent ascending infection as a potential cause
of preterm birth [12]. Such infections are considered potential contributors to late miscarriage and preterm
birth. If the test findings are pathological, targeted antibiotic or antimycotic therapy
must be administered prior to carrying out the cerclage. A vaginal microbiome dominated
by Lactobacillus species is considered protective, while bacterial dysbiosis, especially bacterial
vaginosis, is associated with a higher risk of spontaneous preterm birth [13].
Patients and Methods
Study design and population
A retrospective analysis of patient data from the Gynecology Department of the University Hospital Freiburg
was carried out. Women with an adverse obstetric medical history, defined as late miscarriage or preterm birth who underwent prophylactic cerclage with TCC late in the first trimester or early in the second trimester of pregnancy were included
in the study.
Diagnosis and preoperative preparation
Prior to placement of the cerclage, a microbiological vaginal swab was taken from all patients. If the findings were unsuspicious, the surgical procedure
was performed shortly thereafter. If pathological microorganisms were identified, targeted antibiotic therapy was initiated based on the antibiogram. Cerclage and TCC were carried out after the conclusion of antibiotic treatment irrespective of whether microbiological eradication was confirmed or not.
Surgical technique
Surgical cerclage was carried out using the McDonald technique as it is the preferred procedure used in the investigating hospital because the department
has many years of experience with this technique. Non-absorbable polyfilament suture material was used for mechanical stabilization of the cervix. TCC was additionally carried
out using absorbable sutures.
Assignment into groups based on the interpregnancy interval
Patients were divided into three groups based on the interval between the previous
and the subsequent (current) pregnancy:
-
Group 1: interpregnancy interval of 0 to 6 months
-
Group 2: interpregnancy interval of 6 to 12 months
-
Group 3: interpregnancy interval of > 12 months
Primary endpoint: time of delivery
Primary endpoint was the time of delivery divided into:
Secondary endpoints: neonatal outcome
Secondary endpoints for fetal outcome included:
This retrospective data analysis is a non-interventional study. The Ethics Committee
of Albert Ludwig University Freiburg approved the study (vote no. 24-1552-S1-retro).
Statistical analysis
Fisher’s exact test for r×c contingency tables was used for the statistical analysis of correlations
between interpregnancy interval and pregnancy outcome as it provides robust results
even for small samples [14].
Shapiro-Wilk test was used to evaluate infant parameters (birth weight, Apgar scores, umbilical cord
pH) for normal distribution [15]. Non-parametric tests for birth weight and Apgar scores were done as these parameters were not normally distributed.
-
Comparison of groups: Kruskal-Wallis test
[16].
-
Correlations: Spearman’s rank correlation
-
Umbilical cord pH was evaluated using one-way analysis of variance (ANOVA).
A significance level of α = 0.05 was set for all statistical tests.
Results
The analysis initially included 138 patients. Seven patients had to be excluded because
of missing data, meaning that the final evaluation included a total of 131 patients.
The distribution of interpregnancy intervals was as follows:
-
10 patients had an interval of 0–6 months,
-
25 patients had an interval of 6–12 months,
-
96 patients had an interval of > 12 months.
Patient demographic data
There were only slight differences between the three groups with regard to age and
medical history. Patients with an interval of more than 12 months tended to have a
higher number of gravidities (median 3.5) and more late miscarriages and preterm births.
The mean age in all groups was 32 years ([Table 1]).
Table 1
Patient demographic data. Initial demographic and obstetric characteristics of the
investigated patients grouped according to interpregnancy interval. Age, gravidity,
parity and number of previous late miscarriages and preterm births of the women who
underwent prophylactic cerclage and TCC are presented, with the women divided into
three groups according to the interpregnancy interval: 0–6 months (Group 1, n = 10),
6–12 months (Group 2, n = 25) and > 12 months (Group 3, n = 96). Values are shown
as median with interquartile range (IQR) or arithmetic mean with standard deviation
(SD).
