Maternal age ≥45 years and maternal and perinatal outcomes: A review of the evidence

Midwifery 29 (2013) 479–489

Contents lists available at SciVerse ScienceDirect

Midwifery journal homepage: www.elsevier.com/midw

Maternal age Z45 years and maternal and perinatal outcomes: A review of the evidence Mary Carolan, PhD (Associate Professor Midwifery) School of Nursing and Midwifery, St. Alban’s Campus, Victoria University, PO Box 14228, Melbourne 8001, Australia

a r t i c l e i n f o

abstract

Article history: Received 4 December 2011 Received in revised form 22 March 2012 Accepted 1 April 2012

Objective: to examine the evidence in relation to very advanced maternal age (Z 45 years) and maternal and perinatal outcomes in high-income countries. Background: this review was conducted against a background of increasing fertility options for women aged Z ¼45 years and rising birth rates among this group of women. Methods: established health databases including SCOPUS, MEDLINE, CINAHL, EMBASE and Maternity and Infant Care were searched for journal papers, published 2001–2011, that examined very advanced maternal age (VAMA) and maternal and perinatal outcomes. Further searches were based on references found in located articles. Keywords included a search term for maternal age Z 45 years (very advanced maternal age, pregnancy aged 45 years and older) and a search term for maternal complications (caesarian section, hypertension, pre-eclampsia, gestational diabetes) and/or adverse perinatal outcome (preterm birth, low birth weight, small for gestational age, stillbirth, perinatal death). Of 164 retrieved publications, 10 met inclusion criteria. Data extraction: data were extracted and organised under the following headings: maternal age Z45 years; maternal characteristics such as parity and use of artificial reproductive technology (ART); and preexisting maternal conditions, such as diabetes and hypertension. Additional headings included: gestational conditions, such as pre-eclampsia and gestational diabetes (GDM); and perinatal outcomes, including fetal/ infant demise; gestational age and weight. Study quality was assessed by using the Critical Appraisal Skills Programme (CASP) guidelines. Findings: this review produced three main findings: (1) increased rates of stillbirth, perinatal death, preterm birth and low birth weight among women Z45 years; (2) increased rates of pre-existing hypertension and pregnancy complications such as GDM, gestational hypertension (GH), pre-eclampsia and interventions such as caesarian section; and (3) a trend of favourable outcomes, even at extremely advanced maternal age (50–65 years), for healthy women who had been screened to exclude pre-existing disease. Key conclusions: although there is strong evidence of an association between very advanced maternal age and adverse maternal and perinatal outcomes, the absolute rate of stillbirth/perinatal death remains low, at less than 10 per 1000 births in most high-income countries. Therefore, although women in this age group encounter greater pregnancy risk, most will achieve a successful pregnancy outcome. Best outcomes appear to be linked to pre-existing maternal health, and pregnancy care at tertiary centres may also contribute. This information should be used to counsel women aged Z45 years who are contemplating pregnancy. & 2012 Elsevier Ltd. All rights reserved.

Keywords: Very advanced maternal age Hypertension Preterm birth Low birth weight

Background Recent developments in artificial reproductive technologies (ART), such as oocyte donation, offer pregnancy options for peri-menopausal and postmenopausal women (Blickstein, 2003a; Spandorfer et al., 2007; Krieg et al., 2008; Glasser et al., 2011). Such advances have led to an increasing number of women aged Z45 years, in high-income countries, seeking to become pregnant (Blickstein, 2003a; Yogev et al.,

E-mail address: [email protected] 0266-6138/$ - see front matter & 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.midw.2012.04.001

2010). Currently, births for women aged Z45 years make up approximately 0.05–0.2% of all births (Bre´art et al., 2003; ABS, 2009; Martin et al., 2010), and although low overall, birth rates for this age group have increased in the past decade (Blickstein, 2003a; Martin et al., 2010). This trend of increasing birth rates among women aged Z45 years, is also likely to continue as newer reproductive technologies become available (Blickstein, 2003a). In addition to an increasing incidence of pregnancy among women aged Z45 years, the demographics of very advanced maternal age have also changed, in high-income countries. Although the trend is not universal, contemporarily, pregnant women in this

480

M. Carolan / Midwifery 29 (2013) 479–489

age group, tend to be of low parity and of high socio-economic status (Hammarberg and Clarke, 2005; Joseph et al., 2005) which is in direct contrast to earlier VAMA groups who tended to be of high parity and low socio-economic status (Dildy et al., 1996; Dulitzki et al., 1998; Hossain et al., 2009). For these reasons, women of VAMA may currently have significantly different outcomes than their predecessors as both higher socio-economic status and lower parity are known predictors of greater pregnancy investment and more favourable pregnancy outcomes (Goy et al., 2008; Stephansson et al., 2001; Viau et al., 2002). Women’s socio-economic status and models of maternity care may contribute to outcomes and rates of intervention. In Australia, for example, women with greater resources are more likely to be privately insured and to avail of specialist care (Shorten and Shorten, 2004). Private pregnancy health care, in turn, is linked to greater rates of intervention such as caesarian section, when compared to public hospital care (Roberts et al., 2000; Shorten and Shorten, 2007; Carolan et al., 2011). On the other hand, in countries such as Sweden and Denmark, residents have almost universal access to high quality pregnancy care (McKay, 1993; Jacobsson et al., 2004; Hildingsson and Thomas, 2007; Gunnervik et al., 2010) and lower intervention rates, such as caesarian rates of 11.5% are normal (Gunnervik et al., 2010) and this situation leads to lower interventions rates even at advanced maternal ages. Pregnancy among women of advanced maternal age (435, 440 years) has been linked to higher rates of maternal hypertension and diabetes (Cleary-Goldman et al., 2005; Joseph et al., 2005,) and to incrementally worsening perinatal outcomes, such as stillbirth, preterm birth and low birth weight (LBW) (ClearyGoldman et al., 2005; Fretts, 2005; Salem Yaniv et al., 2011). However, there is no consensus as to the degree of association or to the impact of social and lifestyle factors, such as socioeconomic status and smoking. Similarly, the maternal age at which outcomes are significantly affected, is unknown. On the one hand, several large population studies have found that maternal age greater than 35 years is linked to an increasing stillbirth rates (Cleary-Goldman et al., 2005; Flenady et al., 2011). However, others suggest that although older women are at increased risk of poorer outcomes, that the overall rates are still very small (Joseph et al., 2005; Carolan and Frankowska, 2011). Some of this age related disparity may also relate to parity and low socio-economic status, particularly among groups of women, who for religious or social reasons, continue to bear children from marriage until menopause (Dildy et al., 1996; Dulitzki et al., 1998; Abu-Heija et al., 2000). Lower socio-economic status has been linked to VAMA (Toohey et al., 1995; Hossain et al., 2009) and both parity and socio-economic status are linked to poorer pregnancy outcomes (Fretts, 2005; Hossain et al., 2009). At the same time, and despite a growing interest in childbearing at very advanced maternal age, most current studies have evaluated pregnancy outcomes only to age 44 years (Astolfi et al., 2005; Bahtiyar et al., 2008; Wang et al., 2011) and at present, there is limited evidence to guide health professionals engaged in the care of childbearing women aged Z45 years. Moreover, even among studies that include women of VAMA, it remains difficult to extract data relating specifically to this group, as existing studies most often report on advanced maternal age in composite groups, including all women over 35 years, or all women aged 440 years (Cnattingius et al., 1992; Cleary-Goldman et al., 2005; Joseph et al., 2005; Delbaere et al., 2007). Women aged Z45 years are often included within these studies, though it is not possible to isolate their specific findings. This background of increasing fertility options for women aged Z45 years and a dearth of specific information to guide midwives and health professionals involved in their care, has prompted this review. It sought to investigate the evidence in relation to

maternal and perinatal outcomes for this group. The aims of the review were as follows: 1. To consider the evidence of VAMA related risk of adverse perinatal outcomes such as preterm birth, low birth weight, stillbirth and perinatal death. 2. To consider the evidence of maternal risk of pregnancy complications such as diabetes and hypertension, including chronic and gestational conditions. 3. To consider the evidence in relation to a new group of childbearing women, postmenopausal women (50–65 years) who achieved pregnancy with advanced reproductive technologies.

