PPROM)-A Retrospective Analysis Over the Period 2000–2020

medicina

Article Obstetric and Perinatal Outcomes after Very Early Preterm Premature Rupture of Membranes (PPROM)-A Retrospective Analysis over the Period 2000–2020

Ernesto González-Mesa 1,2,† , Marta Blasco-Alonso 2,† , María José Benítez 3, Cristina Gómez-Muñoz 2, Lorena Sabonet-Morente 2 , Manuel Gómez-Castellanos 2, Osmayda Ulloa 2, Ernesto González-Cazorla 1, Alberto Puertas-Prieto 4 , Juan Mozas-Moreno 4,5,6,7,* , Jesús Jiménez-López 2 and Daniel Lubián-López 8

1 Surgical Specialities, Biochemistry and Inmunology Department, Malaga University, 29071 Málaga, Spain; [email protected] (E.G.-M.); [email protected] (E.G.-C.) 2 Obstetrics and Gynecology Service, Regional University Hospital of Malaga, 29011 Málaga, Spain; [email protected] (M.B.-A.); [email protected] (C.G.-M.); [email protected] (L.S.-M.); [email protected] (M.G.-C.); [email protected] (O.U.); [email protected] (J.J.-L.) 3 Obstetrics and Gynecology Service, Virgen de la Victoria University Hospital, 29010 Málaga, Spain; [email protected] 4 Obstetrics and Gynecology Service, Virgen de las Nieves University Hospital, 18014 Granada, Spain; [email protected] 5 Citation: González-Mesa, E.; Department of Obstetrics and Gynecology, University of Granada, 18016 Granada, Spain 6 Blasco-Alonso, M.; Benítez, M.J.; Consortium for Biomedical Research in Epidemiology & Public Health (CIBER Epidemiología y Salud Pública-CIBERESP), 28029 Madrid, Spain Gómez-Muñoz, C.; Sabonet-Morente, 7 Biohealth Research Institute (Instituto de Investigación Biosanitaria Ibs.GRANADA), 18014 Granada, Spain L.; Gómez-Castellanos, M.; Ulloa, O.; 8 Department of Obstetrics and Gynecology, University Hospital of Jerez de la Frontera, Faculty of Medicine, González-Cazorla, E.; Puertas-Prieto, University of Cadiz, 11407 Cadiz, Spain; [email protected] A.; Mozas-Moreno, J.; et al. Obstetric * Correspondence: [email protected]; Tel.: +34-958242867 and Perinatal Outcomes after Very † These authors contributed equally, and both have to be considered as ﬁrst authors. Early Preterm Premature Rupture of Membranes (PPROM)-A Abstract: Background and Objectives: Pre-term premature rupture of membranes (PPROM) responds Retrospective Analysis over the for one third of preterm births, and it is associated with other complications that increase the risk of Period 2000–2020. Medicina 2021, 57, maternal or fetal poor outcome. To reduce uncertainty and provide accurate information to patients, 469. https://doi.org/10.3390/ the analysis of the large series is of great importance. In order to learn about the evolution over medicina57050469 the time of the obstetric and perinatal outcomes in cases of PPROM at, or before, 28 weeks (very

Academic Editor: Bruce McLucas early PPROM) managed with an expectant/conservative protocol, we have designed the present study. Materials and Methods: We retrospectively studied all cases of very early PPROM attended in Received: 28 March 2021 Malaga University Regional Hospital from 2000 to 2020. Results: Among 119,888 deliveries assisted, Accepted: 7 May 2021 592 cases of PPROM occurred in pregnancies at or before 28 weeks (0.49% of all deliveries, 3.9% Published: 11 May 2021 of all preterm births and 12.9% of all cases of PPROM). The mean duration of the latency period between PPROM and delivery was 13.5 days (range 0 to 88 days), enlarging over the years. The Publisher’s Note: MDPI stays neutral mean gestational age at delivery was 27 weeks (SD 2.9; range 17–34). The proportion of cesarean with regard to jurisdictional claims in deliveries was 52.5%. The overall perinatal mortality rate was 26.5%, decreasing over the period with published maps and institutional affil- a significant correlation Pearson’s coefficient −0.128 (p < 0.05). Conclusions: In the period 2000–2020, iations. there was an improvement in the outcomes of very early PPROM cases and perinatal mortality showed a clear trend to decrease.

