Original Article
823
Obstetric and Neonatal Outcomes for Women 45 years of Age: A Cohort Study Niamh A. McDonnell1 Jennifer M. Walsh, MRCOG1 John J. Morrison, MD, FRCOG1 1 Department of Obstetrics and Gynecology, National University of
Ireland Galway, Galway University Hospital, Ireland
Siobhan C. Carruthers, MRCGP1
Address for correspondence John J. Morrison, MD, FRCOG, Department of Obstetrics and Gynecology, National University of Ireland Galway, Galway University Hospital, Ireland (e-mail: [email protected]).
Abstract
Keywords
► advanced maternal age ► perinatal outcome ► pregnancy complications
Objective To evaluate outcomes in women 45 years of age in comparison to a group of women aged 40 to 44 years. Materials and Methods A cohort study was conducted including women 45 years who delivered at > 24 weeks gestation during the period (1989–2011). Women aged 40 to 44 years formed the comparison group. The maternal demographics, mode of conception, maternal complications, timing and mode of delivery, neonatal features and postpartum complications were included as outcomes. Statistical analyses were performed using the t-test and Chi-square test. Results There were 67,278 deliveries; 140 occurred in women 45 years of age, (2.1/ 1,000). Compared with the 40 to 44 year age group (n ¼ 139), women 45 years had higher body mass index (26.7 4.7 vs. 24.6 7.1, p ¼ 0.01), and were more likely to have a previous pregnancy loss at < 24 weeks gestation (57.9 vs. 44.6%, p ¼ 0.03). There was no difference in the incidence of maternal complications, preterm delivery, birthweight, Apgar scores or admission to neonatal intensive care. The presence of preexisting maternal hypertension was associated with a poor outcome. Women 45 years were more likely to be delivered by cesarean section (45 vs. 30.2%, p ¼ 0.01). Conclusion Women aged 45 years have comparable outcomes to those aged 40 to 44 years, albeit the presence of pre-existing maternal disease is higher and associated with a poor outcome.
In recent years there has been a trend toward more advanced maternal age in many developed countries.1 This trend has been attributed to a complex combination of social and cultural factors, in addition to the advances in assisted conception techniques which are currently available.2 However the incidence of pregnancy in women of very advanced maternal age (i.e., aged 45 years or older at the time of delivery) is still rare, being approximately in the region of 0.1 to 0.2%1,3 even though reliable statistics are not widely available. It is well established that advancing maternal age is associated with a variety of adverse obstetric and neonatal outcomes.1,3,4 Maternal complications include an increased
incidence of hypertensive disorders of pregnancy and gestational diabetes, and a higher risk of intrapartum complications and cesarean delivery.1–6 An increased maternal age also confers a higher risk of adverse perinatal outcomes, including placental insufficiency and a higher likelihood of congenital malformations, and, in particular, aneuploidy.3–7 Much of the published literature has focused on mothers aged 35 years and greater,2,4,8 but in recent years there have been a small number of reports in relation to mothers of more advanced age at the time of delivery (i.e., 40 years, and particularly 45 years).1,3 Most of these studies have outlined increased maternal and fetal risk on an observational basis, or in comparison to younger age groups, and there is a
received June 14, 2013 accepted after revision October 22, 2013 published online December 12, 2013
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1361932. ISSN 0735-1631.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Am J Perinatol 2014;31:823–828.
Advanced Maternal Age and Pregnancy Outcome
McDonnell et al.
need for further data on this topic. What is not clear from the available evidence is whether or not the prospective parturient planning a pregnancy aged 45 years is more vulnerable to morbidity than her counterpart aged 40 to 44 years. The aims of this study were to examine the obstetric and neonatal outcome measures in a cohort of women aged 45 years, and to compare the findings with those observed in a group of women aged 40 to 44 years.
diabetes were examined. Delivery details evaluated included mode of delivery (normal vaginal, operative vaginal, elective and emergency cesarean deliveries) and the occurrence of preterm delivery. The neonatal outcomes analyzed were birth weight, Apgar scores and the need for admission to neonatal intensive care. In the postpartum period the following outcome measures were included: hemorrhage, hypertension, and obstetric anal sphincter injuries.
Statistical Analyses
Materials and Methods Study Design and Data Sources The data for this cohort study were obtained from two sources, an obstetric computerized database to which the data had been entered prospectively over the 22-year period from 1989 to 2011, and an individual patient file review, for the entire cohort. The database used was the EuroKing System (European Information Technology, Ottershaw, Surrey, United Kingdom).Women were selected for the study group on the basis of having been 45 years of age at the time of delivery, and delivering at or beyond 24 weeks of gestation. The comparison group was selected from the same database and included women who were aged 40 to 44 years at the time of delivery, and who also gave birth at or after 24 weeks of gestation. The two groups were not matched for parity, but analysis of both groups after selection revealed that there was a similar number of primigravida in both groups (study group n ¼ 24, 17%; comparison group n ¼ 23, 16%; p ¼ 1.0), and hence also a similar number of parous women.
Definitions of Maternal Characteristics and Outcome Variables The maternal characteristics examined included age, body mass index (BMI), parity (0 and 1 or greater), previous pregnancy loss (less than 24 weeks of gestation), mode of conception (natural, in vitro fertilization [IVF] with or without oocyte donation), and whether or not there was prepregnancy maternal hypertension or diabetes mellitus. Similarly the antenatal complications of hypertension and gestational
Data were assessed for normality using Shapiro Wilk and P-P plot. Comparison of means within groups of patients was accomplished with the independent samples t-test. Results are expressed as mean standard deviation (SD). Statistical significance was set at p < 0.05. The Chi-square test was used for comparing proportions. Multiple logistic regression analysis was employed to adjust for potential confounders such as maternal BMI and the results presented as standardized β-coefficients and corresponding p-values. Statistical analysis was performed using SPSS Windows version 18.0 (SPSS Inc., Chicago, IL). Subgroup analysis was performed to compare outcomes in spontaneous pregnancies with those that resulted from oocyte donation, and to compare outcomes in those with and without pre-existing hypertension or diabetes.
