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Fetal Growth Patterns in Pregnancy-Associated Hypertensive Disorders: NICHD Fetal Growth Studies
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Fetal growth patterns in pregnancy-associated hypertensive disorders: NICHD Fetal Growth Studies Q10
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Julio Mateus, MD, PhD; Roger B. Newman, MD; Cuilin Zhang, MD, PhD; Sarah J. Pugh, PhD; Jagteshwar Grewal; Sungduk Kim; William A. Grobman, MD; John Owen, MD; Anthony C. Sciscione, DO; Ronald J. Wapner, MD; Daniel Skupski, MD; Edward Chien, MD; Deborah A. Wing, MD; Angela C. Ranzini, MD; Michael P. Nageotte, MD; Nicole Gerlanc, PhD; Paul S. Albert, PhD; Katherine L. Grantz, MD, MS
BACKGROUND: Fetal growth patterns in pregnancy-associated hypertensive disorders is poorly understood because prospective longitudinal data are lacking. OBJECTIVE: The objective of the study was to compare longitudinal fetal growth trajectories between normotensive women and those with pregnancy-associated hypertensive disorders. STUDY DESIGN: This is a study based on data from a prospective longitudinal cohort study of fetal growth performed at 12 US sites (2009e2013). Project gestational age was confirmed by ultrasound between 8 weeks 0 days and 13 weels 6 days, and up to 6 ultrasounds were performed across gestation. Hypertensive disorders were diagnosed based on 2002 American College of Obstetricians and Gynecologists guidelines and grouped hierarchically as severe preeclampsia (including eclampsia or HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome), mild preeclampsia, severe gestational hypertension, mild gestational hypertension, or unspecified hypertension. Women without any hypertensive disorder constituted the normotensive group. Growth curves for estimated fetal weight and individual biometric parameters including biparietal diameter, head circumference, abdominal circumference, and femur and humerus length were calculated for each group using linear mixed models with cubic splines. Global and weekly pairwise comparisons were performed between women with a hypertensive disorder compared with normotensive women to analyze differences while adjusting for confounding variables. Delivery gestational age and birthweights were compared among groups.
P
regnancy-associated hypertensive disorders including preeclampsia and gestational hypertension are major contributors to severe maternal and perinatal morbidity and mortality.1 Preeclampsia occurs in 4% to 8% of pregnant women while gestational
Cite this article as: Mateus J, Newman RB, Zhang C, et al. Fetal growth patterns in pregnancy-associated hypertensive disorders: NICHD Fetal Growth Studies. Am J Obstet Gynecol 2014;xxx;xx-xx. 0002-9378/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajog.2019.06.028
RESULTS: Of 2462 women analyzed, 2296 (93.3%) were normoten-
sive, 63 (2.6%) had mild gestational hypertension, 54 (2.2%) mild preeclampsia, 32 (1.3%) severe preeclampsia, and 17 (0.7%) unspecified hypertension. Compared with normotensive women, those with severe preeclampsia had estimated fetal weights that were reduced between 22 and 38 weeks (all weekly pairwise values of P < .008). Women with severe preeclampsia compared with those without hypertension also had significantly smaller fetal abdominal circumference between 23e31 and 33e37 weeks’ gestation (weekly pairwise values of P < .04). Scattered weekly growth differences were noted on other biometric parameters between these 2 groups. The consistent differences in estimated fetal weight and abdominal circumference were not observed between women with other hypertensive disorders and those who were normotensive. Women with severe preeclampsia delivered significantly earlier (mean gestational age 35.9 3.2 weeks) than the other groups (global P < .0001). Birthweights in the severe preeclampsia group were also significantly lower (mean e949.5 g [95% confidence interval, e1117.7 to e781.2 g]; P < .0001) than in the normotensive group. CONCLUSION: Among women with pregnancy-associated hypertensive disorders, only those destined to develop severe preeclampsia demonstrated a significant and consistent difference in fetal growth (ie, smaller estimated fetal weight and abdominal circumference) when compared with normotensive women. Key words: biometric parameters, fetal growth trajectory, gestational
hypertension, preeclampsia, pregnancy-associated hypertensive disorders
hypertension, often viewed as a transitory condition, progresses to preeclampsia in almost half of affected pregnancies.2e4 Failure of deep placentation is a central pathophysiologic feature of new-onset hypertension in pregnancy.5e9 Impaired physiological transformation of spiral arteries seen in deep placentation disorders is characterized by poor trophoblastic invasion, persistent endothelial cells, arterial endothelial activation, and frequently acute atherosis5,6 leading to utero-placental hypoperfusion, oxidative stress, intravascular inflammation, and angiogenic imbalance.5e9 The association of fetal growth restriction (FGR) and pregnancy-associated hypertensive disorders is complex, but