Keywords: very early PPROM; perinatal mortality; premature birth Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Attribution (CC BY) license (https:// Pre-term premature rupture of fetal membranes (PPROM) complicates 2–3% of all creativecommons.org/licenses/by/ pregnancies [1]; responds for one third of all cases of preterm birth [2]; and it is associated 4.0/). with secondary complications, which increase the risk of maternal or fetal poor outcome,

Medicina 2021, 57, 469. https://doi.org/10.3390/medicina57050469 https://www.mdpi.com/journal/medicina Medicina 2021, 57, 469 2 of 12

like placental abruption, cord prolapse and intraamniotic infections [3]. The etiology of PPROM remains unknown in most cases, and some genetic, environmental, mechanical, microbiological and inflammatory factors have been described [4]. It is accepted that preterm uterine contractions or mechanical distention of fetal membranes increase the risk of PPROM [5]. Also, the prevalence of microbial invasion of the amniotic cavity has been reported in half of the cases of PPROM [6], pointing out the role of microbial involvement; and some genetic predisposition regarding polymorphism of MMP-2 has been described to be associated with a higher rate of PPROM [7]. Most neonatal short- and long-term complications in cases of PPROM are predicted by gestational age at delivery [8–10]. The prolongation of pregnancy needs to be considered the primary goal of expectant management when infection is not present [8], especially in very early onsets. In these cases, a careful balance between maternal and neonatal risks is needed since a prolonged latency period between PPROM and delivery improves neonatal outcomes, but it could also increase the risk of chorioamnionitis [11,12]. The perinatal mortality figures associated with very early PPROM (at or before 28 weeks) are high [13,14], but in recent years, some studies have demonstrated that outcomes for neonates delivered following very early PPROM may be better than previously expected [10]. Although the long-term neurodevelopmental outcomes after PPROM will depend on the interaction between gen-environment, and the etiology of some central nervous system injuries that can be found in some children born after very early PPROM remain unclear [8], the short- term benefits of an expectant and conservative management are well established. In fact, we could previously report in our setting [15] an encouraging upward trend in the duration of latency period over the first decade of this century, and a decrease in perinatal mortality associated with PPROM very far from term. In order to learn about the evolution over the time of the obstetric and perinatal outcomes in cases of very early PPROM managed with an expectant/conservative protocol, we have designed the present study. Our goal was to review perinatal survival in cases of very early PPROM attended in our maternity from 2000 to 2020, analyzing the temporal trends of variables such as length of latency period, g.a. at delivery, mode of delivery, obstetric complications (cord prolapse, chorioamnionitis and placental abruption) and perinatal survival.

2. Materials and Methods 2.1. Study Design and Patients We reviewed clinical records for cases of PPROM at or before 28 weeks admitted to our obstetric department between 1 January 2000 and 31 December 2020. After we obtained institutional authorization, we revised Andalusian case mix (mini- mum basic data set registry) [16] to identify the records with diagnostic codes of PPROM at or before 28 weeks. Once all the cases were identiﬁed, we reviewed the medical records for information concerning the length of latency period, mode of delivery, gestational age and obstetric complications as chorioamnionitis, cord prolapse or placental abruption. The perinatal mortality data were obtained from the perinatal database of Neonatology and Obstetrics Departments, identifying newborns delivered alive and admitted to the inten- sive care unit until they were discharged or died. This database also included stillbirths. Extended perinatal mortality was considered, i.e., intrauterine fetal demises from 22 weeks g.a. and neonatal deaths until 28th day of life after delivery.