|
Variable
|
Group 1
0–6 months
(n = 10)
|
Group 2
6–12 months
(n = 25)
|
Group 3
> 12 months
(n = 96)
|
|
Age (years) (median [IQR])
|
33 (10.5)
|
31 (8)
|
33 (8)
|
|
Age (years) (mean ± SD)
|
31.1 ± 5.76
|
32.52 ± 4.48
|
32.53 ± 5.54
|
|
Gravidity (median [IQR])
|
2.5 (2)
|
2 (2)
|
3.5 (2)
|
|
Gravidity (mean ± SD)
|
3.4 ± 1.84
|
2.92 ± 1.54
|
3.92 (1.68)
|
|
Parity (median [IQR])
|
2.0 (0.75)
|
1 (1)
|
2 (3.1)
|
|
Parity (mean ± SD)
|
1.0 ± 0.0
|
1.0 ± 0.0
|
1.46 ± 0.55
|
|
Status post late miscarriage (median [IQR])
|
1.0 (0.0)
|
1 (0)
|
1.0 (1–2)
|
|
Status post late miscarriage (mean ± SD)
|
1.0 ± 0.0
|
1.0 ± 0.0
|
1.46 ± 0.55
|
|
Status post preterm birth (median [IQR])
|
1.0 ± 0.0
|
1.0 ± 0.0
|
1.46 ± 0.55
|
|
Status post preterm birth (mean ± SD)
|
2.0 ± 0.0
|
2.0 ± 0.00
|
1.46 ± 0.55
|
Primary endpoint: time of delivery in the three groups
Preterm births depend on the interpregnancy interval and gestational age
A total of 131 patients who had prophylactic cerclage and TCC after previous late
miscarriage or preterm birth were divided into three groups, based on the interpregnancy
interval since the previous pregnancy: Group 1 (0–6 months, n = 10), Group 2 (6–12
months, n = 25) and Group 3 (> 12 months, n = 96) ([Fig. 1]).
Fig. 1
Pregnancy outcomes according to the interpregnancy interval for 131 women who had
prophylactic cerclage and TCC. Absolute numbers of late miscarriages, preterm births
and term births are shown, grouped according to interpregnancy interval: 0–6 months
(n = 10), 6–12 months (n = 25) and > 12 months (n = 96). Pregnancy outcomes are classified
according to gestational age: late miscarriage (< 24+0 GW), preterm birth (24+0 to
< 37+0 GW), term birth (≥ 37+0 GW).
Time of delivery and distribution of preterm births
A late miscarriage was recorded for 10% (1/10) of women in Group 1; 60% (6/10) had
a preterm birth, four of which were extremely preterm births (< 28+0 GW), one was
a severe (28+1–32+0 GW) and was a moderate/late preterm birth (32+1–36+6 GW). 30%
(3/10) of women achieved a term birth ≥ 37+0 GW.
In Group 2, 4% (1/25) of women had a late miscarriage, 32% (8/25) had a preterm birth
(four < 28+0 GW, two between 28+1 and 32+0 GW, two between 32+1 and 36+6 GW). 64%
(16/25) had a term birth.
The late miscarriage rate in Group 3 was 1% (1/96) and the preterm birth rate was
13.5% (13/96). The distribution of preterm births was five < 28+0 GW, three between
28+1 and 32+0 GW and five between 32+1 and 36+6 GW. The term birth rate was 85.4%
(82/96) ([Fig. 2]).
Fig. 2
Preterm births differentiated according to gestational age at delivery and grouped
according to interpregnancy interval for 131 women who had prophylactic cerclage and
TCC. Preterm births are shown as absolute numbers. Preterm births are classified into:
extremely preterm birth (23+5 to 28+0 GW), severe preterm birth (28+1 to 32+0 GW),
moderate to late preterm birth (32+1 to 36+6 GW). This classification is based on
the classification of the WHO. Grouping of preterm births according to the interpregnancy
interval was: 0–6 months (n = 10), 6–12 months (n = 25) and > 12 months (n = 96).
The data presented here apply only to the 27 preterm births shown in [Fig. 1].
Correlation between interpregnancy interval and pregnancy outcome
The frequency of late miscarriages, preterm births and term births varied significantly,
depending on the interpregnancy interval (p < 0.001; Fisher’s exact test). A longer
interval was associated with a significantly lower preterm birth rate and a higher
rate of term births.
Secondary endpoints: neonatal parameters depending on the interpregnancy interval
The analysis of neonatal parameters showed differences between groups with different
interpregnancy intervals.
Apgar scores differed significantly depending on the interpregnancy interval. The
group with an interval of 0–6 months showed the greatest variability between scores
and had the lowest Apgar scores, especially Apgar scores at one minute (p = 0.02).