Results During the study period, there were 67,278 deliveries of which 140 occurred in women 45 years, resulting in an overall incidence of 2.1/1,000 or 0.2%. The comparison group consisted of 139 women. The maternal demographic features, the details of previous pregnancy loss and the mode of conception, for both groups are demonstrated in ►Table 1. There was a significant difference in the rate of conception by IVF, with 24 cases conceived using this technology in the study group, and 7 in the comparison group (p ¼ 0.0019). There were six multiple pregnancies in total, five in women 45 years of age, and one in the comparison group, all of whom
Table 1 A comparison of baseline maternal characteristics in women aged 40 to 44 years, and those 45 years of age Maternal characteristics
40–44 years n ¼ 139 (%)
45 years n ¼ 140 (%)
p-value
Maternal age
41.14 1.4
45.87 1.2
< 0.001
Primiparity
23 (16.5)
24 (17.1)
Previous pregnancy loss (< 24 weeks)
62 (44.6)
81 (57.9)
0.03
Early pregnancy BMI (kg/m2)
24.63 7.1
26.65 4.7
0.001
In vitro fertilization
7 (5.0)
24 (17.1)
0.0019
Oocyte donation
1 (0.7)
21 (15.0)
< 0.0001
Multiple pregnancies
1 (0.7)
5 (3.6)
0.2
Pregestational Diabetes mellitus
1 (0.7)
6 (4.3)
0.1
Preexisting hypertension
16 (11.5)
22 (15.7)
0.3
Note: The above data are presented as n (%) or mean standard deviation. American Journal of Perinatology
Vol. 31
No. 9/2014
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
824
Advanced Maternal Age and Pregnancy Outcome
McDonnell et al.
825
Neonatal and obstetric outcomes
40–44 years n ¼ 139 (%)
45 years n ¼ 140 (%)
p-value
Preeclampsia
9 (6.5)
9 (6.4)
1.0
Gestational diabetes mellitus
8 (5.8)
2 (1.4)
0.06
Gestational age at delivery (days)
274.6 11.9
270.0 18.7
0.01
Preterm delivery < 37 weeks
9 (6.5)
15 (10.7)
0.2
Preterm delivery < 34 weeks
2 (1.4)
7 (5.0)
0.1
Birth weight
3,478.5 684.7
3,358.3 758.1
0.17
Apgar score < 7 at 5 minutes
1 (0.7)
4 (2.9)
0.4
Neonatal unit admission
16 (11.5)
19 (13.6)
0.7
Chromosomal abnormality
2 (1.4)
3 (2.1)
1.0
Perinatal mortality
1 (0.7)
5 (3.6)
0.2
SVD
83 (59.7)
59 (42.1)
0.004
Operative vaginal delivery
14 (10.1)
18 (12.9)
0.5
Elective cesarean
23 (16.5)
45 (32.1)
0.003
Emergency cesarean
19 (13.7)
18 (12.9)
0.86
Postpartum hemorrhage
2 (1.4)
8 (5.7)
0.1
Sphincter damage
5 (3.6)
4 (3.0)
1.0
Mode of delivery
Abbreviation: SVD, spontaneous vaginal delivery. Note: The above data are presented as n (%) or mean standard deviation.
delivered at or beyond 37 weeks of gestation. Women 45 years were more likely to have prepregnancy diabetes mellitus when compared with the comparison group, but this difference was not statistically significant (6 vs. 1, p ¼ 0.1). Prepregnancy hypertension occurred in 22 members (15.7%) of the study group and in 16 (11.5%) in the comparison group (p ¼ 0.3). There was no significant difference between the two groups in the incidence of preeclampsia, which occurred in nine women from both of the groups (p ¼ 1.0) (►Table 2). Similarly, for gestational diabetes mellitus, the occurrence was similar in both the groups; (study group n ¼ 2, 1.4%, and comparison group n ¼ 8, 5.8%, p ¼ 0.06) (►Table 2). No difference was observed in the incidence of preterm delivery < 37 weeks of gestation (15/140 [10.7%] vs. 9/139 [6.5%], p ¼ 0.2), or < 34 weeks of gestation (7/140 [5%] vs. 2/139 [1.4%], p ¼ 0.1), between the groups respectively. Women in the study group were less likely to achieve a spontaneous vaginal delivery in comparison to women aged 40 to 44 years (59/140 [42.1%] vs. 83/139 [59.7%], p ¼ 0.004) (►Table 2). The details for operative vaginal delivery are shown in ►Table 2. Women 45 years of age were significantly more likely to be delivered by cesarean section (63/140 [45%] vs. 42/139 [30.2%], p ¼ 0.01), and specifically planned cesarean delivery was more common in the study group (►Table 2). The difference in cesarean delivery rates between the two age categories remained significant following adjustment for the difference in maternal BMI with regression analysis, (β¼ 0.18, p ¼ 0.005). The incidence of postpartum maternal complications is outlined in ►Table 2. There was no significant difference between both the groups.
