Management of pregnancy in patients of advanced age

INTRODUCTION — Patients who delay childbearing are at increased risk of pregnancy complications, including ectopic pregnancy, spontaneous abortion, fetal chromosomal abnormalities, some congenital anomalies, placenta previa, gestational diabetes, preeclampsia, and cesarean birth. Such complications may, in turn, lead to preterm birth. There is also an increased risk of perinatal mortality. Benefits of delayed childbearing include that older couples tend to be more emotionally mature and financially stable than when they were younger.

Providing information to all patients of childbearing age about the obstetric risks of advanced maternal age can help them make informed decisions about the timing of childbearing.

This topic will address the management of pregnancy in patients of advanced age, which is generally agreed upon as age ≥35 years. Related topics on the effects of advanced age on pregnancy and fertility are presented separately.

●(See "Effects of advanced maternal age on pregnancy".)

●(See "Evaluation and management of infertility in females of advancing age".)

DEFINITIONS

Advanced maternal age — The age cut-off for advanced maternal age (AMA) pregnancy is not uniformly defined. Historically, AMA was defined as maternal age ≥35 years based on the convergence of the risk of fetal Down syndrome and the risk of amniocentesis to assess for Down syndrome. Other studies have defined AMA as age 40 or greater.

Very advanced maternal age and implications — A category of "very advanced maternal age" has been proposed for patients ≥45 years or ≥50 years, depending on the study [1,2]. Patients of very advanced maternal age have higher complication rates, multiple gestation rates, and an increase in rates of preterm birth and fetal growth restriction (figure 1) [3]. A cohort study comparing patients ≥48 years of age with those ≤47 years of age reported that patients ≥48 years had a nearly threefold increase in cesarean birth, a fourfold increase in gestational diabetes, a sixfold increase in the risk of requiring blood transfusion, and a 33-fold increase in intensive care unit admission, after controlling the data for multiple gestation [1].

INCIDENCE OF BIRTHS TO OLDER PATIENTS — There has been a notable shift to pregnancy at older maternal ages, particularly in resource-rich countries [4]. As an example, in the United States, the rates of pregnancy have decreased for patients under 30 years and increased for patients ages 30 and above from 1990 to 2015 (table 1 and figure 2) [5].

At a time when patients are delaying childbearing, the availability of assisted reproductive technologies for older patients has allowed patients to extend their reproductive options. In the United States, there were 840 births to patients ages ≥50 years in 2017, an increase from 677 births in 2013 [6].

RISK OF PREGNANCY LOSS — The risk of pregnancy loss associated with advancing maternal age has been well recognized. Population-based studies have reported pregnancy loss rates up to 40 percent in 35- to 44-year-old patients and 60 to 65 percent in patients >45 years [7,8]. In addition, the increased risk of pregnancy loss extends beyond the first trimester. In a British study of 76,000 singleton pregnancies with a live fetus, the pregnancy loss rates after 11 weeks of gestation were 1.2 percent for patients under the age of 35, 1.6 percent in patients 35 to 39 years of age, and 2.7 percent in patients 40 years of age or older (figure 3) [9].

SPECIFIC PRENATAL CARE ISSUES — In addition to routine prenatal assessments, we discuss the following issues with patients of advanced maternal age. (See "Prenatal care: Initial assessment".)

First and second trimester — The following suggestions apply to patients ≥35 years of age at the estimated date of delivery:

●Age and obesity are risk factors for development of type 2 diabetes mellitus, as well as gestational diabetes [10]. Since type 2 diabetes may not have been recognized periconceptionally, screening older obese gravida for gestational diabetes in the first trimester, as well as later in pregnancy, is reasonable. (See "Gestational diabetes mellitus: Screening, diagnosis, and prevention".)

●The risk of fetal aneuploidy based on maternal age should be reviewed (table 2). Most data relate to risk of trisomy 21 or composite risk of any aneuploidy, but some data are also available for maternal age-specific prevalence of trisomies 13 and 18 for patients aged 16 to 45 [11].

Testing for fetal aneuploidy can be invasive or noninvasive. Invasive testing, which involves amniocentesis and chorionic villus sampling to obtain fetal/placental cells, is diagnostic. Noninvasive testing of maternal blood (for either specific analyte levels or cell-free DNA), with or without ultrasound examination, is a screening test and requires follow-up testing of patients with screen-positive results. (See "Down syndrome: Overview of prenatal screening" and "Diagnostic amniocentesis" and "Chorionic villus sampling" and "Sonographic findings associated with fetal aneuploidy" and "Prenatal screening for common aneuploidies using cell-free DNA".)

In patients of advanced maternal age, noninvasive prenatal screening to measure cell-free DNA in maternal blood is becoming the preferred test because it has both higher sensitivity and a lower false-positive rate than analyte/ultrasound screening and it is safer than invasive diagnostic testing (table 3) [12]. Down syndrome screening tests have both higher detection rates and higher false-positive rates in older patients than in younger patients because of the higher prevalence of Down syndrome in offspring of older patients. (See "Prenatal screening for common aneuploidies using cell-free DNA".)

