INTRODUCTION

The average age of childbirth has been rising markedly across the Western world.¹ The changing obstetric landscape and multi-morbidity will mean that we will, in time, see these effects across the globe. Advanced maternal age is defined as women >35 years old. Very advanced maternal age (VAMA) and extremely advanced maternal age (EAMA) are defined as women >40 years old and >45 years old, respectively. Women may choose to delay pregnancyies to complete higher education, develop their careers, gain financial security, or and for their own personal choice. Numerous studies have demonstrated a continuum for the risk of both the mother and baby with advancing maternal age. VAMA is an independent risk factor for an adverse pregnancy. In this chapter we will review the current literature, highlight the challenges, and suggest pathways to enable us to manage the complexity involved in VAMA women.

EPIDEMIOLOGY

Pregnancy for the VAMA has increased in many high-income countries over the past several decades, including those in Europe, the USA, Japan, and the UK.^2,3 Birth rates have declined for women agedin  20–29  years old, remain unchanged for women aged 30–34 years old and rose for women aged 35–44 years old. In the UKnited Kingdom the proportion of maternities in women aged >35 years has increased from 8% (approximately 180,000 maternities) in 1985–87 to 20% (almost 460,000 maternities) in 2006–8. In women aged >40 years this has trebled in the same time, from 1.2% (almost 27,000 maternities) to 3.6% (approximately 82,000 maternities). The U.S. maternal mortality rate for women of VAMA (81.9 per 100,000 live births) is nearly eight8 times that for women <25 years old (10.6 per 100,000 live births).⁴ The UK maternal mortality rate for women of VAMA (24 per 100,000 live births) is four4 times that for women aged 20–24 years old (six6 per 100,000 live births).⁵

IMPLICATIONS FOR A VAMA PREGNANCY

The implications of VAMA pregnancy include risks to the mother and, baby and obstetric outcomes. With a VAMA we have to contend with the fact that our women are more likely to have pre-existing health conditions and require more fertility intervention.⁶ For VAMA women, maternal age should be combined with other maternal characteristics and obstetric history when determining an individualized adjusted risk for adverse pregnancy complications.^7,8 Pregnancy in women of VAMA presents ethical and legal implications to both the individual, her family, and society as a whole. These should preferably be considered prior to pregnancy, particularly as reproductive assistance is often required to achieve pregnancy in this age group. With VAMA there is an increased risk of dying – who would be the next of kin and parent to the baby?

The maternal outcomes include: increased morbidity and mortality, gestational diabetes mellitus, hypertensive disorders, and longer length of stay during the postpartum period.^9,10,11 There are worse perinatal outcomes, more preterm delivery, lower birth weight, fetal growth restriction, macrosomia, large for gestational age, perinatal mortality and stillbirth.^12,13 Obstetric outcomes include increased risk of miscarriage, cervical incompetence, placental abruption, more elective and emergency Cesarean sections, postpartum hemorrhage, and sepsis.^14,15

Cardiovascular disease is reported as a leading cause of mortality in the Western world. Many women whose deaths have been documented in these reports did not know of their underlying cardiac disease prior to pregnancy. Age is a known risk factor for both maternal cardiovascular disease and adverse outcomes in pregnancy.¹⁶ A population-based retrospective cohort study found that maternal- age-specific incidence of severe morbidity varied by outcome. EAMA had significantly elevated rates of some of the most severe, potentially life-threatening, morbidities, including renal failure, shock, acute cardiac morbidity, serious complications of obstetric interventions, and ICU admission.¹⁷

With increasing maternal age there is a continuum of growing risks. Complications described in VAMA occur more commonly during the antenatal period than during the postnatal period, followed by a smaller group having problems during the intrapartum period.^14,15 VAMA women have an increased risk of miscarriage, (adjusted OR 2.32, 95% CI, 1.83–2.93).⁷ There is an association wbetweenith increasing maternal age and postpartum hemorrhage in the VAMA women (RR 4.94, 95% CI 4.09–5.96).¹⁴ There iwas also an increasing association with maternal age and elective cCesarean -section in VAMA nulliparous women (RR 8.23, 95% CI 6.23–10.88) versus multiparous (RR 3.73, 95% CI 2.94–4.74). The risk of low birthweight iwas higher in VAMA (RR 1.43, 95% CI 1.19–1.73). A large retrospective study found that VAMA remained an independent risk factor for gestational diabetes mellitus, even after adjusting for confounding factors (OR 2.80 and 3.14 for women aged 40–44 years old and >45 years, old respectively).¹⁵ The risk of placenta previa was also increased (40–44 years, old OR 2.56;, >45 years, old OR 4.83). The EAMA women had an OR 2.62 (95% CI 1.30–5.27) for iatrogenic prematurity. These risks are summarized in Table 1.