There was no difference in birthweight between the two groups (►Table 2). There were 19 (13.6%) neonates in the study group who required admission to the neonatal intensive care unit, while there were 16 admissions (11.5%) from the comparison group (p ¼ 0.7). Four neonates had Apgar scores < 7 at 5 minutes in the study group, and this was confined to one neonate in the comparison group (p ¼ 0.4). In relation to perinatal mortality there were five cases in the study group and one in the comparison group (p ¼ 0.2). The type of perinatal death that occurred (stillbirth or neonatal death), and the associated maternal complications of pregnancy, are described in ►Table 3. All six mothers had significant medical complications of pregnancy. There were five stillbirths and one neonatal death, and the majority of deaths (n ¼ 5) took place < 30 weeks of gestation. All perinatal mortalities occurred in singleton pregnancies. For neonatal aneuploidy there were five cases of trisomy 21(n ¼ 3 study group, n ¼ 2 comparison group, p ¼ 1.0), all of whom survived the neonatal period. Subgroup analyses were performed on two different overall aspects of the study: (1) all pregnancies from both groups that were conceived using oocyte donation (n ¼ 21); (2) all pregnancies from both groups that were complicated by hypertensive disease (n ¼ 38). For the first analysis there were no significant differences in the incidences of hypertensive disorders of pregnancy, gestational diabetes mellitus or delivery preterm between pregnancies conceived using oocyte donation and those that occurred with the mother’s own oocytes. For the second analysis, women with underlying hypertensive disease (prepregnancy or gestational) were American Journal of Perinatology
Vol. 31
No. 9/2014
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Table 2 A comparison of outcomes, both neonatal and obstetric, in women aged 40 to 44 years, and those 45 years of age
Advanced Maternal Age and Pregnancy Outcome
McDonnell et al.
Table 3 Perinatal death in the study group and comparison group No.
Maternal age (years)
GA (weeks)
BW (g)
Maternal complications
Perinatal death
1
45
29 þ 0
2
46
25 þ 0
900
T1 DM, no antenatal care
IUFD
1,200
HTN
IUFD
3
47
29 þ 0
750
HTN, Rhesus incompatibility
IUFD
4 5
48
25 þ 0
960
HTN
IUFD
45
24 þ 5
440
T1 DM, renal failure, kidney and pancreatic transplant, HTN
Neonatal death
6
42
37 þ 5
2,460
HTN
IUFD
Abbreviations: BW, birth weight; GA, gestational age; HTN, hypertension; IUFD, intrauterine fetal death; T1 DM, type 1 diabetes mellitus.
significantly more likely to have a preterm delivery < 34 weeks (5/38 [13.1%] vs. 4/242 [1.7%], p < 0.001), a higher perinatal mortality rate (5/38 [13.1%] vs. 1/242 [0.4%], p < 0.001) and a birth weight < 2.5 kg (7/38 [18.4%] vs. 12/ 242 [5.0%], p < 0.001) (►Table 4).
Discussion This study serves to outline the obstetric and neonatal issues pertinent to the small minority of pregnancies that occur for women delivering in the extremely advanced age group of 45 years. These results also provide data for counseling women considering pregnancy over the age of 40 years, and specifically in relation to the risks involved in a comparative way between the first and second halves of the fifth decade of life. The strengths of this study include the large numbers involved, the fact that all of the computerized data were prospectively entered at the time of delivery, that there is a carefully selected comparison group, and that all outcome measures were confirmed from two sources. The limitations of this study are that it is essentially retrospective in nature and that the adverse outcomes (e.g., perinatal mortality, neonatal aneuploidy), even at this age group, are relatively uncommon, resulting in poor sample size to enable sound conclusions. Additionally, while we did adjust for maternal BMI in our primary analysis, there are likely to be residual potential confounders, such as socioeconomic group, that we do not have sufficient data to account for. There are however many interesting points of conclusion to be made from these findings. Pregnancy in women 45 years is mostly encountered by the high risk obstetric physician but still represents a very
small proportion of all pregnancies. The incidence of pregnancies in this age in the current study was 0.2%, which is remarkably consistent with a recent report of 0.2% from a US population,1 0.3% from an Israeli population3 and is somewhat greater than that reported in an Australian study in 2005 of 0.07%.9 The available literature pertaining to pregnancies in older women is heavily weighted toward maternal age 35 years, and hence this series compliments the relatively small number of reports that exist for the advanced maternal age described here. An interesting conclusion that arises from these data is that most pregnancies in women 45 years are relatively uncomplicated and result in the birth of healthy offspring. The live birth rate was 96.4%, with a preterm delivery rate of 10.7%, and the incidence of gestational hypertensive disease was 6.4%, while that of gestational diabetes mellitus was 1.4%. Admittedly the cesarean delivery rate was 45% overall, however 71% of all of these procedures were performed on a planned or elective basis. This issue, of high elective cesarean delivery rates, has previously been outlined for this age group of women.1 Second, the morbidity (both maternal and fetal) associated with such pregnancies, does not appear to significantly escalate between the first and second halves of the fifth decade of life.10 The only clinical outcome that differed significantly between the two groups was the incidence of elective cesarean delivery, and many factors could potentially have contributed to this, such as maternal request, physician preference and other obstetrical or social factors. The findings from this study have suggested that there was no clear statistically significant difference between the preterm delivery rates, and the perinatal mortality rates, between the study and comparison groups. However, these
Table 4 Pregnancy outcomes in those with hypertension (preexisting or gestational), compared with those without hypertension Pregnancy outcomes
With hypertension n ¼ 38 (%)
Without hypertension n ¼ 242 (%)
p-value
Preterm delivery < 34 weeks
5 (13.1)
4 (1.7)
< 0.001
Perinatal mortality rate
5 (13.1)
1 (0.4)
< 0.001
Birth weight < 2.5 kg
7 (18.4)
12 (5.0)
< 0.001
Note: The above data are presented as n (%). American Journal of Perinatology
Vol. 31
No. 9/2014
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
826
Advanced Maternal Age and Pregnancy Outcome
827
of the fifth decade of life. The results highlight the issue of advanced maternal age alone, and the concept of the older parturient with underlying comorbidities. These findings are of particular relevance when counseling women of advanced maternal age who are considering embarking upon a pregnancy. Future studies on this topic would be greatly assisted by being population based, allowing for greater numbers and the ability to adjust for potential confounders.