●Given the increased risk of congenital fetal anomalies in older patients, a detailed second-trimester ultrasound examination to assess for significant structural anomalies (particularly cardiac defects) is reasonable and is now recommended as a routine part of prenatal care in all pregnant patients. (See "Effects of advanced maternal age on pregnancy", section on 'Congenital malformations'.)

●Events that occur with increased frequency in older gravidae include hypertensive disease and preeclampsia, placenta previa, gestational diabetes, and abruption [13-15]. We educate patients about these conditions as well as the implications of preterm birth, which can be required in management of some of these complications.

For patients >35 years of age and at least one other moderate risk factor (eg, nulliparity, body mass index [BMI] >30 kg/m², family history of preeclampsia in a mother or sister, Black race), we recommend low-dose aspirin for preeclampsia prevention. This is consistent with US Preventive Services Task Force (USPSTF) and American College of Obstetricians and Gynecologists (ACOG) guidelines [16,17], and is discussed in more detail separately. (See "Preeclampsia: Prevention", section on 'Selecting patients at high risk of developing preeclampsia'.)

●The patient's risk for adverse outcome, including preterm birth/low birth weight, intrauterine growth restriction, and stillbirth, should be assessed by considering not only her age, but also the presence or absence of concomitant risk factors such as hypertension, diabetes, obesity, low socioeconomic status, Black race, and previous pregnancy complicated by growth restriction or preterm birth.

Third trimester — As there are no large, randomized trials that have examined the efficacy of routine antepartum testing in patients ages 35 and older, there remains no consensus on the management of late pregnancy for these patients. One strategy is to stratify patients based on their risk factors, such as age and parity, and to consider other factors that might influence risk, such as obesity and race [18].

For pregnant patients ages 35 years and older, we obtain an ultrasound examination at 36 to 37 weeks of gestation to assess fetal growth and amniotic fluid volume. Some centers perform this ultrasound examination earlier (eg, 32 to 36 weeks) for selected patients (eg, 40 years and older, BMI >30 kg/m²). We then perform twice weekly antepartum testing (alternating between a nonstress test and a biophysical profile) and ask patients to monitor daily fetal movement (kick counts) until delivery. We emphasize the importance of fetal movement as a sign of fetal well-being and encourage all of our patients to report decreased fetal movement in a timely fashion. If at any point this testing is not reassuring, then additional testing or induction of labor is warranted. (See "Overview of antepartum fetal assessment" and "Decreased fetal movement: Diagnosis, evaluation, and management".)

A retrospective cohort study of over 4400 patients reported that by following a protocol for pregnant patients ≥35 years that included weekly biophysical profile testing beginning at 36 weeks of gestation and induction of labor by 41 weeks of gestation, the risk of stillbirth ≥36 weeks gestation was the same among advanced maternal age and non-advanced maternal age patients [19]. For patients who are 35 years of age and older who have additional risk factors, such as primiparity or obesity or who are Black, we generally start testing in a way that is convenient for the patient, alternating nonstress tests with ultrasounds weekly at 36 weeks.

Risks of stillbirth versus delivery — The risk of stillbirth increases with increasing maternal age such that patients ≥40 years of age have the same risk of stillbirth at 39 weeks of gestation as patients in their mid-20s have at 41 weeks of gestation [20,21]. In addition to advancing age, parity also impacts the risk of stillbirth, with primiparous patients having a greater risk at each gestational age compared with multiparous patients. A population-based study including over five million births reported the risk of stillbirth after 37 weeks of gestation in primiparous and multiparous patients less than 35 years of age was 1/270 and 1/775, respectively; for patients 35 to 39 years of age, it was 1/156 and 1/502, respectively; and for patients 40 years of age or older, it was 1/116 and 1/304, respectively [22]. In this study, Black patients had a higher risk of stillbirth at 37 weeks of gestation or longer at all maternal ages. Black patients 40 years or older were the highest risk group, with a 2.45-fold increase in stillbirth risk at 37 weeks or longer compared with White patients younger than 35 years of age (lowest risk group). Thus older patients at term and their providers must balance the benefits of remaining pregnant and waiting for spontaneous labor against the risk of stillbirth:

●In a national cohort study of over 829,000 births from 2000 through 2012, the risk of stillbirth after 37 weeks of gestation fell as the frequency of induction of labor increased [23].

●A retrospective database review of over 700,000 deliveries between 37 and 43 weeks of gestation in Scotland from the time period of 1985 to 1996 reported the lowest cumulative probability of perinatal death at 38 weeks of gestation [24].

