First-Trimester Determination of Complications of Late Pregnancy

The term harelip, used to describe facial clefts, arose from a belief that the defect originated from the mother being startled by a hare during her pregnancy.¹ The concept that congenital structural abnormalities of the fetus developed from events during pregnancy is called maternal impression and it continued to be seriously discussed well into the 19th century.¹ However, it is now known that the vast majority of congenital structural fetal malformations are a consequence of aneuploidy or abnormal embryonic development in the first 8 weeks postconception. A series of studies suggest that other complications of pregnancy, such as intrauterine growth restriction, preterm birth, and stillbirth, also have their origins, at least in part, in very early pregnancy. These observations raise the possibility that women who are at increased risk of adverse outcome in late pregnancy may be identifiable in the first trimester of pregnancy, with the potential for trials of screening and early intervention.

The study in this issue of JAMA by Mook-Kanamori et al² presents important new information about first-trimester determination of growth restriction. The authors measured the difference between the expected size of the fetus in the first trimester, based on menstrual history, and the actual size of the fetus, assessed by ultrasound. They demonstrated that when the fetus was smaller than expected in the first trimester, there was an increased risk of preterm birth, delivery of a small-for-gestational age (SGA) infant, and delivery of a low-birth-weight infant. The associations were independent of other maternal characteristics and the risk of these outcomes was increased 2 to 3 fold among fetuses in the lowest quintile of first-trimester growth.

One of the problems in assessing fetal growth is to differentiate between infants who are growth restricted (grew to less than their genetically determined potential) from infants who are constitutionally small. The study by Mook-Kanamori et al² suggests that the associations between first-trimester growth and the risk of delivering an SGA infant are due to growth restriction because smaller than expected size of the fetus in the first trimester was unrelated to maternal weight and height. Moreover, smaller size in the first trimester was associated with more rapid growth in infancy, suggesting ex utero catch-up growth to compensate for true growth restriction in utero.

The findings of Mook-Kanamori et al² confirm a previous study that demonstrated an increased risk of low birth weight, delivery of an SGA infant, and preterm birth among spontaneous conceptions in which the fetus was smaller than expected in the first trimester.³ The relative weakness of both studies is their reliance on menstrual data to establish the expected size of the fetus in early pregnancy. These analyses assume that fertilization took place on day 14 of the menstrual cycle and the first day of the last menstrual period is taken as day 1. It is possible that fertilization at later days in the menstrual cycle could be associated with adverse outcomes and this would also be associated with smaller than expected size of the fetus in the first trimester. However, secondary analysis of a large-scale, multicenter cohort study of Down syndrome screening conducted in the United States analyzed the associations between early pregnancy growth measurements and the risk of delivering an SGA infant among approximately 1000 women who conceived after use of assisted reproductive technology, and for whom the date of conception was known.⁴ This study confirmed a linear relationship between smaller than expected size in the first trimester and both lower birth weight and the proportion of SGA infants. Hence, the association is still observed when the timing of conception is known.

The analysis reported by Mook-Kanamori et al² also described the maternal characteristics associated with reduced growth in the first trimester. After taking into account multiple comparisons, multivariate analyses demonstrated a significant positive relationship between crown to rump length and maternal age and a significant negative relationship between crown to rump length and hematocrit. The association between poor first-trimester growth and a high hematocrit level is of particular interest. Hematocrit normally declines in early pregnancy and higher hematocrit in early pregnancy is associated with increased perinatal mortality.⁵ The association could reflect a direct influence of high hematocrit levels on pregnancy (eg, through alteration in uterine blood flow). Alternatively, it could indicate that the absence of the normal decrease in hematocrit is a marker of some other determinant of adverse pregnancy outcome, such as abnormal placental function. If the latter possibility were correct, it would suggest that first-trimester ultrasonic or biochemical measurements related to placentation may also be predictive of subsequent adverse outcome.

A series of studies have addressed relationships between first-trimester measurements related to the placenta and later outcomes. Invasion of the decidua and myometrium by the trophoblast in early pregnancy is a key event in placentation, and it can be assessed noninvasively by Doppler flow velocimetry of the uterine arteries. A prospective study of 352 women older than 34 years demonstrated that uterine artery Doppler flow resistance measurement in the top quartile at 12 to 13 weeks was associated with 4-fold risk of hypertensive disorders.⁶ Placental-derived proteins can also be measured in the maternal blood in early pregnancy. First-trimester maternal serum levels of pregnancy-associated plasma protein A have been widely studied in the assessment of Down syndrome risk. However, the biology of the protein is such that associations might be anticipated for other complications of pregnancy. Pregnancy-associated plasma protein A is part of the system controlling the insulin-like growth factors in the trophoblast. For instance, mice that did not have the gene encoding pregnancy-associated plasma protein A exhibited severe early onset intrauterine growth restriction.⁷

Two large-scale observational studies demonstrated that low maternal serum levels of pregnancy-associated plasma protein A at 10 to 13 weeks' gestation were associated with an increased risk of delivery of an SGA infant, preterm delivery, preeclampsia, and stillbirth.^{8 - 9} The associations persisted in multivariate analysis. Further analyses of the earlier of the 2 cohorts explored in more detail the associations between pregnancy-associated plasma protein A levels prior to 13 weeks' gestation and later outcome. Analysis of a subgroup of 4288 women with the following characteristics: (1) pregnancy-associated plasma protein A assayed at 8 to 12 weeks' gestation, and (2) an uncomplicated singleton pregnancy ultimately delivering a normal, live newborn at full term, demonstrated that the eventual birth weight and the timing of labor at term were correlated with first-trimester levels of pregnancy-associated plasma protein A.¹⁰ Linkage to a national registry of perinatal deaths allowed first-trimester levels of pregnancy-associated plasma protein A to be related to specific causes of stillbirth in a subgroup of 7934 women. This analysis demonstrated women with first-trimester levels of pregnancy-associated plasma protein A in the lowest 5% had a 50-fold increased risk of stillbirth at 24 to 43 weeks' gestation due to placental causes (associated with growth restriction, placental abruption, or preeclampsia) but were not at increased risk of stillbirths due to other causes.¹¹

First-trimester levels of other placental proteins have also been related to adverse outcomes in later pregnancy. Low first-trimester levels of placenta growth factor were associated with an increased risk of delivering an SGA infant and preeclampsia.¹² First-trimester levels of activin A were comparably predictive of subsequent preeclampsia to pregnancy-associated plasma protein A and associations with inhibin A were somewhat stronger.¹³ In addition, low levels of the placentally produced galectin placental protein 13 in the first trimester were strongly predictive of early onset preeclampsia.¹⁴

Collectively, these observations, including the report from Mook-Kanamori et al² in this issue of JAMA, indicate that fetal and infant growth are significantly related to growth and placental function in the first trimester of pregnancy. Hence, complications of late pregnancy may, at least for some women, already be determined in the first 3 months postconception, even before a woman has sought prenatal care. The multiple associations described suggest that combined ultrasonic and biochemical screening in early pregnancy may be able to identify women at high risk of complications in late pregnancy. The challenges for future research are to produce robust screening tests with acceptable levels of detection and prediction, and to identify interventions that are effective in improving outcome when a pregnancy has been identified as high risk.