Funding This study was funded by the Health Research Board of Ireland.
Acknowledgment The authors wish to thank the Health Research Board, Ireland, for their assistance in funding.
References 1 Yogev Y, Melamed N, Bardin R, Tenenbaum-Gavish K, Ben-Shitrit
2
3
4
5
6
7
8
9
10
G, Ben-Haroush A. Pregnancy outcome at extremely advanced maternal age. Am J Obstet Gynecol 2010;203(6):558.e1–558.e7 Hammarberg K, Clarke VE. Reasons for delaying childbearing—a survey of women aged over 35 years seeking assisted reproductive technology. Aust Fam Physician 2005;34(3):187–188, 206 Laskov I, Birnbaum R, Maslovitz S, Kupferminc M, Lessing J, Many A. Outcome of singleton pregnancy in women 45 years old: a retrospective cohort study. J Matern Fetal Neonatal Med 2012; 25(11):2190–2193 Kenny LC, Lavender T, McNamee R, O’Neill SM, Mills T, Khashan AS. Advanced maternal age and adverse pregnancy outcome: evidence from a large contemporary cohort. PLoS ONE 2013; 8(2):e56583 Salem Yaniv S, Levy A, Wiznitzer A, Holcberg G, Mazor M, Sheiner E. A significant linear association exists between advanced maternal age and adverse perinatal outcome. Arch Gynecol Obstet 2011; 283(4):755–759 Abu-Heija AT, Jallad MF, Abukteish F. Maternal and perinatal outcome of pregnancies after the age of 45. J Obstet Gynaecol Res 2000;26(1):27–30 Waltman LA, Eckel-Passow JE, Sharma RG, Van Dyke DL. Advanced maternal age in polyploidy with concurrent aneuploidy. Am J Med Genet A 2013;161A(5):1200–1202 van Katwijk C, Peeters LLH. Clinical aspects of pregnancy after the age of 35 years: a review of the literature. Hum Reprod Update 1998;4(2):185–194 Callaway LK, Lust K, McIntyre HD. Pregnancy outcomes in women of very advanced maternal age. Aust N Z J Obstet Gynaecol 2005; 45(1):12–16 Kale A, Kuyumcuoğlu U, Güzel A. Is pregnancy over 45 with very high parity related with adverse maternal and fetal outcomes? Clin Exp Obstet Gynecol 2009;36(2):120–122
American Journal of Perinatology
Vol. 31
No. 9/2014
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
findings must be interpreted with caution. The absolute numbers of these adverse events, in both the groups, are low (►Table 2), but there is a trend toward higher rates of both events in the older women, that is, the study group. In our entire hospital obstetric population, the preterm delivery rates during this period were as follows: < 37 weeks, 6 to 7%; and < 34 weeks, 1 to 2%. These figures are remarkably similar to those observed in the 40 to 44 year old women. Similarly, perinatal mortality rates for the entire obstetric population were approximately 7/1,000 (i.e., 0.7%), also similar to that observed in the 40- to 44-year-old women. For women 45 years, the preterm delivery rates observed were as follows: < 37 weeks, 10.7%; and < 34 weeks, 5%. The perinatal mortality rate in this group was five-fold higher than that observed in the 40- to 44-year-old women, at 36/ 1,000, or 3.6%. Despite the lack of statistical significance observed in this study, there is a clear suggestion that the incidence of both of these adverse events increases for women 45 years, and particularly above the baseline of the entire obstetric population. Importantly, however, we did find that pre-existing maternal hypertension conferred a significantly elevated risk of adverse perinatal outcome. Rates of preterm delivery were significantly higher in women with underlying hypertension (13.1 vs. 1.7%). Additionally, five cases of perinatal mortality occurred in women with underlying hypertension and the remaining case occurred in a woman with both hypertension and diabetes mellitus. The absolute number of mortalities was low, and hence sound conclusions are difficult to establish, but there is a clear suggestion from this study that underlying maternal hypertension propels the women in this age group to a more serious level of risk. There were five cases of neonatal Down syndrome diagnosed from the 279 pregnancies examined, resulting in an overall incidence of 1.8%, which was 2.1% in the study group and 1.4% in the comparison group. Excluding women who had oocyte donation, the incidence in the study group was 2.5%. These figures are all consistent with age related occurrence of nondysjunctional trisomy 21. Prenatal screening is not a part of routine obstetric care in Ireland, and is generally embarked upon at the request of the prospective parents. The application of such testing during the study period was variable, and hence the diagnosis of Down syndrome was established postnatally in all five cases. Finally, we did not observe any difference in outcome for pregnancies conceived using oocyte donation, but it is our view that this may be a reflection of the relatively small numbers involved (n ¼ 21). In conclusion, this study outlines the obstetric and neonatal aspects of pregnancies for women 45 years of age, and provides a comparison for such outcomes over the spectrum
McDonnell et al.