To date, the oldest woman known to have had a successful outcome was a primiparous woman following a donor oocyte in vitro fertilization.¹⁸ She delivered by an elective cCesarean section and became a mother at the age of 68 years old.

CONSIDERATIONS AND MEDICAL EVALUATION OF PRE-PREGNANCY COUNSELING

Medical evaluation and counseling prior to pregnancy is essential for the optimalbest outcome of any pregnancy. This is an opportunity to improve health and mitigate by assessment ofing pre-pregnancy lifestyle and, health, as well as the woman’s suitability to embark on a future pregnancy. All women of VAMA should be offered pre-pregnancy counseling (Table 2). Counseling and work-up may need to be bespoke. It is important to address all the psycho-social and physical aspects for everyall VAMA womaen. An open and honest bidirectional conversation balancing the woman’s autonomy and the care giver isare important. TThe VAMA group and the EAMA groups face different risks, with an increased risk of complications in the latterEAMA group compared to the formerVAMA group and to younger aged women (RR 3.32).¹⁹

Women with VAMA also require counseling regarding their pre-existing medical conditions and the risks that pregnancy may pose to themselves and their foetus. Optimization of pre-existing medical conditions is essential, along with risk stratification and harm minimization strategies.

Favorable outcomes for VAMA are possible for healthy women who have been screened to exclude pre-existing disease. This is also an opportunity to separate low- risk and high- risk VAMA women as they proceed to a pregnancy, to enable timely investigations and surveillance to occur.

In v-Vitro fFertilization (IVF) pre-pregnancy work-up is even more important in our VAMA women. There are situations with increasing age in whichthat embryo transfer should be strongly discouraged,; particularly in women with complex multi-morbidity as there could be an exacerbation of their pre-existing condition and an even higher obstetrical risk.

IN -VITRO FERTILIZATION (IVF) AND VAMA

The success rates for assisted reproduction techniques in VAMA are all extremely low, including ovulation induction and intra-uterine insemination, being as low aswith success rates of <1% live births per cycle in this group.²⁰ The same review suggested that IVF offers a relatively higher success rate, of around 13.7% per cycle.

A UK national study examined pregnancy complications in EAMA and compared maternal and neonatal outcomes among 233 women aged between 48–61 years old, compared with 454 comparison women aged 16–46 years old. In the latter groupOf the women aged between 48–61 years old, 76% had conceived following IVF or intra-cytoplasmic sperm injection (ICSI) compared with 4% of the formeryounger group of women. The 48–61 year older group were more likely to be pregnant for the first time, be overweight or obese, have pre-existing medical conditions, and be carrying a multiple pregnancy.²¹ Another study found that IVF and the use of donor eggs are individual risk factors for pre-eclampsia in VAMA women.²²

As assisted reproductive techniques, particularly the use of donor eggs, continues to improve and become more widely available, more VAMA women will use this route to becominge pregnant. The above findings should be considered when counseling VAMA women about their infertility treatment options and consequences.

ANTENATAL CARE

Once pregnancy is confirmed, the advice should be to book as early as possible and have a maternal health assessment with a qualified health professional, including a full medical history and focussed examination (Table 3). Any relevant information from the pre-pregnancy assessment should be made available to the maternity care team at this time. This will aid in stratifying low- and high- risk VAMA women, to facilitate timely investigations and surveillance to occur. TA table 3 lists theof relevant baseline investigations are found below.