Methods A computerised database search was conducted of established health databases, including SCOPUS, MEDLINE, CINAHL, EMBASE and Maternity and Infant Care. The review was conducted in October 2011 and search parameters included publications within the previous 10 years (2001–2011). This period was chosen as in line with an increasing birth rates among women aged Z45 years and also with advances in ART, such as oocyte donation (Blickstein, 2003a). Quantitative studies, from high-income countries, were targeted if they included a keyword for VAMA (very advanced maternal age, pregnancy aged Z45 years, extremes of childbearing age, very delayed childbearing) and/or a search term for maternal outcome/complication (hypertension, diabetes, caesarian section) and a search term for adverse perinatal outcome (preterm birth, low birth weight, stillbirth, perinatal death) in the abstract. Search results were managed in an Endnote library (Endnote X4). After removal of duplicates, this exercise produced 160 abstracts of interest. Hand searches, based on citations and references of already retrieved articles, yielded an additional 4 articles (n¼ 164). Initial screening involved the exclusion of abstracts on the following basis:

 Editorials, letters, opinion pieces, reviews.  Papers not written in English.  Papers not focussed on VAMA and pregnancy outcomes. A total of 22 abstracts remained after this process (see Fig. 1, Table 1) and these full papers were obtained, and screened for fit with the review’s intent. At this stage, papers were excluded on the basis of non-extractable data for women aged Z45 years, meaning that maternal age Z45 years was not considered as a discrete category. Excluded papers fell into two groups: those presenting composite data for all women 435 years; and those presenting data for all women 440 years. After this exclusion process, 10 papers remained and these papers were included in the review (Paulson et al., 2002; Antinori et al., 2003; Canterino et al., 2004; Jacobsson et al., 2004; Callaway et al., 2005; Simchen et al., 2006; Shrim et al., 2010; Yogev et al., 2010; Balayla et al., 2011; Glasser et al., 2011). Quality assessment of included studies Quality assessment of included studies was undertaken using the Critical Appraisal Skills Programme (CASP) guidelines for appraising quantitative studies (CASP, 2003, 2004, 2005). These appraisal tools were developed for use by the NHS and to date, they have been used to determine the quality of nursing and midwifery, medical and maternity services publications (Milne and Oliver, 1996; Luker et al., 2011). The CASP approach assesses publications in three basic ways. It determines if the paper: (1) is

M. Carolan / Midwifery 29 (2013) 479–489

Abstracts of interest identified n = 160

481

Abstracts identified through additional searches n = 4

Total abstracts n = 164

164 Abstracts screened

142 Abstracts excluded as not related to the central question of VAMA and perinatal outcomes (see table 1)

22 Full papers examined for inclusion

12 Papers excluded as maternal age > 45 years was not considered as a discrete category

10 Papers included in analysis

Fig. 1. Selection of papers.

Table 1 Overview of excluded abstracts (n¼ 142). 1. Reviews, letters, editorials, discussion papers 2. Screening for abnormalities Includes different screening approaches Discussion of age-related screening programs 3. IVF techniques and rates of success 4. Extreme maternal morbidity such as cancer 5. Age related fertility decline Includes discussion of peri-menopausal fertility such as oocyte quality and contraception 6. Case studies Includes specific abnormalities such as Prader Willi syndrome 7. Early pregnancy loss 8. Women’s experience Includes emotional and psychological experience and counselling 9. Paternal age as an indicator of fetal outcome 10. Language other than English 11. Physiology Includes discussion of placental micro vasculature 12. Animal studies 13. Miscellaneous—no connection to VAMA Total excluded papers Remaining abstracts n¼ 22

15 29

16 14 14

related to VAMA in high-income countries, Q.11 was considered redundant. Each included question was scored 1 for present and 0 for absent with the exception of Q.6, which was allocated a score of 1 for each question, a total of 2. A final question (Q.13) was included to estimate external validity, and this question was based on Downs and Black’s (1998) work on estimating methodological quality of quantitative studies in health-care settings. The total range of scores was 0–12, with12 indicating the highest possible quality.

7 7 7 5 4 4 4 16 142

trustworthy, (2) shows important results and (3) is relevant to the area of practice (Milne and Oliver, 1996). In the current review, CASP guidelines were used to assess studies for clear focus, appropriate method, suitable recruitment approach, bias, confounding factors, credible results, and for fit with existing evidence (see Box 1). Some minor modification of the guidelines was undertaken for this review, and questions 7 and 11 were omitted. Q.7 related to follow up, which was not compatible with the cross sectional and case series methods used by reviewed studies while Q.11 referred to the applicability of results for the local population. As the intent of this review was to look broadly as outcomes

Findings Characteristics of included studies The original intent of this review was to consider the evidence in relation to VAMA ( Z45 years) and risk of adverse outcomes for both mother and fetus/infant. However, when we started to review the literature, we found that papers sometimes also presented information in relation to postmenopausal women. For this reason, a decision was made to also review the evidence in relation to this group as a separate category. Ten studies were included in the review. Each examined VAMA against various perinatal and maternal measures including stillbirth (Canterino et al., 2004; Balayla et al., 2011), perinatal death, preterm birth, birth weight and congenital abnormality (Antinori et al., 2003; Jacobsson et al., 2004; Callaway et al., 2005; Simchen et al., 2006; Shrim et al., 2010; Yogev et al., 2010; Glasser et al., 2011). The final two studies presented composite outcomes, such as mean gestational age and mean birth weight (Paulson et al., 2002; Shrim et al., 2010). Maternal outcomes included caesarian section, gestational diabetes, gestational hypertension and preeclampsia. Maternal characteristics presented included pre-existing conditions such as diabetes, hypertension, renal disease and

482

M. Carolan / Midwifery 29 (2013) 479–489

Box 1

CASP guidelines

Score 0/1

Q1. Did the study address a clearly focussed issue? Q2. Did the authors use an appropriate method to answer their question? Q3. Was the cohort recruited in an acceptable way? Q4. Was the exposure accurately measured to minimise bias? (maternal age) Q5. Was the outcome accurately measured to minimise bias? (maternal/perinatal/outcome) Q6a. Have the authors identified all important confounding factors? Q6b. Have they taken account of the confounding factors in the design and/ or analysis? Q7a. Was the follow up of subjects complete enough? Q7b. Was the follow up of subjects long enough? Q8. What are the results of this study? (Are they communicated clearly?) Q9. How precise are the results? Q10. Do you believe the results? (How believable are the results?) Q11. Can the results be applied to the local population? Q12. Do the results of this study fit with other available evidence? Q13. Was the study representative of the entire population from which subjects were recruited?