Apgar scores of the group with an interval of 6–12 months were more stable and median
scores at 5 and 10 minutes were higher (p = 0.03 and p = 0.04, respectively). The
highest and most stable Apgar scores were observed in the group with an interpregnancy
interval of more than 12 months, with little variation and almost constantly high
values at all time points (p < 0.01).
Birth weight varied significantly depending on the interpregnancy interval. The neonates
with the lowest birth weights were in the group with an interpregnancy interval of
0–6 months, with a wide range of birth weights including several birth weights under
2500 g (p = 0.01). The birth weights in the group with an interval of 6–12 months
were higher and the variability was lower (p = 0.02). The highest birth weights were
observed in the group with an interval of more than 12 months, with most birth weights
closely grouped around the median and only a few infants with a birth weight < 2500
g (p < 0.01).
There were no significant differences in umbilical cord pH values between groups,
which indicates that umbilical cord pH was not affected by the interpregnancy interval.
The longer the interpregnancy interval between the previous and the subsequent pregnancy,
the fewer neonates required admission to the NICU. In the group with an interval of
0–6 months, 44.4% (4/9) of neonates were admitted to the NICU; in the group with an
interval of 6–12 months 33.3% (8/24) required admission, and in the group with an
interval of more than 12 months 10.6% (10/94) of neonates were transferred to the
NICU. Only live births are included in these figures; late miscarriages were not included.
No information about admission to the NICU was available for one of the patients in
group 3 (interval > 12 months) ([Fig. 3]).
Fig. 3
Neonatal parameters according to interpregnancy interval in 131 women with prophylactic
cerclage and total cervical closure (TCC). Shown are Apgar scores at 1, 5, and 10
minutes (a), birth weight (b), umbilical cord arterial pH (c), and neonatal admission status to the pediatric clinic (d). Grouping was performed according to interpregnancy interval: 0–6 months (n = 10),
6–12 months (n = 25), and > 12 months (n = 95). For the analysis of neonatal admission,
all late miscarriages (n = 3) were excluded. In the group with an interpregnancy interval
> 12 months, information on admission status was missing for one patient.
Discussion
For patients who have had a late miscarriage or preterm birth, the overriding aim
in a subsequent pregnancy is to maximize the probability of a term birth. Early structured
interpregnancy counseling is essential.
Patients should be informed that a short interval between a previous pregnancy and
the next pregnancy is associated with a higher risk of adverse pregnancy outcomes
and neonatal complications [17]
[18].
Cerclage placement is a key element in the preventive care of women with a high risk
of late miscarriage or preterm birth. Depending on the individual risk constellation,
cerclage may be carried out as a primary or secondary procedure, with or without additional
TCC. Cerclage is used as a mechanical means of stabilizing the cervix and is an established
procedure to treat cervical insufficiency or a sonographically shortened cervix.
TCC was additionally carried out to prevent ascending infection as infection is a
relevant pathomechanism for spontaneous late miscarriage and preterm birth. The original
TCC procedure was first described by Szendi in the 1960s and was developed further
by Erich Saling. The concept consists of complete closure of the cervical canal to
avoid bacterial colonization of intrauterine structures [19]
[20]
[21]. Up to now, the potential benefit of TCC has been described primarily in retrospective
case series. In a prospective study of births after a combination of McDonald cerclage
and TCC, Zayyan et al. reported a term birth rate of 92% in a group of patients with
recurrent pregnancy loss in the second trimester [22]. Braun and Klockenbusch discussed the benefit of TCC in the context of a multistage
prevention concept, especially combined with cerclage and pessaries, although their
assessment was primarily based on clinical experience and has not yet been confirmed
in prospective randomized studies [23].
In our patient cohort, all patients with a medical history of late miscarriage or
preterm birth underwent cerclage with TCC. The decision for this combined procedure
was based on the risk profiles of the individual patients and the infection-related
hypothesis that additional mechanical closure could effectively prevent ascending
infection. As there was no comparison group without TCC, our data does not permit
reliable statements to be made about the effectiveness of TCC in isolation.
International recommendations, including those of the WHO, advise women to have an
interpregnancy interval of at least six months after a miscarriage. No specific recommendations
have been issued for pregnancies which ended in preterm birth. The WHO recommends
an interval of at least 24 months after any live birth before the next conception.
