CLINICAL PRACTICE

Effect of age on maternal and fetal outcomes

Abstract
A womans decision regarding the right time to embark upon a pregnancy may vary with personal, family, cultural and religious beliefs. However once a woman over 35 years of age has made a decision to proceed with a pregnancy she faces an increased risk of adverse pregnancy outcome, particularly in those with co-morbidities, multiple pregnancies and/or those conceived through ovum donation. These women need support and carefully planned obstetric care. Women seeking assisted reproductive technologies at over 35 years of age should be offered pre-pregnancy counselling and be advised of the benefit of single embryo transfer. Society as a whole, midwives, obstetricians and gynaecologists, should advocate for policies that enable women to reproduce safely without personal cost to their education, careers, identity and their own or their offsprings health.
Glynn et al, 2008; Wisborg, 2008). When searching for an evidence base from which to counsel such women the literature should be interpreted with the following points in mind: l Any study in this group of women will only include a small number of older mothers (1020% >35 years; 24% >40 years (Gilbert, 1999; Jolly, 2000; Cleary-Goldman, 2005; Reddy et al, 2006; Hoffman, 2007) and 0.005% >50 years (Donoso, 2008) l The control groups used for comparison (e.g. 2029, 3039, 4049, >40 years of age) vary widely and older mothers often have children with older fathers, which very few studies correct for (Astolfi, 2004) l Primiparity, plurality and the use of assisted reproductive technologies all increase with the age of the population studied and independently affect the outcomes observed. By virtue of their advanced age women have had more time to accumulate co-morbidities. They are more likely to have experienced surgery, had car accidents, suffered infectious diseases, gained weight and smoked for longer. The prevalence of medical conditions such as hypertension and diabetes all increase with age. These population changes are mirrored in the ageing pregnant population. Salihu et al (2003) noted more maternal complications including chronic hypertension and diabetes in women >35 years. To correct for these co-morbidites in research may be unrealistic in that few women of advanced age will be disease free, but for those who are, correction allows a more accurate estimation of risk.

Anna P Kenyon Clinical Lecturer/subspecialty trainee in maternal and fetal medicine, Institute for Womens Health, University College London

ithin the UK maternal age at the birth of the first child is steadily increasing (Nwandison and Bewley, 2006; Lewis, 2007; Office for National Statistics, 2008). Women who defer childbearing in this way do so for many reasons. A womans decision regarding the right time to embark upon a pregnancy may vary with personal, family, cultural and religious beliefs. However, once a woman over 35 years of age has made a decision to proceed with a pregnancy she faces a grim reality. Andersen et al (2000) noted that approximately 20% of all wanted pregnancies in 35-year-old women will result in fetal loss (defined as stillbirths, spontaneous abortions, ectopic pregnancies) rising to 54.5% at 42 years of age. A woman aged 3539 years has a risk of spontaneous abortion of 24.6%, rising to 51% at 4044 years and 93.4% at 45 years or more (Andersen, 2000). This means that a woman attending antenatal clinic may previously have had several wanted pregnancies ending in loss. That woman may have come from a peer group within her fertility clinic or social network where friends have failed to achieve a pregnancy at all. Once attending for antenatal care, expectations are high but older women face the unpleasant prospect of being advised of a poorer obstetric outcome than their younger counterparts, with no realistic strategies available to improve outcome. This requires careful counselling, as anxiety itself is associated with worse pregnancy outcomes (Alder, 2007;

Maternal and fetal outcomes

In their prospective study of 36 056 singleton pregnancies Cleary-Goldman et al (2005) showed that placenta praevia (adjusted odds ratio (AOR) 2.8), placental abruption (AOR 2.3) caesarean section (CS) (AOR 2.0) and perinatal mortality (AOR 2.2) were all increased in older mothers when the effects of race, parity, body mass index, education, marital status, smoking, pre-existing medical conditions, previous adverse obstetric outcome and use of assisted reproductive technologies (ART) were controlled for. The authors, however, showed no statistically significant assoBritish Journal of Midwifery June 2010 Vol 18, No 6