0/1 0/1 0/1 0/1 0/1 0/1 0/1 N/A

cardiovascular disease (Jacobsson et al., 2004; Callaway et al., 2005; Yogev et al., 2010; Glasser et al., 2011) and maternal education and other socio-economic measures such as occupation and marriage (Jacobsson et al., 2004). All ten studies employed quantitative methods and all were conducted in high-income countries. Three studies took place in the US; three in Israel, and one study each in Italy, Canada, Australia and Sweden. VAMA related sample size ranged from 45 (Paulson et al., 2002) to 16,739 (Canterino et al., 2004). Study sample size was considerably smaller in several cases than is usual for quantitative cohort studies (Paulson et al., 2002; Callaway et al., 2005; Shrim et al., 2010). However, this is consistent with generally low numbers of pregnancies among women aged Z45 years (0.05–0.2% of all births). Study focus also varied, although all studies contained a central theme of interest in VAMA and maternal and/or perinatal outcomes. Three studies were large retrospective studies using national data (Canterino et al., 2004; Jacobsson et al., 2004; Balayla et al., 2011). Of these, Balayla et al. (2011) and Canterino et al. (2004) examined rates of stillbirth among advanced maternal age groups, while Jacobsson et al. (2004) examined adverse perinatal outcomes such as LBW, preterm birth and perinatal death. Callaway et al. (2005), Simchen et al. (2006); Shrim et al. (2010), and Yogev et al. (2010) each examined maternal and perinatal outcomes for women aged Z45 years who gave birth in selected hospitals. The final group of studies examined pregnancy outcomes principally among postmenopausal women, who had received fertility treatment to conceive (Paulson et al., 2002; Antinori et al., 2003; Glasser et al., 2011) see Table 2.

Methodological quality of included papers On appraisal, all included studies measured well and CASP study quality scores ranged from 7 to 11, out of a total of 12 points. All studies had clearly focussed aims and objectives. Two main quantitative methods were used: retrospective cohort methods (Paulson et al., 2002; Antinori et al., 2003; Canterino et al., 2004; Jacobsson et al., 2004; Callaway et al., 2005; Simchen et al., 2006; Shrim et al., 2010; Balayla et al., 2011) and case series methods (Yogev et al., 2010; Glasser et al., 2011). Both methods are appropriate and contribute different strengths. The retrospective cohort method is useful when examining a cohort for

0/1 0/1 0/1 N/A 0/1 0/1

specific characteristics, such as stillbirth (LoBiondo-Wood and Haber, 2002). These large population based studies are thus a particularly efficient way of looking at population trends and are suited to answering questions about VAMA and adverse perinatal outcomes (Canterino et al., 2004; Jacobsson et al., 2004; Balayla et al., 2011). Case series studies, on the other hand, are considered a useful means of examining outcomes or predictors when a condition is rare (Mann, 2003; Whitaker et al., 2009), as in this case, when numbers of childbearing women aged Z45 years are relatively small. Datasets among the studies varied, and data extraction occurred in the following ways. Three studies extracted data from well-maintained state databases (Canterino et al., 2004; Jacobsson et al., 2004; Balayla et al., 2011) while five studies used data extracted from hospital records and datasets (Callaway et al., 2005; Simchen et al., 2006; Shrim et al., 2010; Yogev et al., 2010; Glasser et al., 2011). The final two studies included records from fertility treatment centres (Paulson et al., 2002; Antinori et al., 2003). In each case, data extraction was controlled by clearly defined inclusion/exclusion criteria, such as birth within selected years, maternal age 45–49 years, 50–65 years, pregnancy outcome beyond 20 weeks/24 weeks gestation. Additional measures were employed to ensure sample reliability, such as including only those records that were complete.

Maternal and perinatal outcomes Results are summarised in Table 2, and maternal age has been presented according to the categorisations used by the reviewed papers. Very advanced maternal age was presented in various ways: 45–49 years (Canterino et al., 2004; Glasser et al., 2011); 445 years (Shrim et al., 2010; Balayla et al., 2011); Z45 years (Jacobsson et al., 2004; Callaway et al., 2005; Simchen et al., 2006; Yogev et al., 2010) and 45–50 years (Antinori et al., 2003). Extremely advanced maternal age was presented as Z50/51 years. Direct comparison between papers was therefore difficult in this review, due to these differing age classifications and the degree of heterogeneity of studies. Methods and particularly, sample size, varied considerably and study authors employed different classifications of outcomes. Each of these features limited comparability. However, despite these challenges, some trends have emerged from the review and findings are presented

M. Carolan / Midwifery 29 (2013) 479–489

below, as maternal (pregnancy complications) and perinatal (fetal/infant) outcomes. Maternal complications included two distinct categories: (1) pre-existing conditions, such as hypertension, diabetes, uterine disorders and less commonly renal disease, cardiac disease and depression and (2) gestational conditions, including gestational diabetes, gestational hypertension and pre-eclampsia. Pre-existing conditions Similar to perinatal outcomes, comparison of pre-existing conditions was not always possible as definitions of terms for maternal complications varied from study to study. For example, conditions such as diabetes and hypertension, are generally discussed as pre-existing or gestational (newly arising in pregnancy). In this review however, two included papers reported on hypertension and diabetes in pregnancy, without clarifying preexisting rates of either condition (Simchen et al., 2006; Shrim et al., 2010). Similarly, rates of pre-eclampsia were, in some studies, included as a separate category, while in others, preeclampsia was included within gestational hypertension rates. Nonetheless, some findings present in the four studies that reported on pre-existing conditions (Jacobsson et al., 2004; Callaway et al., 2005; Yogev et al., 2010; Glasser et al., 2011) and rates for pre-existing hypertension varied from 1.3% (Callaway et al., 2005) to 6.8% (Yogev et al., 2010). Rates of preexisting diabetes were low overall and varied from 0% (Callaway et al., 2005) to just 2% (Glasser et al., 2011). In addition, Callaway et al. (2005) found that 11.6% of their study sample suffered from depression, while rates for uterine leiomyomata (5%) and uterine/ gynaecological surgery (25%) were reported by Callaway et al. (2005) and Glasser et al. (2011), respectively. The highest rates of pre-existing maternal disease presented by Glasser et al.’s (2011) and Yogev et al.’s (2010) Israeli studies, one of which included an entirely primiparous sample (Glasser et al., 2011), and both of which included high rates of ART (Yogev et al., 2010; Glasser et al., 2011). Gestational conditions In terms of gestational conditions, rates for gestational hypertension also varied across a broad range from 3.4% (Jacobsson et al., 2004) to 36% (Glasser et al., 2011) for women aged Z45 years and from 11.7% (Antinori et al., 2003) to 68% (Glasser et al., 2011) for women aged 50–65 years. Pre-eclampsia was reported seperately in four studies (Paulson et al., 2002; Jacobsson et al., 2004; Yogev et al., 2010; Glasser et al., 2011) and varied from 2% (Jacobsson et al., 2004) to 17% for women aged Z45 years (Glasser et al., 2011) and from 23% (Glasser et al., 2011) to 35% for women aged greater than 50 years (Paulson et al., 2002). Gestational diabetes rates also varied widely, from 1.3% (Jacobsson et al., 2004) to 43% (Glasser et al., 2011) for women aged Z45 years and from 20% (Paulson et al., 2002) to 42% for women aged 50–65 years (Glasser et al., 2011). Multiple pregancy rates ranged from 3.3% to 20% ( Z 45 years) and up to 34.6% (50– 65 years) with the highest rates among women receiving ART (Paulson et al., 2002; Yogev et al., 2010; Glasser et al., 2011). Caesarian section rates were high throughout with the exception of Jacobsson et al. (2004) at 30%. Otherwise rates ranged from 49% (Callaway et al., 2005) to 92.4% (Glasser et al., 2011) for women aged Z45 years and from 78% (Paulson et al., 2002) to 100% for women aged 50–65 years (Glasser et al., 2011). Perinatal outcomes reported in the reviewed studies, included: stillbirth, perinatal and neonatal death, preterm birth, LBW (o2,500 GM) and small for gestational age (SGA) (birth weight below the 10th percentile). Differing definitions of terms were employed by study authors, particularly for fetal/infant demise,