2.2. Statistical Analysis Statistical analysis was performed using IBM SPSS Statistics v24 software. The Chi square test was used to compare qualitative variables, and the t-test or ANOVA were used to compare means between groups according to the number of categories of each variable, always after conﬁrming the normality of the distribution. We used Pearson’s coefﬁcient for correlations, and the area under the curve (AUC) analysis to predict the survival probability of fetuses according to the gestational age at diagnosis. Medicina 2021, 57, 469 3 of 12

The data were treated statistically as a whole, aggregate per year and per g.a. at PPROM, with the exception of those pregnancies with pre-viable g.a. at PPROM (before 240/7 weeks) that were considered as a distinct group.

2.3. Instruments In the years of study an expectant-conservative management in cases of PPROM was followed. All patients were hospitalized after diagnosis. A complete bed rest regimen was advised in order to avoid amniotic fluid leakage and cord prolapse. We used prophylactic antibiotics (simultaneous regimen of Ampicillin and Erythromycin for one week), a single course of steroids (betamethasone 12 mg) when g.a. > 240/7 weeks, and tocolitycs (atosiban) during 48 h if contractions were noted. After admission amniotic fluid samples were also taken for conventional aerobic cultures (antibiotic regimen was modified according to the bacterial resistances), and leucocytes and Reactive C Protein (CRP) were assessed every 48 h. If clinically stable, women with pre-viable PPROM (the edge of viability [17] was established at 240/7 weeks), could leave the hospital until viability was reached if they desired, following weekly ambulatory leukocytes and CRP controls. Over the 21 years of study, only a few cases underwent ambulatory management until viability and almost all women chose to remain hospitalized. In the absence of complications either induction of labor or cesarean delivery for obstetric indications were performed in g.a. > 340/7. When PPROM occurred before g.a. 220/7 weeks, the patient could request legal termination. The amniotic fluid sampling for culture was extended to Mycoplasma, Chlamydia and anaerobes search in 2006. Prophylactic antibiotic regimen was modified according to the bacterial resistances observed in antibiograms [18]. The clinical diagnosis of chorioamnionitis were made according to Gibbs’ clinical and biological criteria [19], and in all cases there was histological confirmation. Gibbs’ clinical criteria for chorioamnionitis included temperature of at least 37.8 ◦C, and two or more of the following: Maternal tachycardia, fetal tachycardia, uterine tenderness, foul odor of the amniotic fluid and maternal leukocytosis. In cases of suspected chorioamnionitis that did not meet Gibb’s criteria, amniocentesis was performed to confirm intraamniotic infection if low levels of glucose, positive Gram-straining or microbiological cultures were found in the amniotic fluid analysis. In cases of extremely pre-viable PPROM we included those cases in which patients chose to continue with the pregnancy and therefore the protocol of conservative management was adopted. This means the loss of those other cases in which patients chose the legal termination of pregnancy, where the follow-up was more difficult given that most of the cases were discharged to be sent to specific clinics to undergo termination.

2.4. Ethics The study was conducted in accordance with the Declaration of Helsinki, and the protocol (ecarpmp) was approved on 12 July 2016 by the reference Research Ethics Committee.

3. Results From 1 January 2000 to 31 December 2020 a total of 119,888 deliveries were assisted in Malaga University Regional Hospital. Among them, 14,931 were under 37 weeks, and 4591 cases of PPROM were diagnosed. These represented 3.8% of all deliveries attended and 30.7% of all preterm births. A total of 592 (0.5% of all deliveries, 3.9% of all preterm births and 12.9% of cases all of PPROM) occurred in pregnancies at, or before, 28 weeks (very early PPROM). The prematurity rates and the perinatal mortality rates from 2000 to 2020 in our maternity are shown in Figure1. Medicina 2021, 57, x FOR PEER REVIEW 4 of 13 Medicina 2021,, 57, 469x FOR PEER REVIEW 4 of 1213