However, the AWMF S2k-guideline on the prevention of preterm birth (2022) advocates
an 18-month interval between two pregnancies.
Our data show that an interval of more than 12 months after late miscarriage or preterm
birth is associated with a significantly higher rate of term births and better neonatal
outcomes. The highest rate of births ≥ 37+0 GW (85.4%) was recorded in the group with
an interpregnancy interval of > 12 months. The neonates in this group had higher birth
weights, better Apgar scores and the lowest rate of admissions to the NICU compared
to the other groups. These findings are in accordance with existing recommendations
which view longer interpregnancy intervals as protective. Good neonatal outcomes showed
a clear association with being born at term.
Our analysis clearly showed that the length of the interpregnancy interval affects
the gestational age of preterm births. In the group with the shortest interpregnancy
interval (0–6 months), two thirds of preterm births occurred at a very early gestational
age (< 28+0 GW). Preterm births increasingly shifted to the later weeks of gestation
in the groups with longer interpregnancy intervals. This finding is clinically important
as extremely preterm births are associated with significantly higher neonatal morbidity
and mortality rates.
The close correlation between gestational age and neonatal outcome is well documented.
The earlier the birth, the higher the risk of low birth weight, poor Apgar scores
and the need for intensive medical care. It appears that the interpregnancy interval
is a significant, modifiable risk factor. Women with a medical history of cervical
insufficiency and previous preterm birth could benefit from receiving targeted information
on planning the interval between pregnancies as this could lead to better outcomes.
Our findings are supported by recent meta-analyses. A network meta-analysis by Wen
et al. (2025) identified an interval of between 24 and 29 months as particularly protective
against preterm birth [24]. A systematic dose-response meta-analysis by Ni et al. (2023) showed that both very
short (< 6 months) and very long intervals (≥ 60 months) were associated with an increased
risk of preterm birth, low birth weight, and stillbirth [25].
In accordance with the recommendations of the current S2k-guideline, a microbiological
smear was taken from all patients prior to cerclage placement for the early identification
of potentially pathogenic bacteria. If the results of the smear were pathological,
targeted antibiotic therapy based on the antibiogram was administered prior to the
surgical procedure. The aim of this preintervention diagnosis was to minimize the
risk of ascending infection and thereby prevent complications such as preterm birth
or late miscarriage.
A significant limitation of our analysis was that in the majority of patients, the
previous pregnancy (miscarriage or preterm birth) occurred outside our institution.
Most of the women were referred to us for counseling and cerclage placement by external
hospitals. In many cases, we therefore did not have reliable information about the
precise cause of the previous pregnancy loss, for example, whether it was caused by
infection, premature rupture of membranes or silent cervical dilation. But this information
would have been essential to be able to better estimate the individual risk of preterm
birth and initiate more targeted preventive measures.
An imbalance in the composition of the vaginal microbiome with reduced dominance of Lactobacillus is known to be a relevant risk factor for spontaneous preterm birth. A network meta-analysis identified
Lactobacillus crispatus as a protective marker, while a dysbiotic microbiome profile
significantly increased the risk of preterm birth [26]. It has not yet been conclusively determined whether a short interpregnancy interval
directly results in the development of microbial dysbiosis or whether dysbiosis is
the result of incomplete postpartum regeneration of the vaginal microbiome.
Recent studies have shown, however, that microbial changes such as bacterial vaginosis
can persist postpartum over a period of several weeks to months, and this appears
to be especially clinically relevant for short interpregnancy intervals [27]
[28]. A longer interval between pregnancies might therefore not just promote uterine
recovery but could also contribute to restabilizing the vaginal microbiome. This could
reduce the risk of ascending infection, last miscarriage, and preterm birth. These
associations emphasize the importance of carrying out microbiological tests and providing
high-risk patients with individual counseling on optimal interpregnancy intervals.
Conclusion
The analysis shows that an interpregnancy interval of > 12 months after late miscarriage
or preterm birth in patients who had cerclage and TCC increases the probability of
a term birth. As neonatal outcomes are significantly affected by gestational age at
delivery, an interpregnancy interval of > 12 months was found to be associated with
higher birth weights, better Apgar scores, and lower admission rates to the NICU.
These results underscore the importance of leaving longer intervals between pregnancies.
The recommendation to have an interpregnancy interval of > 12 months is an important
part of individual counseling provided to patients with an adverse obstetric history.
