Pregnancy in advanced ( 40) and very advanced ( 45) reproductive age: maternal and fetal risks

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1 Giorn. It. Ost. Gin. Vol. XXXV - n. 6 Novembre-Dicembre 2013 Department of Gyno-Obstetrics and Urologic Science, Sapienza University of Rome, Rome, Italy clinical case Pregnancy in advanced ( 40) and very advanced ( 45) reproductive age: maternal and fetal risks M.G. DE STEFANO, E. ROSATO, E. MARCOCCIA, M.C. SCHIAVI, I. ZANNINI, O. CAPRI, P. GALOPPI, G. PERRONE SUMMARY: Pregnancy in advanced ( 40) and very advanced ( 45) reproductive age: maternal and fetal risks. M.G. DE STEFANO, E. ROSATO, E. MARCOCCIA, M.C. SCHIAVI, I. ZANNINI, O. CAPRI, P. GALOPPI, G. PERRONE Aim of the study. The aim of our study is to evaluate the pregnancy complications, mode of delivery and neonatal outcome in women of advanced reproductive age ( 40 years) and very advanced reproductive age ( 45 years). Methods and materials. We selected 343 patients aged 40 years who subsequently gave birth at the Department of Obstetrics- Gynecology at the Policlinico Umberto I in Rome, between 2010 and We selected a control group of 527 patients aged between 25 and 35 who gave birth in the same period. After excluding twin pregnancies and intrauterine deaths, the study sample is made up of 312 patients, subdivided into two subgroups according to age: years (group A: 274 patients) and age 45 years (group B: 38 patients), while the control group includes 510 patients. For each group we evaluated the pregnancy outcomes (chronic maternal diseases, gestational maternal diseases, obstetric complications), delivery (mode of delivery, gestational age at birth) and neonatal outcome (birth weight and Apgar). Obstetric history (parity and previous cesarean section), mode of onset of pregnancy (spontaneous or assisted reproductive technology) and duration of the hospital stay were reported. Results. We found in women over 40 compared to the control group a significant increase in the frequency of both chronic and gestational maternal diseases: diabetes mellitus (2.6% vs 0.4%), chronic hypertension (6.1% vs 2%), gestational diabetes (9% vs 2.5%), gestational hypertension (8.7% vs 2%); and of obstetric complications: oligohydramnios (7.4% vs 3.7%), intrauterine growth restricion-iugr (6.7% vs 2.5 %); an increase of cesarean section (70.2% vs 48.2 %) and an increased risk of neonatal complications such as prematurity (20.8% vs 7.5%), low birth weight (17.3% vs 10.6%) and Apgar score less than 7 at the first minute (7.4% vs 1.6%) were evidenced in the study group. We found no significant differences in the frequency of preeclampsia, placental disorders (placenta previa, placental abruption), instrumental delivery. RIASSUNTO: Gravidanza in età riproduttiva avanzata ( 40 anni) e molto avanzata ( 45 anni): complicanze materne e fetali. M.G. DE STEFANO, E. ROSATO, E. MARCOCCIA, M.C. SCHIAVI, I. ZANNINI, O. CAPRI, P. GALOPPI, G. PERRONE Obiettivo. L obiettivo del nostro studio è valutare l andamento della gravidanza, la modalità del parto e l outcome neonatale in donne in età riproduttiva avanzata ( 40 anni) e molto avanzata ( 45 anni). Materiali e metodi. Abbiamo selezionato 343 pazienti di età 40 anni che hanno successivamente partorito presso il Dipartimento di Scienze Ostetriche-Ginecologiche del Policlinico Umberto I di Roma, dal 2010 al Abbiamo poi selezionato un gruppo di controllo costituito da 527 pazienti di età compresa fra 25 e 35 anni che hanno partorito nello stesso periodo. Dopo aver escluso le gravidanze gemellari e le morti intrauterine, il campione di studio risulta costituito da 312 pazienti, a sua volta suddiviso in due sottogruppi in base all età: anni (gruppo A: 274 pazienti) e di età 45 anni (gruppo B: 38 pazienti), mentre il gruppo di controllo comprende 510 pazienti. Per ciascun gruppo abbiamo valutato l andamento