FigureFigure 1. 1. PerinatalPerinatal mortality mortality (‰) (‰) and and prematur prematurityity rates (%) per year of study. Figure 1. Perinatal mortality (‰) and prematurity rates (%) per year of study. TheThe distributions distributions of the 592 cases of very early PPROM per year and g.a. at diagnosis diagnosis The distributions of the 592 cases of very early PPROM per year and g.a. at diagnosis areare shown shown in Figure Figure 22.. MeanMean maternalmaternal ageage inin thethe periodperiod waswas 31.531.5 years,years, withwith aa clearclear trendtrend are shown in Figure 2. Mean maternal age in the period was 31.5 years, with a clear trend toto increase increase over over the the years ( r = 0.14, p < 0.001), 0.001), so so that mean maternal age was 2.4 years to increase over the years (r = 0.14, p < 0.001), so that mean maternal age was 2.4 years higherhigher inin thethe period period 2015–2020 2015–2020 when when compared compared with with theﬁrst the ﬁve-yearsfirst five-years period period (32.8 against (32.8 higher in the period 2015–2020 when compared with the first five-years period (32.8 against30.4 years, 30.4p years,< 0.01). p < We 0.01). also We found also afound negative a negative correlation correlation between between the mean the agemean of age the against 30.4 years, p < 0.01). We also found a negative correlation between the mean age ofparticipants the participants and the and gestational the gestational age at age PPROM at PPROM diagnosis diagnosis (r = − 0.12;(r = −p0.12;< 0.01). p < 0.01). of the participants and the gestational age at PPROM diagnosis (r = −0.12; p < 0.01).

20.4% 20.9% 20.4% 20.9% 2020 2 2020 7w 2019 26 w 27w 2019 26 w 2018 2018 25 w 2017 22.0% 25 w 28 w 34.5% 2017 22.0% 28 w 34.5% 2016 2016 2015 24 w 2015 24 w 2014 <24 w 2014 17.3% <24 w 2013 17.3% 2013 2012 2012 35.8% 2011 35.8% 2011 2010 2010 2009 2009 2008 2008 2007 2007 2006 2006 2005 2005 2004 2004 2003 2003 2002 2002 2001 2001 2000 2000 0 102030405060 0 102030405060 < 24 w 24 w 25 w 26 w 27 w 28 w < 24 w 24 w 25 w 26 w 27 w 28 w FigureFigure 2. 2. YearlyYearly distribution of the sample according to gestational age at diagnosis of PPROM. Figure 2. Yearly distribution of the sample according to gestational age at diagnosis of PPROM.

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In this population population ( (nn == 592), 592), 64 64 placental placental abruption abruption (10.8%), (10.8%), 112 112 clinical clinical chorioamni- chorioam- onitisnionitis (18.9%) (18.9%) and and 9 9cord cord prolapse prolapse (1.5%) (1.5%) were were diagnosed diagnosed during during hospital admission, so that it was necessary to deliver urgently regardlessregardless ofof g.a.g.a. It should be noted that 1919 casescases (3.2%) were carriers of cervical cerclage andand 60 cases (10.1%) needed the use of tocolyticstocolytics (i.v. atosiban for 48 h). In the pre-viable group, cesarean sections were performed only for maternal indications (severe medical conditions or prior uterine surgery). The proportion of cesarean deliveriesdeliveries waswas 52.5%. 52.5%. No No differences differences were were observed observed over over the the years, years, but but cesarean cesar- eandeliveries deliveries were were significantly significantly more more frequent frequent when when g.a. at g.a. delivery at delivery was higher was higher (p < 0.001) (p < (Figure0.001) (Figure3). We 3). did We not did find not any find significant any significant relationship relationship between between maternal maternal age andage theand theduration duration of latency of latency period period between between PPROM PPROM anddelivery, and delivery, the appearance the appearance of complications, of complications,or the type or the of delivery.type of delivery.

Ce sarean delivery Vaginal delivery

28 w

27 w

26 w

25 w

24 w

< 24 w

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Figure 3. Type of delivery according to gestational age at delivery.