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
823
Obstetric and Neonatal Outcomes for Women 45 years of Age: A Cohort Study Niamh A. McDonnell1 Jennifer M. Walsh, MRCOG1 John J. Morrison, MD, FRCOG1 1 Department of Obstetrics and Gynecology, National University of
Ireland Galway, Galway University Hospital, Ireland
Siobhan C. Carruthers, MRCGP1
Address for correspondence John J. Morrison, MD, FRCOG, Department of Obstetrics and Gynecology, National University of Ireland Galway, Galway University Hospital, Ireland (e-mail: [email protected]).
Abstract
Keywords
► advanced maternal age ► perinatal outcome ► pregnancy complications
Objective To evaluate outcomes in women 45 years of age in comparison to a group of women aged 40 to 44 years. Materials and Methods A cohort study was conducted including women 45 years who delivered at > 24 weeks gestation during the period (1989–2011). Women aged 40 to 44 years formed the comparison group. The maternal demographics, mode of conception, maternal complications, timing and mode of delivery, neonatal features and postpartum complications were included as outcomes. Statistical analyses were performed using the t-test and Chi-square test. Results There were 67,278 deliveries; 140 occurred in women 45 years of age, (2.1/ 1,000). Compared with the 40 to 44 year age group (n ¼ 139), women 45 years had higher body mass index (26.7 4.7 vs. 24.6 7.1, p ¼ 0.01), and were more likely to have a previous pregnancy loss at < 24 weeks gestation (57.9 vs. 44.6%, p ¼ 0.03). There was no difference in the incidence of maternal complications, preterm delivery, birthweight, Apgar scores or admission to neonatal intensive care. The presence of preexisting maternal hypertension was associated with a poor outcome. Women 45 years were more likely to be delivered by cesarean section (45 vs. 30.2%, p ¼ 0.01). Conclusion Women aged 45 years have comparable outcomes to those aged 40 to 44 years, albeit the presence of pre-existing maternal disease is higher and associated with a poor outcome.
In recent years there has been a trend toward more advanced maternal age in many developed countries.1 This trend has been attributed to a complex combination of social and cultural factors, in addition to the advances in assisted conception techniques which are currently available.2 However the incidence of pregnancy in women of very advanced maternal age (i.e., aged 45 years or older at the time of delivery) is still rare, being approximately in the region of 0.1 to 0.2%1,3 even though reliable statistics are not widely available. It is well established that advancing maternal age is associated with a variety of adverse obstetric and neonatal outcomes.1,3,4 Maternal complications include an increased
incidence of hypertensive disorders of pregnancy and gestational diabetes, and a higher risk of intrapartum complications and cesarean delivery.1–6 An increased maternal age also confers a higher risk of adverse perinatal outcomes, including placental insufficiency and a higher likelihood of congenital malformations, and, in particular, aneuploidy.3–7 Much of the published literature has focused on mothers aged 35 years and greater,2,4,8 but in recent years there have been a small number of reports in relation to mothers of more advanced age at the time of delivery (i.e., 40 years, and particularly 45 years).1,3 Most of these studies have outlined increased maternal and fetal risk on an observational basis, or in comparison to younger age groups, and there is a
received June 14, 2013 accepted after revision October 22, 2013 published online December 12, 2013
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1361932. ISSN 0735-1631.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Am J Perinatol 2014;31:823–828.
Advanced Maternal Age and Pregnancy Outcome
McDonnell et al.
need for further data on this topic. What is not clear from the available evidence is whether or not the prospective parturient planning a pregnancy aged 45 years is more vulnerable to morbidity than her counterpart aged 40 to 44 years. The aims of this study were to examine the obstetric and neonatal outcome measures in a cohort of women aged 45 years, and to compare the findings with those observed in a group of women aged 40 to 44 years.
diabetes were examined. Delivery details evaluated included mode of delivery (normal vaginal, operative vaginal, elective and emergency cesarean deliveries) and the occurrence of preterm delivery. The neonatal outcomes analyzed were birth weight, Apgar scores and the need for admission to neonatal intensive care. In the postpartum period the following outcome measures were included: hemorrhage, hypertension, and obstetric anal sphincter injuries.
Statistical Analyses
Materials and Methods Study Design and Data Sources The data for this cohort study were obtained from two sources, an obstetric computerized database to which the data had been entered prospectively over the 22-year period from 1989 to 2011, and an individual patient file review, for the entire cohort. The database used was the EuroKing System (European Information Technology, Ottershaw, Surrey, United Kingdom).Women were selected for the study group on the basis of having been 45 years of age at the time of delivery, and delivering at or beyond 24 weeks of gestation. The comparison group was selected from the same database and included women who were aged 40 to 44 years at the time of delivery, and who also gave birth at or after 24 weeks of gestation. The two groups were not matched for parity, but analysis of both groups after selection revealed that there was a similar number of primigravida in both groups (study group n ¼ 24, 17%; comparison group n ¼ 23, 16%; p ¼ 1.0), and hence also a similar number of parous women.
Definitions of Maternal Characteristics and Outcome Variables The maternal characteristics examined included age, body mass index (BMI), parity (0 and 1 or greater), previous pregnancy loss (less than 24 weeks of gestation), mode of conception (natural, in vitro fertilization [IVF] with or without oocyte donation), and whether or not there was prepregnancy maternal hypertension or diabetes mellitus. Similarly the antenatal complications of hypertension and gestational
Data were assessed for normality using Shapiro Wilk and P-P plot. Comparison of means within groups of patients was accomplished with the independent samples t-test. Results are expressed as mean standard deviation (SD). Statistical significance was set at p < 0.05. The Chi-square test was used for comparing proportions. Multiple logistic regression analysis was employed to adjust for potential confounders such as maternal BMI and the results presented as standardized β-coefficients and corresponding p-values. Statistical analysis was performed using SPSS Windows version 18.0 (SPSS Inc., Chicago, IL). Subgroup analysis was performed to compare outcomes in spontaneous pregnancies with those that resulted from oocyte donation, and to compare outcomes in those with and without pre-existing hypertension or diabetes.