della gravidanza (patologie materne croniche, patologie materne gestazionali, complicanze ostetriche), il parto (modalità del parto, epoca gestazionale al parto) e l outcome neonatale (peso alla nascita e Apgar). Sono stati inoltre descritti: anamnesi ostetrica (parità e pregressi TC), modalità di insorgenza della gravidanza (spontanea o tecniche di fecondazione assistita) e durata della degenza. Risultati. Abbiamo riscontrato nelle donne over 40, rispetto al gruppo di controllo, un aumento significativo di frequenza di patologie materne sia croniche sia gestazionali, quali diabete mellito (2,6% vs 0,4%), ipertensione cronica (6,1% vs 2%), diabete gestazionale (9% vs 2,5%), ipertensione gestazionale (8,7% vs 2%); di complicanze ostetriche quali oligoamnios (7,4% vs 3,7%) e ritardo di crescita intrauterino-iugr (6,7% vs 2,5%); un aumentato ricorso al taglio cesareo (70,2% vs 48,2%) e un aumentato rischio di complicanze neonatali quali prematurità (20,8% vs 7,5%), basso peso alla nascita (17,3% vs 10,6%) e Apgar inferiore a 7 al primo minuto (7,4% vs 1,6%). Non abbiamo riscontrato differenze significative nella frequenza di preeclampsia, di disordini placentari (placenta previa e DI- Copyright 2014, CIC Edizioni Internazionali, Roma 740

2 Introduction Pregnancy in advanced ( 40) and very advanced ( 45) reproductive age: maternal and fetal risks Considering only the group over 40, the comparison between group A (40-44 years) and group B ( 45 years) showed a significantly increased frequency of preeclampsia (1.5% vs 13.2%), gestational hypertension (5.8% vs 28.9%), cesarean section (67.2% vs 92.1%), low birth weight (15% vs 34.2%), prematurity (19.3% vs 31.6%) and Apgar score less than 7 at the first minute (5.8% vs 18.4%) in the patients 45 years. No significant differences emerged for maternal chronic diseases (hypertension, diabetes), for gestational diabetes, obstetric complications (oligohydramnios, IUGR, placental disorders) and instrumental delivery. Conclusions. The pregnancy in age 40 is associated with an increased risk for the majority of the maternal-fetal complications, but it is mostly over 45 years that the increase of frequency of gestational diseases involving the cardiovascular system becomes highly prevalent (gestational hypertension and preeclampsia); fetal complications such as low birth weight and prematurity are increased. Our study suggests that becoming pregnant at extremely advanced reproductive age ( 45years) exposes the woman to hypertensive complications such as gestational hypertension and preeclampsia. During the last decades, in industrialized countries, women are voluntarily postponing pregnancy for economic, professional, social and personal reasons. In 2011 in Italy the average age for pregnancy was 31.4 years at time of delivery. This is approximately 1.5 years more than in 2008 (29.8) and in mothers of Italian citizenship the average age of delivery is 32 years. Nearly 7% of children born had a mother at least 40 years of age, more than in 2008 (5.7% of children). At the same time, a reduction in births to mothers less than 25 years old was observed: 10.9 % in 2011 compared with 11.1% in 2008 (1). This tendency has created a social phenomenon characterized by an increase in women of advanced age desiring to obtain a pregnancy (2). Many studies have demonstrated that advanced maternal age has an impact not only on ability to conceive, but also on pregnancy and maternal-fetal health in the following ways: - an increase in chronic and gestational maternal illnesses such as hypertension/preeclampsia and diabetes mellitus (3, 4); - an increase in fetal complications such as chro- PNI -distacco intempestivo di placenta normoinserita) e di parti vaginali operativi. Considerando solo il gruppo over 40, dal confronto fra il gruppo A (40-44 anni) e il gruppo B ( 45 anni) è emerso come nelle over 45 vi sia una