483

which was described as intrauterine death; stillbirth; perinatal death and neonatal death. Canterino et al. (2004), for example, who examined stillbirth in a large cohort study, and were unable to determine the actual time of death, used gestational age at birth as a proxy. These authors referred to stillbirths as fetal deaths at Z24 weeks and Z32 weeks. In contrast, Shrim et al. (2010), combined perinatal and neonatal mortality into a single category, which included stillbirth. Definitions of stillbirth also varied by gestational age, from Z20 weeks gestation (Callaway et al., 2005) to Z24 weeks gestation (Canterino et al., 2004; Balayla et al., 2011) to Z28 weeks gestation (Jacobsson et al., 2004). In all, the bulk of studies reported stillbirth at Z24 weeks gestation, and for that reason, stillbirth at Z24 weeks gestation, has been reported in this review. Nonetheless, despite these limitations, some findings about stillbirth and perinatal/neonatal death, present in this review. Stillbirth incidence was reported as 0%, or it was clear from the number of live births, that there were no stillbirths in most of the hospital based studies (Paulson et al., 2002; Antinori et al., 2003; Callaway et al., 2005; Glasser et al., 2011), while rates were 0.9% and 1.2% were reported in two of the large cohort studies (Canterino et al., 2004; Balayla et al., 2011). Perinatal death was reported by the third large cohort study at 1.66% (Jacobsson et al., 2004) while neonatal death (death of a live born infant within one month of age), was reported by Jacobsson et al. (2004) and Yogev et al. (2010) at 0.5% and 0.74% respectively. Perinatal outcomes Rates for preterm birth were reported by seven studies (Antinori et al., 2003; Jacobsson et al., 2004; Callaway et al., 2005; Simchen et al., 2006; Shrim et al., 2010; Yogev et al., 2010; Glasser et al., 2011) and rates varied widely from 9% to 30% for women aged Z45 years and from 10.6% to 50% for women aged 50–65 years. Infant birth weight was reported in different ways, such as mean birth weight (Paulson et al., 2002; Shrim et al., 2010), rates of LBW (Simchen et al., 2006; Yogev et al., 2010; Glasser et al., 2011) and SGA (Jacobsson et al., 2004; Callaway et al., 2005; Simchen et al., 2006; Yogev et al., 2010; Glasser et al., 2011). A single study reported large for gestational age ( 490th percentile) (Callaway et al., 2005) at 8%. LBW rates varied widely from 16.9–35% for women aged Z45 years and from 10.6% to 68% for women aged 50–65 years. Rates for SGA also ranged widely from 5.3% to 32% for women aged Z45 years and from 9% to49% for women aged 50–65 years.

Discussion This review sought to answer three questions: (1) What are the VAMA related risks of adverse perinatal outcomes such as preterm birth, LBW and perinatal death? (2) What is the maternal risk of pregnancy complications such as diabetes and hypertension, including chronic and gestational conditions? (3) What is the evidence in relation to a new group of childbearing women, postmenopausal women (50–65 years) who achieve pregnancy with advanced reproductive technologies? Despite limitations, some general trends emerged from the review. They include increased rates of stillbirth, preterm birth and LBW infants among women of VAMA; increased rates of pre-existing hypertension and pregnancy complications such as GDM, gestational hypertension (GH), pre-eclampsia and caesarian section, and a trend of favourable outcomes, even at extremely advanced maternal age (50–65 years), for healthy women who had been screened to exclude pre-existing disease such as hypertension. Rates for stillbirth and perinatal death were increased for women aged Z45 years, and this effect was seen particularly in the large cohort studies (Canterino et al., 2004; Jacobsson et al.,

484

Table 2 Characteristics of included papers. Study, country Study description

Maternal age (groups)

Study sample Maternal prerelevant to VAMA (n) existing conditions

ART

Maternal outcomes

Perinatal outcomes

Study Quality Score (0–12)

GH (A)—11.9% GH (B)—11.7% CS 75%y

Multiple pregnancy 6.1%y Perinatal deaths -0 Preterm birth (A) 9.7% (B) 10.6%

7

Stillbirth 0.9%

11

Multiple birth 3.8% Perinatal deaths -0 Preterm birth 13%

10

Antinori et al. (2002), Italy

Prospective case series study (A) 45–50 years of screened postmenopausal (B) 51–60 years women receiving donor oocyte IVF treatment in one Italian centre*

All

363y

None—only screened healthy women Accepted

100%

Balayla et al. (2011), USA

Retrospective cohort study of 4 45 years data from the National Centre for Health Statistics (CDC) to estimate the effect of maternal age on risk of stillbirth (1995– 2004) compared to a reference group of 25-29 year olds

All

825,093y Z 40 years

N/A

N/A

Callaway et al. (2005), Australia

Retrospective cohort study of data from 2 hospitals of a complete cohort of pregnant women aged Z45 (1992– 2001).

Z 45 years

All

76

Hypertension 1.3% 14% Diabetes 0% Uterine Leiomyomata 5% Depression 11.6%

Canterino et al. Retrospective cohort study of 45–49 years (2004), USA US linked birth cert and infant death data (1995–2000). Maternal age related fetal death rates were calculated for infants born at Z24 and Z 32 weeks

All

16,739

N/A

N/A

(A) 45–49 years Glasser et al. Prospective case series study (2011), Israel of all primiparous women age (B) 50–65 years Z45 years (2004–2008) receiving pregnancy care at one Israeli centre

Primip

131 (A) 105 (B) 26

Hypertension 6% Hypothyroidism 7.6% Diabetes 2% Haematological disorder 3% Uterine surgery 25% Cardiac disorder 2%

100%

Hypertension 1.4%

N/A

Z 45 years Jacobsson et al. Prospective cohort study of (2004), Swedish national birth data. Sweden Women of advanced maternal age (1987–2001), were compared to women aged 20– 29 years

Paulson et al. (2002), USA

Retrospective cohort study of 50–63 years ART cycles and pregnancy outcomes among postmenopausal women, with

All

1,205

Diabetes 0.33% Renal 0.5% Other 6%

Primip 26 Multip 19

45

None—only screened healthy women accepted

100%

GH 13% GDM 8% C/S 49%

SGA 10% LGA 8% SCN 17% Congenital abnormality 6% Fetal death rate at gestational age 11 Z24 weeks 0.72% Z32 weeks 0.5%

(A) PE 17% GH 36% GDM 43% C/S 92.4%

Multiple birth (A) 20%, (B) 34.6% (A) Preterm 30% LBW 35%

(B) PE 23% GH 68% GDM 42% C/S 100%

SGA 25% (B) Preterm 50% LBW 68% SGA 43% No stillbirth (A) (B)

PE 2.0 %

Multiple birth 3.3%

GH 3.4% GDM 1.3% C/S 30%

Preterm r 37 weeks 9.4% r34 weeks 3.5% r32 weeks 2.2% SGA 5.23% Perinatal death 1.66% Neonatal death 0.5%

PE 35 % GDM 20% C/S 78%

Multiple birth 31% Mean gestation Singletons 38.4 weeks Twins 36 weeks

8

11

8

M. Carolan / Midwifery 29 (2013) 479–489

Parity

Mean birth weight Singletons 3039 GR Twins 2254GR No stillbirths

no chronic medical conditions, who were accepted into a US fertility programme (1991– 2001) Shrim et al. (2010), Canada

Retrospective cohort study of maternal and neonatal complications in singleton pregnancies among advanced maternal age groups (2001– 2007) compared to women 20–39 years

4 45 years

Z 45 years Simchen et al. Prospective case series study (2006), Israel of women aged 45–49 and 50– 64 years who gave birth in one (A)45–49 Israeli hospital 1999–2004 (B)50–64

n

63

N/A

32%

D Hypertension

Primip 55%

123

N/A

55%

D Hypertension

Multip 45%

(A)99 (B)24

Primip 40% Multip 60%

177

Preterm 12.7% 12.7% D Diabetes 28.6% Mean birth weight 3325 GR C/S 51% SGA 4.8% No Perinatal/neonatal death