has mainly been attributed to placental vascular dysfunction, a common pathologic feature shared by both disorders.5,6,10,11 Preeclampsia is associated with FGR; however, fetal growth remains normal in most pregnancies complicated by this disorder.10,11,12e16 Severe placental abnormalities in- Q3 cluding excessive villous regression and extensive infarction secondary to atherosis are predominant in pregnancies complicated by FGR.11 On the other hand, placental involvement is minimal and fetal growth has been found to be unaffected in pregnancies with milder manifestations of the disease.11 Tay et al17 demonstrated recently that compared with
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AJOG at a Glance Why was this study conducted? To establish fetal growth trajectories in pregnancy-associated hypertensive disorders. To determine gestational timing for any differences of fetal growth in women with pregnancy-associated hypertensive disorders compared with normotensive women. Key findings Women with severe preeclampsia demonstrated reduced estimated fetal weights and abdominal circumferences from as early as 22e23 weeks’ gestation compared with women without hypertension. Fetal growth was similar between the mild preeclampsia and normotensive groups. Fetuses of women with mild gestational hypertension had transitory fetal growth delays that normalized by the third trimester. What does this add to what is known? Women destined to develop severe preeclampsia experienced persistent reduction in fetal growth, with significant divergence from normotensive pregnancies as early as 22 weeks’ gestation. Our study confirms reductions in fetal growth are related to disease severity.
normotensive pregnancies, maternal cardiac output is high and peripheral vascular resistance (PVR) is low in women with preeclampsia without FGR, but CO is low and PVR is elevated when fetal growth is restricted by preeclampsia. Others have postulated that women with preeclampsia have a greater degree of vascular inflammation, endothelial dysfunction, and metabolic abnormalities than those with FGR only.10 Patterns of fetal growth in pregnancyassociated hypertensive disorders are poorly understood, given the lack of prospective studies that compare longitudinal fetal growth between women with and without hypertension. Current evidence is conflicting and limited by several factors including retrospective design,14e16 use of birthweight as a proxy for fetal growth,12,14e18 and use of small for gestational age (SGA) birthweight as a proxy for FGR,12,14e16 and several studies were conducted in populations different from the current US pregnant population.14e16 Srinivas et al12 found that women diagnosed with preeclampsia were at increased risk of having a fetus with SGA,
defined as birthweight <10th percentile (adjusted odds ratio [AOR], 2.7; 95% confidence interval [CI], 1.94e3.86) or birthweight less than the fifth percentile (AOR, 4.3; 95% CI, 2.58e7.17). A retrospective European populationbased study found a 12% mean birthweight reduction, defined as the ratio between the observed and the expected birthweight, in severe preeclampsia and 23% in early-onset severe preeclampsia (<32 weeks’ gestation).14 Another large European study found a significant association of asymmetric SGA, defined as ponderal index (100 g/cm3) <10th or <2.5th percentile, with early-onset preeclampsia (<37 weeks’ gestation), whereas both small and large birthweights were seen in late-onset preeclampsia.15 Also, a large retrospective Chinese cohort study found associations of both small and large birthweights in women with gestational hypertension and preeclampsia, compared with normotensive women.16 A study conducted in 15 US centers found that birthweight at term was significantly lower by 60.7 g in women who developed preeclampsia
compared with the customized standard group (P <.01).18 It is important to note that birthweight reported in these studies is an index of size, not necessarily growth. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Study was a contemporaneous prospective multisite observational study that established standards of normal fetal growth for singleton gestations in a racially/ethnically diverse pregnant population.19 Importantly, that study excluded women with factors, such as medical comorbidities before entering pregnancy, adverse environmental exposures, and previous abnormal pregnancy outcomes, which potentially were associated with abnormal intrauterine growth. Our objectives were to establish fetal growth trajectories for estimated fetal weight (EFW) and individual fetal anthropometric parameters from the NICHD Fetal Growth Studies cohort in pregnancies complicated by hypertensive disorders of pregnancy compared with normotensive pregnancies and to determine the gestational timing of any potential differences. This research work was presented at the 37th annual meeting of the Society for MaternalFetal Medicine, Las Vegas, NV, 2017 (poster number 210).20