●A trial comparing labor induction with expectant management in patients ages 35 years or older reported no significant difference in the risk of cesarean section or neonatal outcomes, including birth weight <2500 g, Apgar score of 4 to 7, umbilical-cord blood arterial pH <7.00, or neonatal intensive care unit admission [25]. Of note, the study was not adequately powered to assess the risk of perinatal mortality.

Based on the above data, we favor delivery in the 39^th week of gestation for patients ages 35 years and older because of the increased risk of stillbirth beyond this gestational age, the diminishing reproductive options for patients in this age group, and the low risk of neonatal morbidity/mortality at this gestational age [21,22,26]. We more strongly favor induction at 39 weeks of gestation for patients who are ≥35 years and primiparous, ≥39 years of age, of Black race, or who have additional risk factors for stillbirth such as obesity. That said, we discuss both the options of induction and ongoing surveillance with these patients and respect the patient's preference regarding timing and type of intervention.

Patients who decline induction are managed with twice weekly testing and daily kick counts until spontaneous labor, nonreassuring testing, or 41 weeks of gestation (when induction is typically recommended for late-term gestation) is achieved [27]. For patients ≥40 years, we generally discourage expectant management (with surveillance) beyond 40 weeks of gestation.

Induction of labor — While induction of labor appears to reduce the risk of stillbirth, concerns have been raised that increasing use of induction will increase the rates of cesarean birth, which has its own risks. However, the data do not support such increases for all patients or patients of advanced maternal age [28,29]. (See "Induction of labor with oxytocin", section on 'Risk-reducing induction'.)

In a meta-analysis of four studies including over 2500 patients comparing induction of labor versus expectant management at term for patients ≥35 years of age, there was no statistically significant difference in cesarean birth rates between the induction and expectant management groups [30]. In a trial that randomly assigned over 600 patients ≥35 years of age to either induction of labor between 39+0 and 39+6 weeks of gestation or to expectant management, the cesarean birth and operative vaginal birth rates were similar between the two groups [25]. There were also no differences in the rates of adverse maternal or neonatal outcomes. No maternal or infant deaths occurred in either group. A retrospective cohort study of over 26,000 births reported that, for patients of advanced maternal age, delivery between 38+5 and 39+6 weeks optimized the balance among maternal cesarean birth rate, neonatal intensive care unit admission rate, maternal third- and fourth-degree perineal laceration rates, and newborn Apgar ≤6 [31].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility" and "Society guideline links: General prenatal care".)

SUMMARY AND RECOMMENDATIONS

●Definitions

•Advanced maternal age (AMA) is generally considered as maternal age ≥35 years and is based on the convergence of the risk of fetal Down syndrome and the risk of amniocentesis to assess for Down syndrome; other definitions (eg, age ≥40 years) are sometimes used. (See 'Advanced maternal age' above.)

•Very advanced maternal age is generally considered as maternal age ≥45 years or ≥50 years, depending on the study. (See 'Very advanced maternal age and implications' above.)

●Complications – Pregnancy complications that occur with increased frequency in older gravidae include: ectopic pregnancy, spontaneous abortion, fetal chromosomal abnormalities, some congenital anomalies, placenta previa, gestational diabetes, preeclampsia, and cesarean birth. Such complications may, in turn, result in preterm birth. There is also an increased risk of perinatal mortality. (See 'Introduction' above.)

●Management in the first and second trimesters

•Testing for fetal aneuploidy – For pregnant patients ≥35 years of age at the estimated date of delivery, we suggest offering prenatal diagnosis or screening for aneuploidy and a detailed second trimester ultrasound examination (18 to 20 weeks of gestation) to look for significant structural anomalies (particularly cardiac defects) (Grade 2C). (See 'First and second trimester' above.)

•Aspirin prophylaxis – For patients >35 years of age and at least one other moderate risk factor (eg, nulliparity, body mass index [BMI] >30 kg/m², family history of preeclampsia in a mother or sister, Black race), we recommend low-dose aspirin for preeclampsia prevention. This is discussed in detail separately. (See 'First and second trimester' above and "Preeclampsia: Prevention", section on 'Selecting patients at high risk of developing preeclampsia'.)

●Management in the third trimester

•Fetal testing – We obtain an ultrasound examination at 36 to 37 weeks of gestation to assess fetal growth and amniotic fluid volume. We then perform twice weekly antepartum testing and ask patients to monitor daily fetal movement (kick counts) until delivery. Earlier testing (32 to 36 weeks) may be performed for selected patients (eg, 40 years and older, BMI >30 kg/m²). (See 'Third trimester' above.)

•Timing of delivery – For pregnant patients ≥40 years of age at the estimated date of delivery, we suggest induction of labor at 39 weeks of gestation (Grade 2C). We also favor this approach in patients ≥35 but <40 years. We also discuss the alternative of ongoing close fetal and maternal surveillance and respect the patient's preference regarding timing and type of intervention. However, we generally discourage expectant management with close surveillance beyond 40 weeks of gestation. (See 'Risks of stillbirth versus delivery' above.)