10

(A) Preterm r 34 weeks 9%

10

(A) 27% (B) 33% D Diabetes (A)19% (B) 29% C/S (A) 68% (B) 100%

Hypertension 6.8% Obesity 24%

Recruitment years not available. Age breakdown not available. 1. C/S caesarean section. 2. GH—gestational hypertension—hypertension arising for the first time in pregnancy. 3. GDM—gestational diabetes mellitus. 4. PE—pre-eclampsia. 5. DHypertension (unclear what percentage is pregnancy related or chronic disease). 6. DDiabetes (unclear what percentage is pregnancy related or chronic disease). 7. ART—artificial reproductive technologies. 8. LBW—low birth weight (o 2,500 GR). 9. VLBW—very low birth weight (o 1500 GR). 10. SGA—small for gestational age (o 10th percentile). 11. Preterm—birth before 37 completed weeks gestation. 12. SCN—admission to Special Care Nursery. 13. NICU—admission to Neonatal Intensive Care Unit. 14. NND—Neonatal death (death of a liveborn infant from birth to four weeks of life (Ahman and Zupan, 2006)). 15. Stillbirth (birth of a stillborn infant of Z20 weeks gestation). 16. Perinatal death (stillbirth and infant death from 28 weeks of gestation to 1 week of life).

79%

GH 9.0 % GDM17% C/S 78.5% PE 10.7%

r32 weeks 3% LBW 32% VLBW 5% SGA 30% (B) Preterm r 34 weeks 18% r32 weeks 6% LBW 61% VLBW9% SGA 49% 1 intrauterine death (A) Multiple birth 6.8% Preterm r37 weeks 21.5% r34 weeks 6.2% r32 weeks 2.3% LBW 16.9% VLBW 1.7% SGA 11.3% NND 0.74% Major Congenital Abnormality 2.2% Metabolic complications 4.5% NICU 10.7

9

M. Carolan / Midwifery 29 (2013) 479–489

Z 45 years Yogev et al. Prospective case series study (2010), Israel of women age Z 45 years who gave birth in one Israeli hospital (2000–2008)

All

y

485

486

M. Carolan / Midwifery 29 (2013) 479–489

2004; Balayla et al., 2011). Reported rates were well in excess of the 0.5% found in the general population, in most high-income countries (Flenady et al., 2011). However, differences in stillbirth definitions, in terms of gestational age, impact on study results and interpretation of those results. For international comparisons, the World Health Organization (WHO) definition of stillbirth is 28 weeks gestation, though, the USA and Australia each use 20 weeks gestation, while the UK uses 24 weeks gestation (Goldenberg et al., 2004; Ahman and Zupan, 2006; Flenady et al., 2011). In this review, two of the large cohort studies used 24 weeks gestation as the cut-off point for stillbirth (Canterino et al., 2004; Balayla et al., 2011), while the third reported on perinatal death (28 weeks or more) rather than stillbirth (Jacobsson et al., 2004). However, each of these studies compared rates of fetal demise for VAMA women against rates for women aged 35–39 years and/or 40–44 years, from the same population and this internal comparison may be a better measurement for age related effect in these studies. In each case, stillbirth and perinatal death rates were increased for VAMA women. Compared to women aged 35–39 years, stillbirth rates were more than doubled for VAMA women (Canterino et al., 2004; Balayla et al., 2011). When compared to women aged 40–44 years, the difference was not so large, however VAMA women continued to have increased odds for stillbirth and perinatal death at adjusted odds ratios (AOR) (2.22–2.80 compared to AOR 1.60–1.68, using women aged 20–29 years as the reference group) (Canterino et al., 2004; Jacobsson et al., 2004; Balayla et al., 2011). This effect continued after adjustment for a range of factors such as maternal education, race, marital status, smoking, maternal disease and multiple pregnancy (Canterino et al., 2004; Jacobsson et al., 2004; Balayla et al., 2011). As such, it appears to be a stable and valid association and may relate to higher general rates of pre-existing disease as women age. Existing studies appear to be in agreement and Goldenberg et al. (2004), for example, found that as many as 50–70% of mothers of stillborn infants had pregnancy related complications such as hypertension. However, although the large cohort studies showed a link to increased rates of stillbirth and perinatal death, hospital based studies generally reported good outcomes, with no stillbirth, or no perinatal/neonatal death reported by the majority (Paulson et al., 2002; Antinori et al., 2003; Callaway et al., 2005; Shrim et al., 2010; Glasser et al., 2011). Only two hospital-based studies reported perinatal/ neonatal death (Simchen et al., 2006; Yogev et al., 2010). In these studies, Simchen et al. (2006) reported a single intrauterine death of a severely growth restricted twin, while Yogev et al. (2010) reported a neonatal death rate of 0.74%, without detailing the causes. Yogev et al. (2010) also reported rates of major congenital abnormality at 2.2% and this factor, together with high rates of preterm birth, may have contributed to neonatal death rates in that study. Overall, hospital based studies reported very favourable outcomes with minimal fetal/ infant demise, and this finding may be related to the large tertiary hospitals or medical centres where the studies were conducted. Advanced pregnancy care is generally available in these centres and the excellent outcomes seen in this review may have some correspondence to the pregnancy care the women received. It may also relate in part to the higher socio-economic status of study subjects, as women of advanced maternal age and women receiving ART treatments tend to be well educated and financially secure (Hammarberg and Clarke, 2005; Joseph et al., 2005). The absolute impact of parity is also unclear, although there is a strong suggestion that primiparity among women of advanced maternal age is linked to stillbirth (Huang et al., 2008; Flenady et al., 2011). The evidence in relation to high and low parity is less clear. An earlier study by Fretts et al. (1995) considered high parity (Z para 4) to be linked to increasing stillbirth rates among

older mothers, however, more recent extensive reviews by Huang et al. (2008) and Flenady et al. (2011), were unable to determine a link between high or low parity and stillbirth. Rates for preterm birth, LBW and SGA were all increased for VAMA women in this review. Rates were approximately 1.5–2 times greater for birth o37 weeks and twice to three times the rate for birth o32 weeks (Jacobsson et al., 2004; Simchen et al., 2006; ABS, 2007; Shrim et al., 2010; Yogev et al., 2010). The largest differences presented in the Israeli studies, by Glasser et al. (2011) and Yogev et al. (2010). These studies reported rates approximately 2–3 times higher than other included studies, for preterm birth o37 weeks. These findings may relate in part to the high rates gestational conditions such as GH and GDM found within these study populations (Yogev et al., 2010; Glasser et al., 2011). Moreover, all subjects in Glasser et al.’s (2011) study were primiparous, and primiparity has been linked to higher rates of preterm birth (Hemminki Gissler, 1996; Joseph et al., 2005; Usta and Nassar, 2008). Subjects in Glasser et al.’s (2011) study were also accepted for ART treatment without screening for preexisting disease, which is in direct contrast to other studies, where programme acceptance criteria were based on screened healthy women (Paulson et al., 2002; Antinori et al., 2003). These higher rates of pre-existing disease (Yogev et al., 2010; Glasser et al., 2011) may also have contributed to the disparity in preterm births, seen in the review. Interestingly, Simchen et al. (2006) who also conducted a case series study of women aged 45–64 years in Israel, with high rates of primarity and maternal hypertension and diabetes, nonetheless did not report very high rates of preterm birth for women aged 45–49 years (9%), only for women aged 450 years (18% at o37 weeks). LBW and SGA were also more prevalent in this review. LBW was reported by just three studies (Simchen et al., 2006; Yogev et al., 2010; Glasser et al., 2011) at many times the rate found in the general population (Laws and Sullivan, 2009; Yogev et al., 2010). Rates for SGA were similarly high, and many times in excess of the 5–9% rate found in the general population (Laws and Sullivan, 2009; Yogev et al., 2010; D’Angelo et al., 2011). This trend of age related increased incidence of preterm birth, LBW and SGA was almost universal in the review, which suggests that it is an association of some importance. A number of possible explanations, for this association, are offered in the literature. For example, Cano et al. (1995) and Simchen et al. (2009) suggested that poorer performance of the aging uterus contributed to poorer placental development and therefore to poorer fetal growth. Others suggest a link between higher incidence of maternal conditions such as hypertension and intrauterine growth restriction (Joseph et al., 2005). Sheiner et al. (2004), postulate that the presence of uterine leiomyomas, which are more common as women age, also contribute. Finally, complications such as LBW, preterm labour and stillbirth are all more likely with multiple births (Cassell et al., 2004; Ventura et al., 2009) and women of very advanced maternal age, particularly those availing of ART, are considerably more likely to have multiple births. In this review, multiple birth rates are reported in two ranges: at approximately 3–7% (Antinori et al., 2003; Jacobsson et al., 2004; Callaway et al., 2005; Yogev et al., 2010); and at between 20% and 35% in two studies where all subjects received ART treatment (Paulson et al., 2002; Glasser et al., 2011). This is considerably in excess of rates for multiple births occurring in the gereral population, which range from approximately 1.7–3% (Jacobsson et al., 2004; Laws and Sullivan, 2009). Rates of pre-existing hypertension varied in this review and findings are grouped into low, medium and high ranges. The lowest rates were reported among the studies that screened women prior to acceptance for ART (Paulson et al., 2002; Antinori et al., 2003). Medium rates were reported for the