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ciation between age 35 years or older and other outcomes e.g. threatened abortion, pre-eclampsia (PET), gestational hypertension, pre-term labour and operative vaginal delivery. Interestingly, this study did not show advancing age to be associated with hypertensive complications despite confirming that chronic hypertension was more common among older women. The authors suggest this is as a result of controlling for covariates associated with gestational hypertension and PET e.g. history of medical conditions and use of ART (Cleary-Goldman, 2005). Hoffman (2007) looked only at singleton pregnancies in a multiethnic population and compared women 3539 years (13 902) and 40 or more years old (3953) with those less than 35 years. Hoffman noted that after correcting for race, parity, chronic hypertension, PET, diabetes, gestational diabetes and gestational age at delivery the risk of having an infant of low birthweight was increased: <2500 g AOR 1.4 (95% CI 1.241.58) aged 40 or more; <1500g odds ratio (OR) 1.5 (1.171.93). The odds ratio for pre-term birth (<28 weeks) was also increased in women over 40 compared to women under 35 years old (AOR 1.27 (95% CI 1.061.53)) (Hoffman, 2007). However, Salihu et al (2003), in a large retrospective US study of 12 066 854 pregnancies, found that women over 30 years old with a singleton pregnancy have higher risks of all morbidity and mortality indices compared to women 2029 years. Risks of PET, eclampsia, abruption and placenta praevia also all showed an increasing linear trend with age. Others have confirmed the increased incidence of placenta praevia in older mothers; AOR 10.5 (5.420) in nulliparous and 2.7 (1.83.6) in multiparous women over 40 years old compared to 2029-year-olds (Gilbert, 1999). Multiple pregnancies conceived either spontaneously or artificially occur more frequently in women of advancing age with reported rates of up to 5% at 4049 years (Salihu, 2003) or 37% at over 50 years of age (Salihu, 2003). Luke (2007) considered outcome among multiple pregnancies correcting for race, smoking status, maternal education, and trimester of prenatal care in women without diabetes or chronic hypertension. Within the same plurality, increasing maternal age was associated with reported significantly higher risks of pregnancy associated hypertension and excessive bleeding (including placental abruption, placenta praevia, excessive bleeding during labour and delivery). Not all studies describe the proportion of multiple pregnancies arising as a result of ART and this figure may be as high as 78% in women over 45 years of age (Porreco, 2005). The source of the ova in an older mother may
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The risks of adverse pregnancy outcome appear to increase with advancing maternal age, particularly in those with multiple pregnancies conceived with ovum donation.

have an important effect on outcome. In a study of 42 women aged 49.2 4.3 years of age carrying twins conceived via ovum donation compared with 417 control pregnancies, hypertensive complications (50%), diabetes in pregnancy (31%) and hospitalization in pregnancy (69%) were all high in the study group. Mean gestational age at delivery was lower for the study group compared with controls with 35.7% of infants in the study group born less than 34 weeks gestation compared with 21.8% of controls (OR 1.99, 95%; CI 1.023.89). Mean birthweight was also significantly lower for study group infants compared with controls

Approximately one fifth of all wanted pregnancies in women of 35 years of age will result in spontaneous abortion, ectopic pregnancy or stillbirth
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(OR 2.22, 95%; CI: 1.33.77) (Simchen et al, 2009). In a study by Porreco (2005) PET was significantly more prevalent among patients conceiving with ovum donation (OR 2.67, 1.046.82), even though 22% of the control group developed PET. One of 11 women (9%) over 45 years conceiving spontaneously developed PET compared to 20/39 (51%) conceiving with ART and donor eggs (P 0.016) (Porreco, 2005). Henne (2007) reported an increase in pre-term labour, PET and protracted labour in women conceiving after ovum donation correcting for parity.