frequenza significativamente aumentata di preeclampsia (1,5% vs 13,2%), ipertensione gestazionale (5,8% vs 28,9%), ricorso al taglio cesareo (67,2% vs 92,1%), basso peso alla nascita (15% vs 34,2%), prematurità (19,3% vs 31,6%) e Apgar inferiore a 7 al primo minuto (5,8% vs 18,4%). Nessuna differenza significativa è emersa per le patologie materne croniche (ipertensione, diabete) né per diabete gestazionale, complicanze ostetriche (oligoamnios, IUGR, anomalie placentari) e parti vaginali operativi. Conclusioni. La gravidanza in età 40 anni comporta un aumento di rischio per la maggior parte delle complicanze materno-fetali, ma è soprattutto sopra i 45 anni che l aumento di frequenza di alcune patologie gestazionali che coinvolgono il sistema cardiovascolare diventa fortemente prevalente (ipertensione gestazionale e preeclampsia); ad esse si associano complicanze fetali quali il basso peso alla nascita e la prematurità. Il nostro studio suggerisce come una gravidanza insorta in età riproduttiva estrema ( 45anni) esponga la donna soprattutto a complicanze ipertensive quali ipertensione gestazionale e preeclampsia. KEY WORDS: Very advanced maternal age - Maternal complications - Neonatal complications. Età materna molto avanzata - Complicanze materne - Complicanze neonatali. mosomal abnormalities and malformations (5), IUGR and intra-uterine death (6-8); - an increase in complications during birth which leads to an increase in C-sections and instrumental delivery (3, 4, 9, 10); - an increase in neonatal complications such as premature birth, low birth weight, IUGR and macrosomia (3, 4, 7); - an increase in maternal post-partum complications such as hemorrhage (4, 11). Some questions are still left to be addressed. While during the Sixties the pregestational health condition was an important risk factor for complications in pregnancy, in later years women s health has improved in industrialized countries and it is therefore important to consider other risk factors and clinical aspects which could affect pregnancy outcome in advanced maternal age. Finally it is still an open debate about what the age limit is which puts a woman at greater risk for the development of pregnancy complications: it is not yet clear whether there is in late reproductive years, before menopause (> 45 years old), a risk profile more specific than that detected beyond the generic limit of 40 years old and what is the most appropriate surveillance in pregnancy. The aim of our study is to evaluate the pregnancy 741

3 complications, mode of delivery and neonatal outcome in women of advanced reproductive age (> 40 years) and very advanced reproductive age (> 45 years) compared to younger women (25-35 years). Materials and methods In our retrospective observational study of a total of 3650 women who gave birth at the Department of Gynaecologic-Obstetric Sciences and Urologic Sciences, from January 2010 to December 2011 (hospitalized at the Department of Obstetrics and transferred to room delivery room) there were 343 (9.3%) patients aged > 40 years identified. We selected a sample as a control group of 527 women aged between 25 and 35 years hospitalized to give birth during the same period. From selected groups we excluded twin pregnancies and pregnancies resulting in intrauterine death. The final sample is thus represented by a study group consisting of 312 women aged > 40 years, and by a control group of 510 women aged between 25 and 35 years. The study group was further divided according to age into two subgroups: (87.8%) aged between 40 and 44 years (group A); - 38 (12.2%) aged > 45 years (group B). The following data were analyzed: - Body Mass Index (BMI: kg/m²); - obstetric anamnesis (parity and previous deliveries); - assisted vs spontaneous conception; - gestational morbidity: chronic maternal diseases (diabetes mellitus, chronic hypertension) gestational