M. Carolan / Midwifery 29 (2013) 479–489

Australian and Swedish studies (Jacobsson et al., 2004; Callaway et al., 2005) and highest rates were reported in the studies accepting unscreened women for ART(Yogev et al., 2010; Glasser et al., 2011). The reasons behind this heterogeneity of results is not immediately clear, however one possible explanation may be the general health of the studied population. High rates of natural conception in Callaway et al.’s (2005) study, for example, may suggest a healthy group who concieved naturally at very advanced ages. Although rates of natural conception are not available for the study by Jacobsson et al. (2004), oocyte donation was not legally available in Sweden, during the study period, therefore it seems likely that rates or ART in that study were also low. In addition, Jacobsson et al. (2004) identify the study population as healthy and well educated and with almost universal access to comprehensive health care (Jacobsson et al., 2004). Each of these factors may contribute to lower rates of pre-existing hypertension. Rates of gestational conditions, such as GDM, GH and pre-eclampsia, and for caesarian section were also lowest in Jacobsson et al.’s (2004) study and highest in Glasser et al.’s (2011) study. This finding would seem to support the argument of higher rates of maternal complications in unscreened recipients of ART, particularly among primiparous women. The impact of ART on maternal and perinatal morbidity for women aged Z45 years raises some interesting questions, particularly in terms of iatrogenic effects (Blickstein, 2003b). Women of VAMA are very likely to use ART technologies to conceive (Blickstein, 2003a) and ART procedures are, in turn, associated with higher rates of hypertension, particularly preeclampsia (Le Ray et al., 2012; Kort et al., 2011), multiple birth (Tosti et al., 2006; Allen et al., 2008; Le Ray et al., 2012) and sequelae such as preterm birth, and LBW (Tosti et al., 2006; Allen et al., 2008; Le Ray et al., 2012). Although this association would appear to be well supported in the literature, a number of studies refute the link, and suggest that the evidence is unclear at this time. Halliday (2007), for example, suggests that it is unclear whether patient infertility or confounding factors such as smoking, rather than in vitro fertilisation (IVF) technologies, contribute to the adverse outcomes seen among this group. Similarly, when multiple births are considered, Yang et al. (2011), found little difference in outcomes among twins conceived by IVF compared to spontaneous multiple conception. In addition, Gleicher and Barad (2009), who reviewed the evidence of risk for different groups of twins, concluded that twins conceived by IVF actually demonstrated better outcomes than naturally conceived twins. Although the reasons remain controversial, highest rates of complication in this review were associated with ART use among women who were not screened for pre-existing medical conditions. Lowest rates of complications were seen among healthy populations with a high percentage of natural conception. In addition, caesarian section rates were very high in reviewed studies, with almost 100% of women aged more that 50 years giving birth surgically. A similar trend has been reported in the literature, where increasing maternal age is strongly associated with greater intervention in birth (Carolan et al., 2011; Carolan and Frankowska, 2011). In summary, the association between VAMA and increased risk of preterm birth, LBW and SGA was essentially similar across reviewed studies, despite the studies’ heterogeneity. The principal difference was the degree of association, which may relate to the health of the population and the rate of natural conception. Adjustment for a range of potential confounders had little effect on this association. It therefore seems likely that the association between VAMA and poorer perinatal outcomes, such as preterm birth, LBW and SGA is a valid one. In terms of stillbirth and perinatal/neonatal death, it is evident that VAMA is related to increased rates of fetal/infant loss and this is clear from the large

487

cohort studies. However, this appears to be a gradual increase as women age, rather than a dramatic increase at Z45 years (Jacobsson et al., 2004). At the same time, hospital based studies continue to show excellent results with very low rates of fetal/ infant loss suggesting that advanced pregnancy care may impact positively on pregnancy outcomes. Moreover, the absolute rate of stillbirth among VAMA women is small, at approximately less than 10 per 1000 births in most high-income countries (CEMACH, 2007; Laws and Sullivan, 2009; WHO, 2010). This suggests that with adequate pregnancy care that the majority of women of VAMA will achieve a good pregnancy outcome (take home baby).

Limitations Limitations of the review include variations in study characteristics, such as methodological approach, sample size and the populations from which samples were drawn, which all impacted on the ability to generalise results. Because of these inconsistencies, it was difficult to assess the true impact of very advanced maternal age on maternal or perinatal outcomes for women aged Z45 years and over 50 years.

Conclusion In conclusion, although the association between VAMA and adverse maternal and perinatal outcomes appears strong, we must remain mindful that the absolute rate of stillbirth among VAMA women is small, at approximately less than 10 per 1,000 births, in most high-income countries. Therefore, despite encountering greater pregnancy risk, most women of VAMA will achieve a take home baby. Women in this age group, and their infants are however, more likely to suffer from a range of morbidities and findings in this review foreshadow an increasing demand on maternity services, midwives, health professionals and bed days as trends of maternity Z45 years continue. An increase in maternal morbidity and mortality due to the complications of caesarian birth may also occur, as caesarian rates are extremely high in this group. Many questions still remain about the impact of ART on pregnancy outcome, and this is of concern as women in this age group frequently avail of ART to conceive. Further research is therefore warranted into patterns of maternal and perinatal morbidity among women aged Z45 years, and particular emphasis should be focussed on women using ART. Overall, best outcomes appear to be linked to pre-existing maternal health and possibly to pregnancy care at tertiary centres. This information should be used to counsel women of VAMA contemplating pregnancy.