In thethe veryvery early early PPROM PPROM population population the the mean mean gestational gestational age atage delivery at delivery was 27 was weeks 27 (SDweeks 2.9; (SD range 2.9; 17–34). range 17–34). The mean The duration mean dura of latencytion of periodlatency between period between PPROM PPROM and delivery and wasdelivery 13.5 was days 13.5 (range days 0 (range to 88 days),0 to 88 enlarging days), enlarging over the over study the (12.3 study days (12.3 in days theperiod in the period2000–2010 2000–2010 and 15.1 and in the15.1 second in the second period, period,p < 0.05), p < as 0.05), shown as shown in Figure in4 Figure. 4.

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Medicina 2021, 57, x FOR PEER REVIEW 7 of 14 Figure 4. Temporal trend for latency period between PPROM and delivery.

Mean latency values between PPROM and delivery for the periods 2000–2005, 2006– 2010, 2011–2015 and 2016–2020 were 10.1, 12.8, 16.8, and 12.9, respectively (Figure5).

Figure 4. Temporal trend for latency period between PPROM and delivery.

Mean latency values between PPROM and delivery for the periods 2000–2005, 2006– Figure 5. Mean latency2010 period, 201 between1–2015 PPROM and 201 and6–2020 delivery were in 10.1, groups 12.8, of gestational 16.8, and age12.9 at, respectively PPROM diagnosis. (Figure 5).

We have observed a decreased in the duration of the latency period between PPROM and delivery during the last ﬁve-year period. According to g.a. at PPROM diagnosis, a signiﬁcant reduction of the latency between PPROM and delivery has been found in the group of pre-viable PPROM, in the second half of the last decade (mean difference between the periods 2011–2015 and 2016–2020 = 8.3 days, SD 3.7; p < 0.01).

Figure 5. Mean latency period between PPROM and delivery in groups of gestational age at PPROM diagnosis.

We have observed a decreased in the duration of the latency period between PPROM and delivery during the last five-year period. According to g.a. at PPROM diagnosis, a significant reduction of the latency between PPROM and delivery has been found in the

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We have observed a decreased in the duration of the latency period between PPROM and delivery during the last five-year period. According to g.a. at PPROM diagnosis, a Medicina 2021, 57, 469 7 of 12 significant reduction of the latency between PPROM and delivery has been found in the group of pre-viable PPROM, in the second half of the last decade (mean difference between the periods 2011–2015 and 2016–2020 = 8.3 days, SD 3.7; p < 0.01). A significant signiﬁcant correlation between the duration of the latency period between PPROM and deliverydelivery andand thethe year year of of study study was was found found in in the the period period 2000–2010 2000–2010 (Pearson’s (Pearson´s coefﬁcient coeffi- =cient 0.148; = 0.148;p < 0.01), p < 0.01), but notbut withinnot within the periodthe period from from 2011 2011 to 2020. to 2020. In the In groupthe group of previable of previ- PPROM,able PPROM, a clear a clear trend trend towards towards the prolongation the prolongation of latency of latency between between PPROM PPROM and deliveryand de- waslivery observed was observed since 2005, since so 2005, that inso 2009that in and 200 20109 and more 2010 than more half than of patients half of withpatients PPROM with beforePPROM 24 0/7beforeweeks 240/7 reached weeks viability,reached andviability, in 2010 and one in out 2010 of threeone out exceeded of three 28 exceeded weeks. This 28 trendweeks. decreased This trend during decreased the period during 2016–2020, the period so 2016–2020, that in the so last that year in the of observation last year of (2020),obser- onlyvation the (2020), 39.9% only of pre-viable the 39.9% PPROM of pre-viable reached PPROM viability reached (7/18), viability and none (7/18), of them and reachednone of 28them weeks reached (Figure 28 6weeks). (Figure 6).