maternal diseases (gestational diabetes, gestational hypertension, preeclampsia) and obstetric complications (IUGR, placental disorders, oligohydramnios); - type of delivery (cesarean section, spontaneous delivery, instrumental delivery) and gestational age at delivery; - neonatal outcome (birth weight, Apgar score in first minute); - days of hospital stay. The statistics were analyzed using SPSS 16.0 for Windows. Comparisons between the groups were performed with ANOVA and χ². The significance was considered for values of p< M.G. De Stefano et al. Results The mean age was 41.4 ± 1.2 years in group A, 46.5 ± 1.9 in group B and 29.8 ± 3.2 in control group. The mean BMI of patients was 27.5 ± 3.8 in group A, 27.8 ± 5.2 in group B and 26.5 ± 4 in control group. With regards to obstetric anamnesis the percentage of nulliparity was greater in control group in comparison with study group (38.1% vs 53.7%, p < 0.001) with a decrease in previous C-sections (15.7% vs 32,7%, p<0.001). However, taking into consideration only those women above age 40, in group A (40-44 years) the percentage of nulliparity is less with respect to group B (> 45 years) (33.9% vs 68.4%, p<0.001). The need for assisted reproduction was significantly higher in women over 40 with respect to those between 25 and 35 years (9.3% vs 0.2% p<0.001) and in particular in group B over 45 years (50% of women over 45 used assisted reproduction). The morbidity during pregnancy (chronic maternal diseases, gestational maternal diseases and obstretric complications), delivery outcome (type of delivery, gestational age at delivery), neonatal outcome (birth weight and neonatal Apgar score) and hospitalization stay are showed in Table 1 and Table 2. An increased frequency of chronic maternal diseases (chronic hypertension and diabetes mellitus) in the study group compared to control group was noted (respectively 6.1% vs 2%, p<0.005 and 2.6% vs 0.4% p<0.05). Gestational maternal diseases and obstetric complications were also more frequent in the group > 40 years with respect to control group: gestational diabetes 9% vs 2.5% (p<0.001), oligohydramnios 7.4% vs 3.7 (p< 0.05), IUGR 6.7% vs 2.5% (p< 0.005). No significant differences were noted for preeclampsia (2.9% vs 1.2%) and placental disorders (4.8% vs 2.4% ) (Table 1). Over 45 years (group B) greater differences were noted compared with women between 40 and 44 years (group A) in terms of gestational hypertension (28.9% vs 5.8% p<0.001) and preeclampsia (13.2% vs 1.5% p< 0.001) (Table 2). Regarding delivery, we highlighted in the age group > 40 years compared to the control group an increase of the number of cesarean section (70.2% vs 48.2%, p <0.001), an increase in the frequency of preterm delivery between 37 and 34 weeks (16% vs 742

4 Pregnancy in advanced ( 40) and very advanced ( 45) reproductive age: maternal and fetal risks 6.7%, p <0.001) and very preterm delivery < 34 weeks (4.8% vs 6.7%, p <0.001) and a reduction in average gestational age at delivery (38.1 weeks vs 38.7 weeks, p <0.05) (Table 1). Analyzing group A (40-44 years) compared to group B (> 45 years) (Table 2) confirmed a significant increase in the use of cesarean section (67.2% vs 92.1%, p <0.005), an increase in the frequency of preterm delivery between 37 and 34 weeks (15.3% vs 21.1%, p <0.05) and very preterm delivery < 34 weeks (4% vs 10.5%, p <0, 05) and a reduction in average gestational age at delivery (38.3 weeks vs 37.1 weeks, p <0.001). The C-sections most frequently performed in patients of group B (> 45 years) compared with group A (40-44 years) had the following indications: - gestational hypertension (23.4% vs 9.5%, p<0.05); - preeclampsia (12.8% vs 3.5%, p<0.05); - maternal request (27.7% vs 7.5%, p<0.001). In addition, considering neonatal outcome, several important differences were noted among groups. In the study groups > 40 years compared