Results During the study period, there were 67,278 deliveries of which 140 occurred in women 45 years, resulting in an overall incidence of 2.1/1,000 or 0.2%. The comparison group consisted of 139 women. The maternal demographic features, the details of previous pregnancy loss and the mode of conception, for both groups are demonstrated in ►Table 1. There was a significant difference in the rate of conception by IVF, with 24 cases conceived using this technology in the study group, and 7 in the comparison group (p ¼ 0.0019). There were six multiple pregnancies in total, five in women 45 years of age, and one in the comparison group, all of whom
Table 1 A comparison of baseline maternal characteristics in women aged 40 to 44 years, and those 45 years of age Maternal characteristics
40–44 years n ¼ 139 (%)
45 years n ¼ 140 (%)
p-value
Maternal age
41.14 1.4
45.87 1.2
< 0.001
Primiparity
23 (16.5)
24 (17.1)
Previous pregnancy loss (< 24 weeks)
62 (44.6)
81 (57.9)
0.03
Early pregnancy BMI (kg/m2)
24.63 7.1
26.65 4.7
0.001
In vitro fertilization
7 (5.0)
24 (17.1)
0.0019
Oocyte donation
1 (0.7)
21 (15.0)
< 0.0001
Multiple pregnancies
1 (0.7)
5 (3.6)
0.2
Pregestational Diabetes mellitus
1 (0.7)
6 (4.3)
0.1
Preexisting hypertension
16 (11.5)
22 (15.7)
0.3
Note: The above data are presented as n (%) or mean standard deviation. American Journal of Perinatology
Vol. 31
No. 9/2014
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
824
Advanced Maternal Age and Pregnancy Outcome
McDonnell et al.
825
Neonatal and obstetric outcomes
40–44 years n ¼ 139 (%)
45 years n ¼ 140 (%)
p-value
Preeclampsia
9 (6.5)
9 (6.4)
1.0
Gestational diabetes mellitus
8 (5.8)
2 (1.4)
0.06
Gestational age at delivery (days)
274.6 11.9
270.0 18.7
0.01
Preterm delivery < 37 weeks
9 (6.5)
15 (10.7)
0.2
Preterm delivery < 34 weeks
2 (1.4)
7 (5.0)
0.1
Birth weight
3,478.5 684.7
3,358.3 758.1
0.17
Apgar score < 7 at 5 minutes
1 (0.7)
4 (2.9)
0.4
Neonatal unit admission
16 (11.5)
19 (13.6)
0.7
Chromosomal abnormality
2 (1.4)
3 (2.1)
1.0
Perinatal mortality
1 (0.7)
5 (3.6)
0.2
SVD
83 (59.7)
59 (42.1)
0.004
Operative vaginal delivery
14 (10.1)
18 (12.9)
0.5
Elective cesarean
23 (16.5)
45 (32.1)
0.003
Emergency cesarean
19 (13.7)
18 (12.9)
0.86
Postpartum hemorrhage
2 (1.4)
8 (5.7)
0.1
Sphincter damage
5 (3.6)
4 (3.0)
1.0
Mode of delivery
Abbreviation: SVD, spontaneous vaginal delivery. Note: The above data are presented as n (%) or mean standard deviation.
delivered at or beyond 37 weeks of gestation. Women 45 years were more likely to have prepregnancy diabetes mellitus when compared with the comparison group, but this difference was not statistically significant (6 vs. 1, p ¼ 0.1). Prepregnancy hypertension occurred in 22 members (15.7%) of the study group and in 16 (11.5%) in the comparison group (p ¼ 0.3). There was no significant difference between the two groups in the incidence of preeclampsia, which occurred in nine women from both of the groups (p ¼ 1.0) (►Table 2). Similarly, for gestational diabetes mellitus, the occurrence was similar in both the groups; (study group n ¼ 2, 1.4%, and comparison group n ¼ 8, 5.8%, p ¼ 0.06) (►Table 2). No difference was observed in the incidence of preterm delivery < 37 weeks of gestation (15/140 [10.7%] vs. 9/139 [6.5%], p ¼ 0.2), or < 34 weeks of gestation (7/140 [5%] vs. 2/139 [1.4%], p ¼ 0.1), between the groups respectively. Women in the study group were less likely to achieve a spontaneous vaginal delivery in comparison to women aged 40 to 44 years (59/140 [42.1%] vs. 83/139 [59.7%], p ¼ 0.004) (►Table 2). The details for operative vaginal delivery are shown in ►Table 2. Women 45 years of age were significantly more likely to be delivered by cesarean section (63/140 [45%] vs. 42/139 [30.2%], p ¼ 0.01), and specifically planned cesarean delivery was more common in the study group (►Table 2). The difference in cesarean delivery rates between the two age categories remained significant following adjustment for the difference in maternal BMI with regression analysis, (β¼ 0.18, p ¼ 0.005). The incidence of postpartum maternal complications is outlined in ►Table 2. There was no significant difference between both the groups.