% of Previable PPROM reaching viability

100

0 2000 2001 2002 2003 3004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 N Cases PPROM : 3 3 3 1 4 8 6 5 10 5 9 10 12 10 10 10 10 10 9 16 18 Reached viability: 1 1 1 1 1 6 2 2 4 3 5 9 10 10 8 9 7 5 8 6 7 Mean Latency: 4.3 1.3 2.0 5.0 15.5 29.7 10.1 20.4 10.1 14.0 34.1 33.4 19.7 34.3 19.1 17.1 18.1 17.1 25.1 14.1 10.7 Figure 6. Rate of cases with pre-viable PPROM that reachesreaches viabilityviability (gestational(gestational ageage 2424 weeks).weeks).

Considering the overall sample of pre-viable PPROM (n = 169), at the momentmoment ofof diagnosis and admission to the hospital the chance to deliver at 28 weeks g.a. was 13.7%. After seven uneventful uneventful days days following following the the diagno diagnosis,sis, the the probability probability to todeliver deliver at at26 26or or28 28weeks weeks of g.a. of g.a.was was54.5%, 54.5%, or 45.9%, or 45.9%, respectively, respectively, and 76.4% and 76.4%or 62.3% or 62.3%after 14 after days 14 of dayslatency of latency(ROC curves (ROC at curves Figure at 7). Figure 7). When pre-viable PPROM occurred before 17, 20 or 22 weeks the probability to deliver over the 28 weeks g.a. was 6%, 26.7%, and 65.8% respectively, and 6.5%, 27.6% and 66.7% to deliver at least at 26 weeks g.a. The overall perinatal mortality rate was 26.5%, decreasing over the period, and showing a significant correlation Pearson´s coefficient −0.128 (p < 0.05). Neonatal deaths accounted for 58.7% of the whole perinatal mortality, and fetal mortality was 42.3%. While in the first decade the rate was as high as 30.6%, in the period from 2011 to 2020 it was 22.3% (Figure8).

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1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4

0.2 AB0.2

0.0 0.0

0.0 0.2 0.4 0.6 0.8 0.0 0.2 0.4 0.6 0.8 1.0

A: Area under the curve 0.97 (std error 0.24; p< 0.0001); 23 positive/146 negative Medicina 2021B: Area, 57 under, x FOR the curvePEER 0.908 REVIEW (std error 0.21; p<0.0001); 46 positive/123 negative 9 of 13

FigureFigure 7. 7.ROCROC curves curves for for latency latency duration duration an andd delivery delivery over over 28 28 or or 26 26 weeks. weeks.

When pre-viable PPROM occurred before 17, 20 or 22 weeks the probability to deliver Perinatal death ratesover (%) the from 28 2000 weeks to 2020 g.a. according was 6%, to g.a. 26.7%, at diagnosis and of 65.8%PPROM respectively, and 6.5%, 27.6% and 66.7% 100 to deliver at least at 26 weeks g.a. The overall perinatal mortality rate was 26.5%, decreasing over the period, and show- 2000-2005 2006-2010 2011-2015 2016-2020 90 ing a significant correlation Pearson´s coefficient −0.128 (p < 0.05). Neonatal deaths accounted for 58.7% of the whole perinatal mortality, and fetal mortality was 42.3%. While 80 in the first decade the rate was as high as 30.6%, in the period from 2011 to 2020 it was 22.3% (Figure 8). 70

0 < 24 w 24 w 25 w 26 w 27 w 28 w

Figure 8. Perinatal mortality rate according to gestational age at PPROM diagnosis.

Figure 8. PerinatalThe mortality duration rate of according the latency to period gestational from age diagnosis at PPROM until diagnosis. delivery correlated significantly with perinatal mortality (Pearson’s coefﬁcient 0.234; p < 0.0001). However, the perinatalThe mortalityduration inof thethe samplelatency was period high from regardless diagnosis g.a. atuntil diagnosis delivery of correlated PPROM, reaching signifi- 46.2%cantly (75/162)with perinatal in the mortality group of (Pearson´s previable pregnancies coefficient 0.234; (Figure p <9 0.0001).), and 37.8 However, (25/66), the 25.3% per- (21/83),inatal mortality 22.6% (17/75), in the sample 10.6% (8/75) was high and 7.75%regardless (9/116) g.a. in at cases diagnosis of PPROM of PPROM, at 24, 25, reaching 26, 27, and46.2% 28 (75/162) weeks, respectively.in the group of previable pregnancies (Figure 9), and 37.8 (25/66), 25.3% (21/83), 22.6% (17/75), 10.6% (8/75) and 7.75% (9/116) in cases of PPROM at 24, 25, 26, 27, and 28 weeks, respectively.