Stillbirth
Risk of stillbirth may increase with advanced maternal age. In the general population, stillbirths affect 1 in 200 pregnancies (Smith and Fretts, 2007). The additional risk that advanced

Table 1: Studies reporting risks of stillbirth with maternal age

Ref Stillbirth definition Fetal death Fetal death Risk Study population Population Age in years (n) >50 (217) >40 (3 953) Comparator 3540 Age in years years 2034 <40 2.28 at 40 41 weeks 2.93 at 28 31 weeks (1.764.92) 1.44** (1.381.5) 2.1 (1.82.4) 3.8 for 4044 (2.26.4) years 1.94 (1.672.26) singletons 4049 years 2.20 (1.01 4.75) singletons 1.6 (0.43.00) multiples >40 years >45 years >50 years

Donoso (2008) Hoffman (2008)*

OR 2 817 959 (95% CI) AOR 126 402 (95% CI)

3.7 (1.210.5)

Luke (2007)

Infant death AOR 22 991 306 (unspecified) (95% CI) AOR 1 566 313 (95% CI) AOR 12 066 854 (95% CI)

>40 (45 982 612 singletons) 4044 2029 (31 662) >45 (1,205) 4049 (3 982 062 ) 2029

Jacobsson Intrauterine (2004) fetal death >28 weeks Salihu (2003) Loss >20 weeks

>50 (539) >40 (24 032) 2029

0.72 (0.431.2) multiples at 4049 years 1.2 (0.8-1.8) nulliparous 1.5 (1.3-1.8) multiparous 1.41 (1.17 1.70) 1.54 (1.38 1.72) 1.28 (1.24 1.32) 1.83 (1.292.61) 2.54 (2.143.03)

Gilbert (1999)

Infant death

AOR 1 160 000 (95% CI)

Jolly (2000) Reddy et al (2006)

Stillbirth

OR 385 120 (95% CI) 5 458 735 RR (95% CI)

>40 (7331) 3540 (41 327) 35-39 (545,873) >40 (109,174) 3539 (650 723) >40 (130 857)

1834

Stillbirth

<35

Bateman (2006)

Stillbirth

5 874 203

2034

1.72 (1.631.81)

* adjusted for ethnic group, parity, hypertension, pre-eclampsia, gestational diabetes ** adjusted for race/parity AOR: adjusted odds ratio OR: odds ratio