with control group (Table 1) there was: - a reduction in average birth weight ( grams vs grams, p<0.05); - an increase in the percentage of birth weight TABLE 1-FREQUENCY OF CHRONIC MATERNAL DISEASES, COMPLICATIONS IN PREGNANCY, TYPE OF DELI- VERY, COMPLICATIONS OF CHILDBIRTH AND DAYS OF HOSPITALIZATION IN WOMEN AGED 40 AND IN CONTROLS. Characteristics > 40 years (n = 312) years (n = 510) p Chronic hypertension % (n) 6,1 (19) 2 (10) <0,005 Diabetes mellitus pregestational % (n) 2,6 (8) 0,4 (2) <0,05 Gestational hypertension % (n) 8,7 (27) 2 (10) <0,001 Preeclampsia % (n) 2,9 (9) 1,2 (6) ns Gestational diabetes % (n) 9 (28) 2,5 (13) <0,001 Placental disorder % (n) 4,8 (15) 2,4 (12) ns Oligohydramnios % (n) 7,4 (23) 3,7 (19) <0,05 IUGR % (n) 6,7 (21) 2,5 (13) <0,005 Cesarean delivery % (n) 70,2 (219) 48,2 (246) <0,001 Spontaneous delivery % (n) 27,6 (86) 50,8 (259) <0,001 Instrumental delivery % (n) 2,2 (7) 0,8 (4) ns Gestational age at delivery (weeks), mean ± SD 38,1±2,05 38,7±1,56 <0,05 Prematurity (< 37 weeks) % (n) 20,8 (65) 7,5 (38) <0,001 Birth weight (grams), mean ± SD 3060,2±607,5 3155,3±528,5 <0,05 Birth weight < 2500 grams % (n) 17,3 (54) 10,6 (54) <0,001 Apgar score <7 in the first minute % (n) 7,4 (23) 1,6 (8) <0,001 Days of hospitalization, mean ± SD 5,6±2,6 4,6+0,9 <0,05 743

5 < 2500 grams (17.3% vs 10.6%, p<0.001); - an increase in the percentage of Apgar scores < 7 in the first minute (7.4% vs 1.6%, p< 0,001). These differences are very evident from the comparison between group A and group B (Table 2): - a reduction in average birth weight ( grams vs grams, p <0.05); - an increase in the percentage of birth weight <2500 grams (15% vs 34.2%, p <0.001); - an increase in the percentage of Apgar score < 7 in the first minute (5.8% vs 18.4%, p: 0.005). Finally, hospitalization is longer in the study group compared with the control group (5.6 days vs 4.6 days p<0.05) particularly of note 5.5 days for M.G. De Stefano et al. TABLE 2 - FREQUENCY OF CHRONIC MATERNAL DISEASES, COMPLICATIONS IN PREGNANCY, TYPE OF DELIVERY, COMPLICATIONS OF CHILDBIRTH AND DAYS OF HOSPITALIZATION IN WOMEN AGED (GROUP A) AND > 45 YEARS (GROUP B). Characteristics years (n = 274) > 45 years (n = 38) p Chronic hypertension % (n) 5,8 (16) 7,9 (3) ns Diabetes mellitus pregestational % (n) 2,2 (6) 5,3 (2) ns Gestational hypertension % (n) 5,8 (16) 28,9 (11) <0,001 Preeclampsia % (n) 1,5 (4) 13,2 (5) <0,001 Gestational diabetes % (n) 8,8 (24) 10,5 (4) ns Placental disorders % (n) 4,4 (12) 7,9 (3) ns Oligohydramnios % (n) 6,9 (19) 10,5 (4) ns IUGR % (n) 6,2 (17) 10,5 (4) ns Cesarean delivery % (n) 67,2 (184) 92,1 (35) <0,005 Spontaneous delivery % (n) 30,7 (84) 5,3 (2) <0,005 Instrumental delivery % (n) 2,2 (6) 2,6 (1) ns Gestational age at delivery (weeks), mean ± SD 38,3±1,98 37,1±2,18 <0,001 Prematurity (< 37 weeks) % (n) 19,3 (53) 31,6 (12) <0,05 Birth weight (grams), mean ± SD 3089,3±587,9 2851,1±707,7 <0,05 Birth weight < 2500 grams % (n) 15 (41) 34,2 (13) <0,001 Apgar score < 7 in the first minute % (n) 5,8 (16) 18,4 (7) <0,01 Days of hospitalization, mean ± SD 5,5+2,5 6,3+3,3 <0,05 women between 40 and 44 (group A) and 6.3 days in women > 45 years (group B). Discussions and conclusions Between January 2010 and December 2011, in our department, births by women > 40 years of age were 9.3% of total births (343 out of 3650), within the Italian statistical average (1). Notwithstanding the progressive increase of advanced maternal age births and an improvement in women s health in developed nations, maternal and fetal complications in the decade preceding menopause 744