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Perinatal mortality in cases of previable PPROM (under g.a. 24 w) in the whole period 2000-2020.

35 35

25 25 Perinatal survival 22 Perinatal death 20 20

15 12 10 10 88

5 5 4 3 3 2 2 N 1 0 16 w 17 w 18 w 19 w 20 w 21 w 22 w 23 w

FigureFigure 9.9. Perinatal mortality andand survivalsurvival inin casescases ofof pre-viablepre-viable PPROM.PPROM.

4. Discussion This paper paper shows shows the the obstetric obstetric outcomes outcomes and and perinatal perinatal mortality mortality rates rates in a large in a largesam- sampleple of pregnancies of pregnancies complicated complicated with with very very early early PPROM PPROM admitted admitted at at Malaga Malaga University Regional Hospital during the period 2000–2020.2000–2020. We confirmedconfirmed thethe decreasingdecreasing trendtrend inin thethe perinatal mortality rates associatedassociated with thisthis complication,complication, as wellwell asas thethe prolongationprolongation ofof the latencylatency periodperiod untiluntil deliverydelivery overover thethe years.years. However,However, somesome fluctuationsfluctuations havehave beenbeen observed throughout the the whole whole period, period, but but a aclear clear trend trend towards towards the the improvement improvement is en- is ensured,sured, we we must must be be aware aware of of the the increase increase in in the the mortality mortality figures figures found found in the last fivefive years, specificallyspecifically in thethe groupgroup ofof pre-viablepre-viable PPROMPPROM inin whichwhich perinatalperinatal deathsdeaths reachedreached 42%, nine points over thethe raterate observedobserved inin thethe periodperiod 2011–2015.2011–2015. ThisThis increaseincrease isis mainlymainly due to the the number number of of deaths deaths registered registered during during the the last last two two years years of the of period the period greater greater than than those observed before (28% in 2017, 20% in 2018, 35% in 2019 and 36.5% in 2020). those observed before (28% in 2017, 20% in 2018, 35% in 2019 and 36.5% in 2020). We do We do not have a clear explanation for this increase because there were no changes in the not have a clear explanation for this increase because there were no changes in the man- management of these pregnancies, except for some necessary changes in the staff who agement of these pregnancies, except for some necessary changes in the staff who pro- provided care in the obstetric ward, and for all the organizational changes in the obstetric vided care in the obstetric ward, and for all the organizational changes in the obstetric ward due to the COVID-19 pandemic during 2020. The pandemic produced some changes ward due to the COVID-19 pandemic during 2020. The pandemic produced some changes in the obstetric care, due to the need for hospital beds to admit patients with Covid-19, and in the obstetric care, due to the need for hospital beds to admit patients with Covid-19, to the effects of the pandemic on the hospital staff. These changes could have influenced and to the effects of the pandemic on the hospital staff. These changes could have influ- the results. enced the results. At present, it is clear enough that the use of prophylactic antibiotics is beneficial for At present, it is clear enough that the use of prophylactic antibiotics is beneficial for newborns and their mothers. It has been shown a prolongation of the latency period, a newborns and their mothers. It has been shown a prolongation of the latency period, a decrease in diagnoses of chorioamnionitis, neonatal respiratory distress and sepsis [20,21]. Indecrease our Hospital in diagnoses the ORACLE of chorioamnionitis, II study provided neonatal consistency respiratory in distress antibiotic and treatments sepsis [20,21]. for PPROM,In our Hospital subjected the toORACLE some variability II study provided until 2003 consistency [22]. Benefits in antibiotic arising thetreatments use of cor- for