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maternal age poses has been investigated in several studies (Table 1) and appears to increase in a continuum with rising age (Andersen, 2000; Bateman, 2006). The largest increase in risk for women 35 years or older may start at 39 weeks gestation and peak at 41 weeks. Extremes of gestation are associated with the highest weekly risk of stillbirth (>41 weeks and 2023 weeks) and women at 40 years or older appear to have the largest risk (Reddy et al, 2006). The risk appears to persist even when confounding variables are taken into consideration. For example, in the study by Reddy et al (2006) the effect of maternal age persisted despite accounting for medical disease, parity, race and ethnicity. Fretts and Duru (2008) have suggested that the risk of stillbirth in women >40 years of age may be as high as 1 in 116 pregnancies at >37 weeks. This increased risk is still observed when corrections are made for coexisting medical conditions, which not only are more common in women of advanced age but also are independently associated with stillbirth (PET, gestational diabetes mellitus, multiple pregnancies) (Fretts et al, 1995; Fretts, 2005; Hoffman, 2007). Fretts et al (1995) report that even when recognized coexisting conditions that contribute to fetal death are controlled for, women over 35 years of age have a risk of fetal death twice as high as that among their younger counterpart. Causes of the increased risk remain unclear, however, placental abruption and umbilical cord complications all appear to rise with increasing age (Bateman, 2006). Cleary-Goldman (2005) suggested that for singletons greater than 40 weeks gestation the risk of abruption is an odds ratio of 2.3. Other important maternal risk factors for stillbirth such as nulliparity and obesity are also seen to rise in women of advanced maternal age (Nwandison and Bewley, 2006; Lewis, 2007; Smith and Fretts, 2007; Office for National Statistics, 2008). However, the most significant contribution to the increased risk of stillbirth in woman of advanced age is the increased risk of unexplained fetal death (OR 2.2, 1.33.8) (Bateman, 2006). It should be noted that older mothers have benefitted from the reduction in stillbirth in general populations that we have seen over time, and this is confirmed by Fretts et al (1995). Between the years 19601993 stillbirth rates declined overall and in women aged 35 years or older, the rate of stillbirths per 1000 births decreased from 16.5 in 1960 to 5.8 in 19901993. The absolute risk of stillbirth has been greatly reduced, however, the higher relative risk for older women persists and exactly what clinicians should do to reduce this is
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not clear (Stein and Susser, 2000). Older age, whether because of the co-morbidities that accompany it, the plurality that is observed, or the effect of age alone, does appear to be associated with adverse outcome. Prospective mothers presenting pre-conception or in early pregnancy (following referral as a result of age identified on risk factor screening) may wish to know the risk associated with their pregnancy (Gilbert, 1999), and in the context of that increased risk what interventions are available to them to improve outcome. However, few studies have addressed interventions in older mothers. In considering stillbirth, Hannah et al (1992) have shown that in any pregnancy of more than 41 weeks gestation induction of labour results in lower rates of caesarean section than serial antenatal monitoring with similar rates of perinatal morbidity and mortality. Given that women of 40 years or older have a similar stillbirth risk at 39 weeks to 2529-year-olds at 41 weeks (Andersen, 2000) perhaps interventions should therefore be offered earlier in these women. However, a word of caution: women of advance age may not labour as efficiently as their younger counterparts. A Dublin group employing active management of labour in all nulliparous women attending their unit in spontaneous labour undertook an analysis of outcome with respect to age. The need for oxytocin, the incidence of prolonged labour, instrumental delivery, intrapartumcaesarean section and intrapartum caesarean section because of dystocia all increased with increasing maternal age (Treacy, 2006). The observed differences were not accounted for by differences in birthweight, epidural use or gestational age. Heffner et al (2003) reported risks for caesarean section by induction status, gestational age and maternal age stratified for parity in singleton pregnancies over 36 weeks. Maternal age greater than 35 years was associated with an increased caesarean section rate among nulliparous women and maternal age over 40 years was associated with an increased risk in multiparous women (Heffner et al, 2003). Similar increased caesarean section rates were reported by Gilbert et al (Gilbert, 1999); 47% caesareasn setion in nulliparous women 40 years old or more compared to 22.5% in those aged 2029 years. However the authors acknowledge that a diagnosis of dystocia is physician-derived and that they were unable to conclude what anxiety maternal age brought to clinical decision making on the part of the parturient and the doctor (Gilbert, 1999). This suggests that intervention might reduce the risk of stillbirth, but may increase caesarean section and maternal morbidity rates.
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Conclusions