Using multivariate logistic regression analysis and, adjusting for confounders, the risk for late-onset pre-eclampsia has been shown to increase by 4% with every 1-one year increase in maternal age >32 years old.²³ For all women of VAMA aspirin (75–150 mg once daily nocte) is beneficial. More recent evidence highlights the dose of 150 mg of aspirin in women with risk factors for early onset pre-eclampsia is even more favorable.²⁴

Ongoing care

Regular review and continuity of care in an appropriate maternity care setting is important for VAMA women. VAMA women with any known medical complications and who are deemed as high risk should be seen regularly in a joint obstetric/maternal medicine antenatal clinic. An early OGTToral glucose tolerance test is important to screen for gestational diabetes for all VAMA women. A joint multi-disciplinary team meeting with the high- risk VAMA woman should be scheduled for 32–34 weeks' gestation to plan the mode and timing of delivery.

VAMA women should be considered for additional fetal monitoring in late pregnancy and the intrapartum period. During the antenatal period surveillance, serial growth scans, cardiotocography and kick charts can be helpful. A low threshold to be reviewed within a maternity setting should be advised if there are any concerns.

DuringStudies of the intrapartum period studies have shown that there is a higher risk of perinatal mortality at this time. One study found that VAMA was independently associated with risk of anoxic death among primiparous (adjusted OR 5.34, 95% CI 2.34–12.20) and multiparous women (adjusted OR 2.14, 95% CI 0.99–4.60).²⁵ Continuous electronic fetal monitoring should be considered for VAMA women during the intrapartum period.

CARDIAC SYMPTOMS IN VAMA PREGNANCY

The increasing rates of obesity and metabolic syndrome are further accelerating the rate of acquired cardiac disease among VAMA women. The MBRRACE reports have highlighted that cardiac disease is the leading cause of indirect maternal mortality. In the latest report, the VAMA women were athad an increased risk of cardiac disease (RR 2.21, CI 95% CI 0.46–9.32). The VAMA women are also at increased risk of cardiomyopathy and acute coronary syndrome. The incidence of these conditions is increased 3–4- fold with pregnancy, and the risk is even higher in a VAMA pregnancy.^26,27 This can easily be missed,; particularly if there has been no work- up for maternal health prior to pregnancy. Investigation should not be compromised simply because the woman is pregnant, because as most imaging can be performed safely in pregnancy (see cChapter on Radiation in Pregnancy).

VAMA women with dyspnea, or any chest pain should have a focused and timely set of investigations including an ECG, troponin, cardiac ECHO, and coronary artery/pulmonary imaging if indicated. If symptoms do not resolve, all efforts should be made to make a diagnosis rather than simply tonot just exclude one.

Timing of delivery

The risk of stillbirth increases with increasing maternal age, such that women ≥40 years of age have the same risk of stillbirth at 39 weeks of gestation as thosewomen in their mid-20s have at 41 weeks of gestation.^28,29 For this reason, it is considered appropriate to offer delivery at around at 39–40 weeks in women of VAMA unless there are other obstetric considerations. The timing of delivery should involve shared decision making. There areis no specific data regarding VAMA women, although induction of labor in low- risk nulliparous women does not appear to increase the risk of cesarean delivery.³⁰

The timing of delivery should involve shared decision making. One randomized control study showed no increase in emergency cesarean rate or adverse outcome for eitherthe mother or neonate when induced at 39 weeks versus expectant care (RR 0.99, 95% CI 0.87–1.14).³¹AOne meta-analysis found that VAMA women were more likely to have been offered an induction of labor and elective cesarean deliveryies.³² The reasons behind this are complex. From a large maternity hospital, retrospective data found an increasing association with maternal age and elective cCesarean -section in VAMA nulliparous women (RR 8.23, 95% CI 6.23–10.88) versus multiparous (RR 3.73, 95% CI 2.94–4.74).¹⁴ This most likely reflects the mother’s preference and health professional’s' preferences for a low threshold for risk avoidance.

Intrapartum care

Increasing maternal age is found to be associated with intrapartum complications, including postpartum hemorrhage and emergency cesarean -section. The EAMA women in one study had an adjusted OR of 2.03 (95%  CI 1.50–2.74) for an emergency cCesarean -section.¹⁵ EAMA women have approximately eight8-fold risk for postpartum hemorrhage.³³ The incidence of peripartum hysterectomy was 1% in mothers <under 20 years and 13% in VAMA mothers.³⁴ Delivery should be planned, preferably in a hospital setting, where there is access to obstetric services and early critical care within in-reach if complications arise.