There was no difference in birthweight between the two groups (►Table 2). There were 19 (13.6%) neonates in the study group who required admission to the neonatal intensive care unit, while there were 16 admissions (11.5%) from the comparison group (p ¼ 0.7). Four neonates had Apgar scores < 7 at 5 minutes in the study group, and this was confined to one neonate in the comparison group (p ¼ 0.4). In relation to perinatal mortality there were five cases in the study group and one in the comparison group (p ¼ 0.2). The type of perinatal death that occurred (stillbirth or neonatal death), and the associated maternal complications of pregnancy, are described in ►Table 3. All six mothers had significant medical complications of pregnancy. There were five stillbirths and one neonatal death, and the majority of deaths (n ¼ 5) took place < 30 weeks of gestation. All perinatal mortalities occurred in singleton pregnancies. For neonatal aneuploidy there were five cases of trisomy 21(n ¼ 3 study group, n ¼ 2 comparison group, p ¼ 1.0), all of whom survived the neonatal period. Subgroup analyses were performed on two different overall aspects of the study: (1) all pregnancies from both groups that were conceived using oocyte donation (n ¼ 21); (2) all pregnancies from both groups that were complicated by hypertensive disease (n ¼ 38). For the first analysis there were no significant differences in the incidences of hypertensive disorders of pregnancy, gestational diabetes mellitus or delivery preterm between pregnancies conceived using oocyte donation and those that occurred with the mother’s own oocytes. For the second analysis, women with underlying hypertensive disease (prepregnancy or gestational) were American Journal of Perinatology
Vol. 31
No. 9/2014
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Table 2 A comparison of outcomes, both neonatal and obstetric, in women aged 40 to 44 years, and those 45 years of age
Advanced Maternal Age and Pregnancy Outcome
McDonnell et al.
Table 3 Perinatal death in the study group and comparison group No.
Maternal age (years)
GA (weeks)
BW (g)
Maternal complications
Perinatal death
1
45
29 þ 0
2
46
25 þ 0
900
T1 DM, no antenatal care
IUFD
1,200
HTN
IUFD
3
47
29 þ 0
750
HTN, Rhesus incompatibility
IUFD
4 5
48
25 þ 0
960
HTN
IUFD
45
24 þ 5
440
T1 DM, renal failure, kidney and pancreatic transplant, HTN
Neonatal death
6
42
37 þ 5
2,460
HTN
IUFD
Abbreviations: BW, birth weight; GA, gestational age; HTN, hypertension; IUFD, intrauterine fetal death; T1 DM, type 1 diabetes mellitus.
significantly more likely to have a preterm delivery < 34 weeks (5/38 [13.1%] vs. 4/242 [1.7%], p < 0.001), a higher perinatal mortality rate (5/38 [13.1%] vs. 1/242 [0.4%], p < 0.001) and a birth weight < 2.5 kg (7/38 [18.4%] vs. 12/ 242 [5.0%], p < 0.001) (►Table 4).
Discussion This study serves to outline the obstetric and neonatal issues pertinent to the small minority of pregnancies that occur for women delivering in the extremely advanced age group of 45 years. These results also provide data for counseling women considering pregnancy over the age of 40 years, and specifically in relation to the risks involved in a comparative way between the first and second halves of the fifth decade of life. The strengths of this study include the large numbers involved, the fact that all of the computerized data were prospectively entered at the time of delivery, that there is a carefully selected comparison group, and that all outcome measures were confirmed from two sources. The limitations of this study are that it is essentially retrospective in nature and that the adverse outcomes (e.g., perinatal mortality, neonatal aneuploidy), even at this age group, are relatively uncommon, resulting in poor sample size to enable sound conclusions. Additionally, while we did adjust for maternal BMI in our primary analysis, there are likely to be residual potential confounders, such as socioeconomic group, that we do not have sufficient data to account for. There are however many interesting points of conclusion to be made from these findings. Pregnancy in women 45 years is mostly encountered by the high risk obstetric physician but still represents a very
small proportion of all pregnancies. The incidence of pregnancies in this age in the current study was 0.2%, which is remarkably consistent with a recent report of 0.2% from a US population,1 0.3% from an Israeli population3 and is somewhat greater than that reported in an Australian study in 2005 of 0.07%.9 The available literature pertaining to pregnancies in older women is heavily weighted toward maternal age 35 years, and hence this series compliments the relatively small number of reports that exist for the advanced maternal age described here. An interesting conclusion that arises from these data is that most pregnancies in women 45 years are relatively uncomplicated and result in the birth of healthy offspring. The live birth rate was 96.4%, with a preterm delivery rate of 10.7%, and the incidence of gestational hypertensive disease was 6.4%, while that of gestational diabetes mellitus was 1.4%. Admittedly the cesarean delivery rate was 45% overall, however 71% of all of these procedures were performed on a planned or elective basis. This issue, of high elective cesarean delivery rates, has previously been outlined for this age group of women.1 Second, the morbidity (both maternal and fetal) associated with such pregnancies, does not appear to significantly escalate between the first and second halves of the fifth decade of life.10 The only clinical outcome that differed significantly between the two groups was the incidence of elective cesarean delivery, and many factors could potentially have contributed to this, such as maternal request, physician preference and other obstetrical or social factors. The findings from this study have suggested that there was no clear statistically significant difference between the preterm delivery rates, and the perinatal mortality rates, between the study and comparison groups. However, these
Table 4 Pregnancy outcomes in those with hypertension (preexisting or gestational), compared with those without hypertension Pregnancy outcomes
With hypertension n ¼ 38 (%)
Without hypertension n ¼ 242 (%)
p-value
Preterm delivery < 34 weeks
5 (13.1)
4 (1.7)
< 0.001
Perinatal mortality rate
5 (13.1)
1 (0.4)
< 0.001
Birth weight < 2.5 kg
7 (18.4)
12 (5.0)
< 0.001
Note: The above data are presented as n (%). American Journal of Perinatology
Vol. 31
No. 9/2014
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
826
Advanced Maternal Age and Pregnancy Outcome
827
of the fifth decade of life. The results highlight the issue of advanced maternal age alone, and the concept of the older parturient with underlying comorbidities. These findings are of particular relevance when counseling women of advanced maternal age who are considering embarking upon a pregnancy. Future studies on this topic would be greatly assisted by being population based, allowing for greater numbers and the ability to adjust for potential confounders.