Materials and Methods Study protocol The study was based on data from the NICHD Fetal Growth Studiese Singletons, a prospective study conducted in 12 US health care centers between July 2009 and January 2013.19,21 Nonobese (body mass index [BMI] 19.0 to <30.0 kg/m2) women with spontaneous conceptions without medical comorbidities including chronic hypertension, adverse environmental exposures (smoking, alcohol, and illicit drugs), or recognized obstetrical risk factors for abnormal fetal growth were eligible for enrollment. To improve generalizability, women with a BMI 30.0e45.0 kg/m2 were also recruited, although the inclusion and exclusion criteria were not as strict, given
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that obesity is associated with many comorbidities as well as alterations in fetal growth.22 Recalled pregravid weight and self-reported height were used for the calculation of BMI at enrollment. Human subjects’ approval was obtained from all participating sites, the NICHD, and the data coordinating center. All women provided informed consent prior to any data collection. Of 2802 women enrolled, we excluded 168 who deactivated from the study (33 were lost to follow-up, 93 refused to continue, 29 moved, 9 had voluntary termination of the pregnancy, and 4 for other reasons), 17 ineligible after enrollment, 86 who had structural fetal abnormalities, 5 who had fetal chromosomal abnormalities, 11 with pregnancy loss <20 weeks’ gestation, 19 with fetal demise, and 29 with missing data, leaving 2467 who are included in the descriptive analysis (Table 1). For the analyses, we further excluded 5 women with severe gestational hypertension, given that their small number precluded meaningful analysis, leaving a total of 2462 pregnancies.
Sonographic population Ultrasound screening between 8 weeks 0 days and 13 weeks 6 days was performed to ensure dating consistency with the patient’s reported first day of the last menstrual period. Following a standardized ultrasound between 10 weeks 0 days and 13 weeks 6 days, women were randomized to 1 of 4 sonogram schedules, with 5 additional planned study visits (16e22, 24e29, 30e33, 34e37, and 38e41 gestational weeks). By design, this mixed longitudinal randomization scheme captured weekly fetal growth data without exposing women to weekly ultrasound examinations. Study sonographers underwent training and credentialing prior to enrollment. At each ultrasound, biometric measurements for biparietal diameter (BPD, outer to inner), humerus length (HL), and femur length (FL) using the linear function and for head circumference (HC) and abdominal circumference (AC) using the ellipse function were
performed using standard protocols and identical equipment. Study sonographers were blinded to both the gestational age at the measurements and the patient’s clinical condition. EFW was computed from HC, AC, and FL using a Hadlock formula.23 A detailed study protocol has been published elsewhere.19,21,24
Hypertensive groups Prospectively, the study protocol guidebooks instructed the research nurse abstractors to document the presence and severity of pregnancy-associated hypertensive disorders as recorded in the medical record. Diagnosis of pregnancyassociated hypertensive disorders was made by clinicians at participating centers following the 2002 American College of Obstetricians and Gynecologists (ACOG) criteria.13 Gestational hypertension was defined as elevated blood pressure (systolic blood pressure [SBP] 140 mm Hg or a diastolic blood pressure [DBP] 90 mm Hg) after 20 weeks of gestation without proteinuria in a women with previously normal blood pressure. Severe gestational hypertension was defined as gestational SBP 160 mm Hg or DBP 110 mm Hg without proteinuria. Preeclampsia was defined as newonset hypertension after 20 weeks with proteinuria (0.3 g of protein in a 24 hour urine specimen). The criteria for severe preeclampsia included SBP 160 mm Hg or DBP 110 mm Hg, proteinuria 5 g or >3 or greater on 2 random urine samples, oliguria <400 mL in 24 hours, cerebral or visual disturbances, pulmonary edema or cyanosis, epigastric or right upperquadrant pain, impaired liver function, thrombocytopenia, and fetal growth restriction.13 The postpartum discharge diagnoses were as listed in the medical record and abstracted by research nurses: mild gestational hypertension, severe gestational hypertension, mild preeclampsia, severe preeclampsia (including eclampsia or HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome) and unspecified hypertension (all were recorded as mild but
Original Research
lacked sufficient modifiers to differentiate between mild gestational hypertension and mild preeclampsia). For the present analysis, we grouped the hypertensive disorders in a hierarchical manner as severe preeclampsia, mild preeclampsia, severe gestational hypertension, mild gestational hypertension, and unspecified hypertension. Women without any hypertensive disorder recorded as a discharge diagnosis were categorized as normotensive.