The risks of adverse pregnancy outcome appear to increase with advancing maternal age, particularly in those with multiple pregnancies conceived with ovum donation. Women seeking ART over 35 years of age should be offered a full and frank discussion and be advised of the benefit of single embryo transfer. Society as a whole, midwives, obstetricians and gynaecologists should advocate for policies that enable women to reproduce safely without personal cost to their education, careers, identity and their own or offsprings health. BJM Acknowledgement
The author would like to thank Dr Susan Bewley without whose inspiration and assistance this would not have been possible and Dr M Nwandison in her contribution to the original article. This topic is covered in greater depth in: Kehoe S, Bewley S, Ledger W, Nikolaou D, eds (2009) Reproductive ageing in older mothers. 56th RCOG Study Group, London Alder J, Fink N, Bitzer J, Hosli I, Holzgreve W (2007) Depression and anxiety during pregnancy: A risk factor for obstetric, fetal and neonatal outcome? A critical review of the literature. J Matern Fetal Neonatal Med 20(3): 189209 Andersen AMN (2000) Maternal age and fetal loss: population based register Linkage study. Br Med J. 320(7251): 170812 Astolfi P (2004) Late paternity and stillbirth risk. Hum Reprod 19(11): 2497501 Bateman BT (2006) Higher rate of stillbirth at the extremes of reproductive age: A large nationwide sample of deliveries in the United States. Am J Obstet Gynecol 194(3): 8405 Cleary-Goldman J C Fc (2005) Impact of maternal age on obstetric outcome. Obstet Gynecol 105(5): 98390 Donoso E (2008) Maternal, perinatal and infant outcome of spontaneous pregnancy in the sixth decade of life. Maturitas 59(4): 3816 Fretts RC (2005) Etiology and prevention of stillbirth. Am J Obstet Gynecol 193(6): 192335 Fretts RC, Duru UA (2008) New indications for antepartum testing: Making the case for antepartum surveillance or timed delivery for women of advanced maternal age. Semin Perinatol 32(4): 3127 Fretts RC, Schmittdiel J, McLean FH, Usher RH, Goldman MB (1995) Increased maternal age and the risk of fetal death. N Engl J Med 333(15): 9537 Gilbert WM (1999) Childbearing beyond age 40: Pregnancy outcome in 24,032 cases. Obstet Gynecol 93(1): 914 Glynn LM, Schetter CD, Hobel CJ, Sandman CA (2008) Pattern of perceived stress and anxiety in pregnancy predicts preterm birth. Health Psychology Jan;27(1): 43-51 Hannah ME, Hannah WJ, Hellmann J, Hewson S, Milner R, Willan A (1992) Induction Of Labor As Compared With Serial Antenatal Monitoring In Postterm PregnancyA Randomized Controlled Trial. N Engl J Med 326(24): 158792 Heffner LJ, Elkin E, Fretts RC (2003) Impact of labor induction, gestational age, and maternal age on cesarean delivery rates. Obstet Gynecol 102(2): 28793 Henne MB (2007) Comparison of obstetric outcomes in recipients of donor oocytes vs. women of advanced maternal age with autologous oocytes. Journal of Reproductive Medicine 52(7): 58590 Hoffman MC (2007) Pregnancy at or beyond age 40 years is associated with an increased risk of fetal death and other adverse outcomes. Am J Obstet Gynecol 196(5) Jacobsson B (2004) Advanced maternal age and adverse perinatal outcome. Obstet Gynecol 104(4): 72733 Jolly M (2000) The risks associated with pregnancy in women aged 35 years or older. Hum Reprod 15(11): 24337 Luke B (2007) Contemporary risks of maternal morbidity and adverse outcomes with increasing maternal age and plurality. Fertility and Sterility 88: 28393 Lewis GE (2007) Saving mothers lives: Reviewing maternal deaths to make motherhood safer20032005. The Confidential Enquiry into Maternal and Child Health (CEMACH). London Nwandison M, Bewley S (2006) What is the right age to reproduce. Fetal and Maternal Medicine Review 17(3): 185204 Office for National Statistics (2008) Birth Statistics 2004. United Kingdom; 1940-2004. www.statistics.gov.uk/ downloads/theme_population/FM1_33/FM1_33.pdf (accessed 20 May 2010) Porreco RP (2005) Expectation of pregnancy outcome among mature women. Am J Obstet Gynecol 192(1): 3841 Reddy UM, Ko CW, Willinger M (2006) Maternal age and the risk of stillbirth throughout pregnancy in the United States. Am J Obstet Gynecol 195(3): 76470 Salihu HM (2003) Childbearing beyond maternal age 50 and fetal outcomes in the United States. Obstet Gynecol 102(5): 100614 Simchen MJ, Shulman A, Wiser A, Zilberberg E, Schiff E (2009) The aged uterus: multifetal pregnancy outcome after ovum donation in older women. Hum Reprod 24(10): 25003 Smith GCS, Fretts RC (2007) Stillbirth. Lancet 370: 171525 Stein Z, Susser M (2000) The risks of having children in later life. Br Med J 320(7251): 16812 Treacy A (2006) Dystocia increases with advancing maternal age. Am J Obstet Gynecol 195(3): 7603 Wisborg K, Barklin A, Hedegaard M, Henriksen TB (2008) Psychological stress during pregnancy and stillbirth: prospective study. BJOG 115(7): 882-5
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Key points
l It is impossible (and wrong) for others to determine when it is the right time for a woman, or couple, to have a baby. Women who defer childbearing do so for many reasons, both within and outside their control. Care, support and respect of these and all women should be the health professionals first concern. l The risks of adverse pregnancy outcome appear to increase with advancing maternal age. l Women seeking assisted reproductive technology and/or ovum donation over 35 years of age should receive pre-pregnancy counselling and be advised of the benefit of single embryo transfer. l The available data suggest that in terms of physiology, age 2035 years remains the best age for childbearing.

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