Funding This study was funded by the Health Research Board of Ireland.
Acknowledgment The authors wish to thank the Health Research Board, Ireland, for their assistance in funding.
References 1 Yogev Y, Melamed N, Bardin R, Tenenbaum-Gavish K, Ben-Shitrit
2
3
4
5
6
7
8
9
10
G, Ben-Haroush A. Pregnancy outcome at extremely advanced maternal age. Am J Obstet Gynecol 2010;203(6):558.e1–558.e7 Hammarberg K, Clarke VE. Reasons for delaying childbearing—a survey of women aged over 35 years seeking assisted reproductive technology. Aust Fam Physician 2005;34(3):187–188, 206 Laskov I, Birnbaum R, Maslovitz S, Kupferminc M, Lessing J, Many A. Outcome of singleton pregnancy in women 45 years old: a retrospective cohort study. J Matern Fetal Neonatal Med 2012; 25(11):2190–2193 Kenny LC, Lavender T, McNamee R, O’Neill SM, Mills T, Khashan AS. Advanced maternal age and adverse pregnancy outcome: evidence from a large contemporary cohort. PLoS ONE 2013; 8(2):e56583 Salem Yaniv S, Levy A, Wiznitzer A, Holcberg G, Mazor M, Sheiner E. A significant linear association exists between advanced maternal age and adverse perinatal outcome. Arch Gynecol Obstet 2011; 283(4):755–759 Abu-Heija AT, Jallad MF, Abukteish F. Maternal and perinatal outcome of pregnancies after the age of 45. J Obstet Gynaecol Res 2000;26(1):27–30 Waltman LA, Eckel-Passow JE, Sharma RG, Van Dyke DL. Advanced maternal age in polyploidy with concurrent aneuploidy. Am J Med Genet A 2013;161A(5):1200–1202 van Katwijk C, Peeters LLH. Clinical aspects of pregnancy after the age of 35 years: a review of the literature. Hum Reprod Update 1998;4(2):185–194 Callaway LK, Lust K, McIntyre HD. Pregnancy outcomes in women of very advanced maternal age. Aust N Z J Obstet Gynaecol 2005; 45(1):12–16 Kale A, Kuyumcuoğlu U, Güzel A. Is pregnancy over 45 with very high parity related with adverse maternal and fetal outcomes? Clin Exp Obstet Gynecol 2009;36(2):120–122
American Journal of Perinatology
Vol. 31
No. 9/2014
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
findings must be interpreted with caution. The absolute numbers of these adverse events, in both the groups, are low (►Table 2), but there is a trend toward higher rates of both events in the older women, that is, the study group. In our entire hospital obstetric population, the preterm delivery rates during this period were as follows: < 37 weeks, 6 to 7%; and < 34 weeks, 1 to 2%. These figures are remarkably similar to those observed in the 40 to 44 year old women. Similarly, perinatal mortality rates for the entire obstetric population were approximately 7/1,000 (i.e., 0.7%), also similar to that observed in the 40- to 44-year-old women. For women 45 years, the preterm delivery rates observed were as follows: < 37 weeks, 10.7%; and < 34 weeks, 5%. The perinatal mortality rate in this group was five-fold higher than that observed in the 40- to 44-year-old women, at 36/ 1,000, or 3.6%. Despite the lack of statistical significance observed in this study, there is a clear suggestion that the incidence of both of these adverse events increases for women 45 years, and particularly above the baseline of the entire obstetric population. Importantly, however, we did find that pre-existing maternal hypertension conferred a significantly elevated risk of adverse perinatal outcome. Rates of preterm delivery were significantly higher in women with underlying hypertension (13.1 vs. 1.7%). Additionally, five cases of perinatal mortality occurred in women with underlying hypertension and the remaining case occurred in a woman with both hypertension and diabetes mellitus. The absolute number of mortalities was low, and hence sound conclusions are difficult to establish, but there is a clear suggestion from this study that underlying maternal hypertension propels the women in this age group to a more serious level of risk. There were five cases of neonatal Down syndrome diagnosed from the 279 pregnancies examined, resulting in an overall incidence of 1.8%, which was 2.1% in the study group and 1.4% in the comparison group. Excluding women who had oocyte donation, the incidence in the study group was 2.5%. These figures are all consistent with age related occurrence of nondysjunctional trisomy 21. Prenatal screening is not a part of routine obstetric care in Ireland, and is generally embarked upon at the request of the prospective parents. The application of such testing during the study period was variable, and hence the diagnosis of Down syndrome was established postnatally in all five cases. Finally, we did not observe any difference in outcome for pregnancies conceived using oocyte donation, but it is our view that this may be a reflection of the relatively small numbers involved (n ¼ 21). In conclusion, this study outlines the obstetric and neonatal aspects of pregnancies for women 45 years of age, and provides a comparison for such outcomes over the spectrum
McDonnell et al.
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