Due to age-related changes in the spine, there may be more technical difficulties while placing athe neuraxial block. PThe performance of the neuraxial anesthesia in the VAMA mother may be different regarding the absorption, distribution, and clearance of the local anesthetics compared to the pharmacokinetics in a younger woman.¹⁸

One cohort study examined risk factors for peripartum hysterectomy using data from Africa, Asia, Europe, and the Americas. The authors speculate that the reason behind the lower threshold for hysterectomy; is that VAMA women were thought to less likely to have more offspring. There is an increased risk of peripartum hysterectomy at cesarean section in VAMA women when compared to thatrisk of a mother aged 20 years old (aOR 11.73, 95% CI 6.3–21.85 ).³⁴

VAMA wais found to have worse perinatal outcomes includingsuch as preterm delivery, low birthweight babies (RR 1.43, 95% CI 1.19–1.73), higher rates of neonatal intensive care unit admission, and worse Apgar scores¹⁴ VAMA have a two ofold increased risk of delivery related to perinatal death.²⁵ Surveillance and multidisciplinary working with the obstetricians, anesthetists, neonatologists, and midwives is essential at this time.

POSTPARTUM CARE AND LACTATION

There areis limited data around the outcomess during the postpartum period of a VAMA pregnancy. Post-partum chronic hypertension at around 3 months is associated with advanced maternal age (adjusted OR 1.10, 95% CI 1.01–1.21).³⁵ It is particularly relevant for VAMA women with hypertension during pregnancy or the post-partum period to have a follow-up with their general practitioner. All VAMA women should receive contraception advice and a plan should be in place prior to discharge.

There is a paucity of data of the effect of lobular involution in VAMA and breastfeeding. OneA meta-analysis found that older maternal age was associated with a higher prevalence of poor sleep quality.³⁶

LONG-TERM CONSEQUENCES

The long-term clinical manifestations for VAMA mothers and children are unfolding at this time.³⁷

During pregnancy, VAMA women are more likely to have complications including pre-eclampsia and intra-uterine growth retardation, resulting in a known increase in cardiovascular disease later in life for both the mother and child. The Women’s Health Initiative Study found that women who had their last pregnancy at VAMA, were at increased risk of hemorrhagic stroke compared with those whosewomen with their last pregnancy was at <40 years. The rate forof ischemic stroke was 3.8% versus 2.4%, hemorrhagic stroke was 1.0% versus 0.5%, and cardiovascular mortality was 3.9% versus 2.3% in women respectively.³⁸ There was also a trend towards a higher rate of acute coronary syndrome among women with their last pregnancy at VAMA, at 3.0% versus 2.5% too. One population-based cohort study reviewed all hospitalizations of children up to the age of 18 years of age and born toof VAMA women, and found they did not appear to be at increased risk for long-term morbidity.³⁹ More studies are required to determine whetherif VAMA mothers and their children are at risk long -term, and, if so, development of strategies for identifying and preventing long-term morbidity isare required. Albeit for now, a targeted assessment should be performed on all VAMA women to try and reduce their cardiovascular morbidity risk over the long -term.

IMPLICATIONS FOR HEALTH SYSTEMS IN LOW- RESOURCE COUNTRIES

Due to the obstetric shift, more VAMA women will become pregnant worldwide. This has implications for the health of boththe woman and her offspring, as well as broader implications on health care resourcing including access to assisted reproductive technologies as well as pregnancy and long-term care. With many competing health priorities, these issues need to be addressed within socio-political frameworks. The responsibility for addressing these issues must be shared with the full range of stakeholders, including, the VAMA woman and her family, health care providers and healthcare delivery organizations.

CONCLUSIONS

Maternal age should be combined with other maternal risk factors and obstetric history when calculating an individualized adjusted risk for adverse pregnancy complications. There is strong evidence of an association between VAMA and adverse maternal outcomes, severe medical and obstetric morbidity during pregnancy.⁴⁰ The perinatal outcomes and the absolute rate of stillbirth/perinatal death remains low, <at less than 10 per 1000 births in most high-income countries. The best outcomes appear to be linked to optimization of pre-existing maternal health prior to pregnancy and on-going antenatal care with a multidisciplinary team approach.^41,42

It is vital withGiven this growing and evolving VAMA population, ongoing education of, and awareness by,of health care providers and the VAMA women areis imperative for a satisfactorygood outcome for boththe VAMA mother and baby.

PRACTICE RECOMMENDATIONS