References ABS: Australian Bureau of Statistics, 2009. Births Australia 2009, 3301.0 DO007. Australian Government Press, Canberra. ABS: Australian Bureau of Statistics, 2007. 4102.0—Australian Social Trends, Australia’s Babies. Australian Government Press, Canberra. Abu-Heija, A.T., Jallad, M.F., Abukteish, F., 2000. Maternal and perinatal outcome of pregnancies after the age of 45. Journal of Obstetrics and Gynaecology Research 26 (1), 27–30. Ahman, E., Zupan, Z., 2006. Neonatal and perinatal mortality: country, regional and global estimates. WHO; World Health Organisation, Department of Making Pregnancy Safer, Geneva. Allen, C., Bowdin, S., Harrison, R.F., et al., 2008. Pregnancy and perinatal outcomes after assisted reproduction: a comparative study. Irish Journal of Medical Science 177 (3), 233–241. Antinori, S., Gholami, G.H., Versaci, C., et al., 2003. Obstetric and prenatal outcome in menopausal women: a 12-year clinical study. Reproductive BioMedicine Online 6 (2), 257–261.

488

M. Carolan / Midwifery 29 (2013) 479–489

Astolfi, P., De Pasquale, A., Zonta, L., 2005. Late childbearing and its impact on adverse pregnancy outcome: stillbirth, preterm delivery and low birth weight. Revue d’E´pide´miologie et de Sante´ Publique 53 (Suppl. 2), 97–105. Bahtiyar, M.O., Funai, E.F., Rosenberg, et al., 2008. Stillbirth at term in women of advanced maternal age in the United States: when could the antenatal testing be initiated? American Journal of Perinatology 25 (5), 301–304. Balayla, J., Azoulay, L., Assayag, J., Benjamin, A., Abenhaim, H.A., 2011. Effect of maternal age on the risk of stillbirth: a population-based cohort study on 37 million births in the United States. American Journal of Perinatology 28 (8), 643–650. Blickstein, I., 2003a. Motherhood at or beyond the edge of reproductive age. International Journal of Fertility and Women’s Medicine 48 (1), 17–24. Blickstein, I., 2003b. The worldwide impact of iatrogenic pregnancy. International Journal of Gynecology and Obstetrics 82 (3), 307–317. Bre´art, G., Barros, H., Wagener, Y., Prati, S., 2003. Characteristics of the childbearing population in Europe. European Journal of Obstetrics Gynecology and Reproductive Biology 111 (Suppl. 1), S45–S52. Callaway, L.K., Lust, K., McIntyre, H.D., 2005. Pregnancy outcomes in women of very advanced maternal age. Australian and New Zealand Journal of Obstetrics and Gynaecology 45 (1), 12–16. Cano, F., Simon, C., Remohi, J., Pellicer, A., 1995. Effect of aging on the female reproductive system: evidence for a role of uterine senescence in the decline in female fecundity. Fertility and Sterility 64 (3), 584–589. Canterino, J.C., Ananth, C.V., Smulian, J., Harrigan, J.T., Vintzileos, A.M., 2004. Maternal age and risk of fetal death in singleton gestations: USA, 1995–2000. Journal of Maternal–Fetal and Neonatal Medicine 15 (3), 193–197. Carolan, M., Davey, M.A., Biro, M.A., Kealy, M., 2011. Older maternal age and intervention in labor: a population-based study comparing older and younger first-time mothers in Victoria, Australia. Birth 38 (1), 24–29. Carolan, M., Frankowska, D., 2011. Advanced maternal age and adverse perinatal outcome: a review of the evidence. Midwifery 27 (6), 793–801. CASP, 2003. Critical Appraisal Skills Programme Appraisal Tools. Public Health Resource Unit, NHS, Oxford. CASP, 2004. 12 Questions to Help you Make Sense of a Cohort Study, Critical Appraisal Skills Programme. Public Health Resource Unit, Oxford. CASP: Critical Appraisal Skills Programme, 2005. Evidence-Based Health Care. /http://www.cebm.net/?o=1018S (last accessed 12 March 2011). Cassell, K.A., O’Connell, C.M., Baskett, T.F., 2004. The origins and outcomes of triplet and quadruplet pregnancies in Nova Scotia: 1980 to 2001. American Journal of Perinatology 21 (8), 439–445. CEMACH: Confidential Enquiry into Maternal and Child Health, 2007. Perinatal Mortality Surveillance Report. Cleary-Goldman, J., Malone, F.D., Vidaver, et al., 2005. Impact of maternal age on obstetric outcome. Obstetrics and Gynecology 105 (5I), 983–990. Cnattingius, S., Forman, M.R., Berendes, H.W., Isotalo, L., 1992. Delayed childbearing and risk of adverse perinatal outcome. A population-based study. Journal of the American Medical Association 268 (7), 886–890. D’Angelo, D.V., Whitehead, N., Helms, K., Barfield, W., Ahluwalia, I.B., 2011. Birth outcomes of intended pregnancies among women who used assisted reproductive technology, ovulation stimulation, or no treatment. Fertility and Sterility 96 (2), 314–320. e312. Delbaere, I., Verstraelen, H., Goetgeluk, S., Martens, G., De Backer, G., Temmerman, M., 2007. Pregnancy outcome in primiparae of advanced maternal age. European Journal of Obstetrics Gynecology and Reproductive Biology 135 (1), 41–46. Dildy, G.A., Jackson, G.M., Fowers, G.K., Oshiro, B.T., Varner, M.W., Clark, S.L., 1996. Very advanced maternal age: pregnancy after age 45. American Journal of Obstetrics and Gynecology, 175 (31), 668–674. Downs, S.H., Black, N., 1998. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and nonrandomised studies of health care interventions. Journal of Epidemiology and Community Health 52 (6), 377–384. Dulitzki, M., Soriano, D., Schiff, E., Chetrit, A., Mashiach, S., Seidman, D.S., 1998. Effect of very advanced maternal age on pregnancy outcome and rate of cesarean delivery. Obstetrics and Gynecology 92 (6), 935–939. Flenady, V., Koopmans, L., Middleton, et al., 2011. Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet 377 (9774), 1331–1340. Fretts, R., 2005. Etiology and prevention of stillbirth. American Journal of Obstetrics and Gynecology 193 (6), 1923–1935. Fretts, R.C., Schnittdiel, J., McLean, F.H., Usher, R.H., Goldman, M.B., 1995. Increased maternal age and the risk of fetal death. Journal of American Medical Association 333 (15), 953–957. Glasser, S., Segev-Zahav, A., Fortinsky, P., Gedal-Beer, D., Schiff, E., Lerner-Geva, L., 2011. Primiparity at very advanced maternal age ( Z 45) years fertility and Sterility 95 (8), 2548–2551. Gleicher, N., Barad, D., 2009. Twin pregnancy, contrary to consensus, is a desirable outcome in infertility. Fertility and Sterility 91 (6), 2426–2431. Goldenberg, R.L., Kirby, R., Culhane, J.F., 2004. Stillbirth: a review. Journal of Maternal–Fetal and Neonatal Medicine 16 (2), 79–94. Goy, J., Dodds, L., Rosenberg, M.W., King, W.D., 2008. Health-risk behaviours: examining social disparities in the occurrence of stillbirth. Paediatric and Perinatal Epidemiology 22 (4), 314–320. ¨ A., Sydsjo, ¨ G., 2010. Attitudes towards mode of Gunnervik, C., Josefsson, A., Sydsjo, birth among Swedish midwives. Midwifery 26 (1), 38–44.