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ticosteroids to accelerate fetal lung maturation and reduce the risk of necrotizing ente- rocolitis and intraventricular hemorrhage cases of PPROM over 240/7 weeks are also important [23–25]. In our series, the latency period has been progressively extended over the years. Actions, such as the homogeneity in antibiotic treatment promotion, periodical sampling for amniotic fluid cultures and additional antibiotic courses in cases of isolation of pathogens according to the antibiogram, have contributed to increase the latency period until delivery. This reduces the effect of extreme prematurity in the figures perinatal mortality associated to PPROM. When PPROM complicates the pregnancy far from term, at pre-viable g.a., obstetri- cians have to deal with the uncertainty that this condition entails. The lack of prospective, randomized and controlled trials, and the variety of variables influencing neonatal and maternal outcomes in cases of PPROM, means that clinicians have to deliver information based on the results of retrospective studies with a limited number of cases. In order to provide accurate information to these patients, the analysis of the results of large local series is of great importance. In our experience, when the information includes encouraging data, in terms of latency prolongation and survival rate of preterm newborns, women often accept an active/expectant management with hospitalization, bed rest, antibiotics and corticosteroids from g.a. 240/7 weeks. On the other hand, when the information is limited to providing perinatal mortality and morbidity rates, women usually request legal termination of the pregnancy. In our maternity, the diagnosis of PPROM involves the patient’s institutionalization in order to facilitate early diagnosis of possible chorioamniotic infection. We also recommend bed rest, at least during the first days after diagnosis, to prevent loss of amniotic fluid and cord prolapse. Although there is not enough evidence of the benefits of hospitalization, bed rest [26,27] or amnioinfusion in patients with pre-viable PPROM [28–30], most of the women with pre-viable PPROM opt for admission in the obstetric ward and bed rest. In these cases, weight-adjusted daily doses of low-molecular-weight heparin are included in the treatment. All the data included in this paper provide valuable information to advance a fore- cast about perinatal outcome after extremely PPROM diagnosis, being the largest sample (592 cases) of very early PPROM that has been published in our country. However, its design has some limitations derived from the retrospective review of the clinical information and the accuracy of the records. Over the years of study, some important changes in the information and recording systems made it very difficult to gather homogeneous data sets on sociodemographic and non-clinical variables, and only maternal age was available for analysis as a cofactor. Also, this series only includes the cases of women with pre-viable PPROM that opt for an active/expectant management, and not those who request legal termination, whose records were not available.

5. Conclusions We have conﬁrmed a decreasing trend in the perinatal mortality rates associated with PPROM, and a prolongation of the latency period until delivery over the years of study.

Author Contributions: Conceptualization, E.G.-M., M.B.-A.; methodology, E.G.-M., M.B.-A., D.L.-L., A.P.-P., J.M.-M., C.G.-M., and M.J.B.; software, O.U.; formal analysis, E.G.-M., M.B.-A.; investigation, D.L.-L., L.S.-M., M.G.-C., J.J.-L.; resources, J.M.-M., A.P.-P.; data curation, E.G.-M., M.B.-A., E.G.- C., C.G.-M., and M.J.B.; writing—original draft preparation, E.G.-M., M.B.-A., D.L.-L.; writing— review and editing, E.G.-M., M.B.-A. All authors have read and agreed to the published version of the manuscript. Funding: This publication was ﬁnanced with funds from the University of Malaga. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Ethics Committee of Malaga (protocol code ecarpmp and date of approval 12 July 2016). Medicina 2021, 57, 469 11 of 12

Informed Consent Statement: Patient consent was waived due to the exemption authorized by the Ethics Committee because it was a retrospective study with a high number of patients and the data collected was anonymized. Data Availability Statement: No new data were created or analyzed in this study. Data sharing is not applicable to this article. Acknowledgments: Authors acknowledge the administrative support of Ines Ortega. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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