6 Pregnancy in advanced ( 40) and very advanced ( 45) reproductive age: maternal and fetal risks (between 40 and 50 years) seem greater when compared with pregnancies under 40 years of age. In fact, from this study emerges the frequency with which women beyond 40 years of age display chronic maternal diseases (chronic hypertension, diabetes mellitus) and gestational maternal diseases/ obstetric complications (gestational hypertension, gestational diabetes, oligohydramnios, IUGR). In 70% of the cases a C-section is performed and preterm and very preterm delivery are observed. Newborn with low birth weight and with Apgar score < 7 at 1 minute are observed. Hospital stays are longer with higher frequency of pre and post-partum complications. These conditions become more relevant when analyzing women over 45 particularly with regard to gestational hypertension (28.9%) and preeclampsia (13.2%). The causes of the relationship between advanced maternal age and gestational hypertension and preeclampsia are to be examined in the placental uterine vascular system. Sclerotic arterial uterine lesions increase with age from 11% between 17 and 29 years 61% between 30 and 39 years and 83% over 39 years. This vascular failure is responsible for the uterus being unable to adapt to the increased hemodynamic requests during a pregnancy (12). These studies further confirm the American Heart Association s claim that pregnancy is a stress test to the cardiovascular system and, in particular, for women who develop preeclampsia, a failed stress test which unmasking early or preexisting endothelial dysfunction and vascular disease (13). It remains unclear, however, whether assisted reproduction technologies over age 45 (50% of women > 45) are responsible for such illnesses or whether they are due to age. As well evidenced in certain studies (3, 14-16) assisted methods of reproduction have an impact on maternal diseases like preeclampsia. Also in the women > 45 years is very high the C- section rate (92%), especially elective C-section, the frequency of preterm delivery (21.1%) and very preterm delivery (10.5%), of infants with low birthweight (34.2%) and Apgar score <7 in the first minute (18.4%). One in three women opted for a C-section and a motivating factor is assisted methods of conception making the pregnancy precious (3). A second motivating factor for C-sections is due to a greater cultural conditioning in women of advanced reproductive age who perceive a greater risk to themselves and the fetus compared with younger women (17). We must bear in mind the debate on C-sections without medical indications is still very vibrant (18-23). There is no evidence that a C-section performed without medical cause is any safer for the mother s health or the newborn s health with respect to a vaginal birth. In light of these results, women over 45 should be considered most at risk for particular pregnancy complications (gestational hypertension, preeclampsia, preterm delivery, low birth weight). For this reason it is necessary to have detailed counseling on the maternal and fetal risks, a close monitoring of the pregnancy, and prenatal and obstetric assistance, targeted to the prevention of these complications. One limitation of our study is the sample size of women > 45 years, which represents the true advanced reproductive age and deserves further evaluation in multicenter studies. Finally, it remains an open question: Why fetal and maternal outcomes are unfavorable in spite of the good health and economic conditions typical of these patients of advanced reproductive age?. The impact of better economic conditions, social and health in older age group it is still not clear why it should set up a potentially preventive role of risk, but the advanced maternal age per sé is a real independent risk factor for the majority of maternal complications discussed above but especially for gestational hypertension and preeclampsia. It would be a long-term post pregnancy follow-up of these patients to assess the impact of pregnancy in advanced reproductive age on cardiovascular risk in menopause. 745

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