Halliday, J., 2007. Outcomes of IVF conceptions: are they different? Best Practice and Research: Clinical Obstetrics and Gynaecology 21 (1), 67–81. Hammarberg, K., Clarke, V.E., 2005. Reasons for delaying childbearing—a survey of women aged over 35 years seeking assisted reproductive technology. Australian Family Physician 34 (3), 187–189. Hemminki, E., Gissler, M., 1996. Births by younger and older mothers in a population with late and regulated childbearing: Finland 1991. Acta Obstetricia et Gynecologica Scandinavica 75 (1), 19–27. Hildingsson, I., Thomas, J.E., 2007. Women’s perspectives on maternity services in Sweden: processes, problems, and solutions. Journal of Midwifery and Women’s Health 52 (2), 126–133. Hossain, N., Khan, N., Khan, N.H., 2009. Obstetric causes of stillbirth at low socioeconomic settings. Journal of the Pakistan Medical Association 59 (11), 744–747. Huang, L., Sauve, R., Birkett, N., Fergusson, D., Van Walraven, C., 2008. Maternal age and risk of stillbirth: a systematic review. CMAJ 178 (2), 165–172. Jacobsson, B., Ladfors, L., Milsom, I., 2004. Advanced maternal age and adverse perinatal outcome. Obstetrics and Gynecology 104 (4), 727–733. Joseph, K.S., Allen, A.C., Dodds, L., Turner, L.A., Scott, H., Liston, R., 2005. The perinatal effects of delayed childbearing. Obstetrics and Gynecology 105 (6), 1410–1418. Kort, D.H., Gosselin, J., Choi, J.M., Thornton, M.H., Cleary-Goldman, J., Sauer, M.V., 2011. Pregnancy after age 50: defining risks for mother and child. American Journal of Perinatology 29 (4), 245–249. Krieg, S.A., Henne, M.B., Westphal, L.M., 2008. Obstetric outcomes in donor oocyte pregnancies compared with advanced maternal age in in vitro fertilization pregnancies. Fertility and Sterility 90 (1), 65–70. Laws, P., Sullivan, E.A., 2009. Australia’s Mothers and Babies 2007. Australian Institute of Health and Welfare, Sydney. Le Ray, C., Scherier, S., Anselem, O., Marszalek, A., Tsatsaris, V., Cabrol, D., Goffinet, F., 2012. Association between oocyte donation and maternal and perinatal outcomes in women aged 43 years or older. Human Reproduction 27 (3), 896–901. LoBiondo-Wood, G., Haber, J., 2007. Nonexperimental design. In: LoBiondo-Wood, G., Haber, J., (Eds.), Nursing research: Methods, Critical Appraisal and Utilization, Mosby, St Louis, pp. 195–219. Luker, J.A., Wall, K., Bernhardt, J., Edwards, I., Grimmer-Somers, K.A., 2011. Patients’ age as a determinant of care received following acute stroke: a systematic review. BMC Health Services Research, in press, 11: (art. no. 161), http://dx.doi.org/10.1186/1472-6963-11-161. Mann, C.J., 2003. Observational research methods. Research design II: cohort, cross sectional, and case-control studies. Emergency Medicine Journal 20 (1), 54–60. Martin, J., Hamilton, B.E., Sutton, P.D., et al., 2010. Births: Final Data for 2008. National Center for Health Statistics, Hyattsville, MD. McKay, S., 1993. Models of midwifery care. Denmark, Sweden, and the Netherlands. Journal of Nurse–Midwifery 38 (2), 114–120. Milne, R., Oliver, S., 1996. Evidence-based consumer health information: developing teaching in critical appraisal skills. International Journal for Quality in Health Care 8 (5), 439–445. Paulson, R.J., Boostanfar, R., Saadat, et al., 2002. Pregnancy in the sixth decade of life: obstetric outcomes in women of advanced reproductive age. Journal of the American Medical Association 288 (18), 2320–2323. Roberts, C.L., Tracy, S., Peat, B., 2000. Rates for obstetric intervention among private and public patients in Australia: population based descriptive study. British Medical Journal 321, 7254. 137, 139–141. Salem Yaniv, S., Levy, A., Wiznitzer, A., Holcberg, G., Mazor, M., Sheiner, E., 2011. A significant linear association exists between advanced maternal age and adverse perinatal outcome. Archives of Gynecology and Obstetrics 283 (4), 755–759. Sheiner, E., Bashiri, A., Levy, A., Hershkovitz, R., Katz, M, Mazor, M., 2004. Obstetric characteristics and perinatal outcome of pregnancies with uterine leiomyomas. Journal of Reproductive Medicine for the Obstetrician and Gynecologist 49 (3), 182–186. Shorten, A., Shorten, B., 2007. What happens when a private hospital comes to town? The impact of the ‘public’ to ‘private’ hospital shift on regional birthing outcomes. Women and Birth 20 (2), 49–55. Shorten, B., Shorten, A., 2004. Impact of private health insurance incentives on obstetric outcomes in NSW hospitals. Australian Health Review 27 (1), 27–38. Shrim, A., Levin, I., Mallozzi, A., et al., 2010. Does very advanced maternal age, with or without egg donation, really increase obstetric risk in a large tertiary center? Journal of Perinatal Medicine 38 (6), 645–650. Simchen, M.J., Shulman, A., Wiser, A., Zilberberg, E., Schiff, E., 2009. The aged uterus: multifetal pregnancy outcome after ovum donation in older women. Human Reproduction 24 (10), 2500–2503. Simchen, M.J., Yinon, Y., Moran, O., Schiff, E., Sivan, E., 2006. Pregnancy outcome after age 50. Obstetrics and Gynecology 108 (5), 1084–1088. Spandorfer, S.D., Bendikson, K., Dragisic, K., Schattman, G., Davis, O.K., Rosenwaks, Z., 2007. Outcome of in vitro fertilization in women 45 years and older who use autologous oocytes. Fertility and Sterility 87 (1), 74–76. Stephansson, O., Dickman, P.W., Johansson, A.L., Cnattingius, S., 2001. The influence of socio-economic status on stillbirth risk in Sweden. International Journal of Epidemiology 30, 1296–1301. Toohey, J., Keegan Jr, K.A., Morgan, M., Francis, J., Task, S., DeVeciana, M., 1995. The ‘dangerous multipara’: fact or fiction? American Journal of Obstetrics and Gynecology 172 (2 I), 683–686.

M. Carolan / Midwifery 29 (2013) 479–489

Tosti, E., Fortunato, A., Settimi, A., 2006. The impact of in vitro fertilization on the health of the mother and the offspring. Current Women’s Health Reviews 2 (4), 239–247. Usta, I.M., Nassar, A.H., 2008. Advanced maternal age. Part I: obstetric complications. American Journal of Perinatology 25 (8), 521–534. Ventura, S., Abma, J.C., Mosher, W.D., Henshaw, S.K., 2009. National Vital Statistics Report; Estimated Pregnancy Rates for the United States, 1990–2005: An Update. National Center for Health Statistics, Hyattsville, MD. Viau, P.A., Padula, C.A., Eddy, B., 2002. An exploration of health concerns healthpromotion behaviors in pregnant women over age 35. MCN: The American Journal of Maternal/Child Nursing 27 (6), 328–334. ˜ Wang, Y., Tanbo, T., Abyholm, T., Henriksen, T., 2011. The impact of advanced maternal age and parity on obstetric and perinatal outcomes in singleton gestations. Archives of Gynecology and Obstetrics 284 (1), 31–37.

489

Whitaker, H.J., Hocine, M.N., Farrington, C.P., 2009. The methodology of selfcontrolled case series studies. Statistical Methods in Medical Research 18 (1), 7–26. WHO: World Health Organisation, 2010. National, Regional, and Worldwide Estimates of Stillbirth Rates in 2009 With Trends Since 1995. World Health Organisation, Geneva. Yang, H., Choi, Y.S., Nam, K.H., Kwon, J.Y., Park, Y.W., Kim, Y.H., 2011. Obstetric and perinatal outcomes of dichorionic twin pregnancies according to methods of conception: spontaneous versus in-vitro fertilization. Twin Research and Human Genetics 14 (1), 98–103. Yogev, Y., Melamed, N., Bardin, R., Tenenbaum-Gavish, K., Ben-Shitrit, G., Ben-Haroush, A., 2010. Pregnancy outcome at extremely advanced maternal age. American Journal of Obstetrics and Gynecology 203 (6), 558. e1–7.