Statistical analysis Baseline and clinical data were compared for participants by type of hypertensive disorder. Overall differences (P < .05) were determined using c2 or analysis of variance for categorical and continuous data, respectively. Where overall tests indicated significant differences across the no-hypertension and hypertension groups, pairwise c2 or Tukey’s studentized range test were used to determine significant differences between these groups. Fetal growth curves for the ultrasound biometric measures BPD, HC, AC, FL, and HL, and calculated EFW were generated for each hypertensive group (severe preeclampsia, mild preeclampsia, mild gestational hypertension, unspecified hypertension, and normotensive). The ultrasound biometric measures and EFW were log transformed to stabilize variance across gestational ages and to optimize approximations for the error structures.24 Linear mixed models with cubic splines for the fixed effects were used for the primary analysis to estimate specific fetal growth curves.25 Three-knot points (25th, 50th, and 75th percentiles) were selected at gestational ages that evenly split the distributions. Percentiles (fifth, 50th, and 95th) were estimated for EFW and each biometric parameter in the studied groups from the 11th to 40th week of gestation based on the assumed normal distribution of the random effects on error structure. The overall differences in the curves of EFW and each biometric measure for each group were calculated using a likelihood-ratio test. When the global
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Maternal characteristics among normotensive and pregnancy-associated hypertensive disorders Q6
Variables
Severe preeclampsia (n ¼ 32)
Mild preeclampsia (n ¼ 54)
Severe gestational hypertensiona (n ¼ 5 )
Mild gestational hypertension (n ¼ 63)
Unspecified hypertension (n ¼ 17)
Maternal age, y, mean SD
26.6 (6.0)
26.2 (5.8)
29.0 (6.8)
28.0 (5.5)
25.6 (5.4)
Normotensive (n ¼ 2296)
All (n ¼ 2467)
28.3 (5.4)
28.2 (5.5)
9 (28.1%)
14 (25.9%)
1 (20.0%)
22 (34.9%)
4 (23.5%)
634 (27.6%)
684 (27.7%)
Black/non-Hispanic
14 (43.8%)
22 (40.7%)
1 (20.0%)
25 (39.7%)
10 (58.8%)
602 (26.2%)
674 (27.3%)
Hispanic
6 (18.8%)
18 (33.3%)
1 (20.0%)
14 (22.2%)
3 (17.6%)
667 (29.1%)
709 (28.7%)
Asian
3 (9.4%)
2 (40.0%)
2 (3.2%)
393 (17.1%)
400 (16.2%)
Gravidity, n, %
.1360
1
15 (46.9%)
24 (44.4%)
2
8 (25.0%)
16 (29.6%)
3
9 (28.1%)
14 (25.9%)
3 (60.0%) 2 (40.0%)
28 (44.4%)
5 (29.4%)
729 (31.7%)
804 (32.6%)
18 (28.6%)
5 (29.4%)
713 (31.0%)
760 (30.8%)
17 (27.0%)
7 (41.2%)
854 (37.2%)
903 (36.6%)
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White/non-Hispanic
< .0001c
Parity, n, % 0
24 (75.0%)
39 (72.2%)
1
4 (12.5%)
10 (18.5%)
2
4 (12.5%)
5 (9.3%)
4 (80.0%) 1 (20.0%)
40 (63.5%)
10 (58.8%)
1040 (45.3%)
1157 (46.9%)
15 (23.8%)
4 (23.5%)
807 (35.1%)
840 (34.0%)
8 (12.7%)
3 (17.6%)
449 (19.6%)
470 (19.1%) < .0001d
Prepregnancy BMI, kg/m2, n, % <25.0
10 (31.3%)
15 (28.3%)
2 (40.0%)
20 (31.7%)
5 (31.3%)
1327 (58.2%)
1379 (56.3%)
25.0e30.0
13 (40.6%)
20 (37.7%)
2 (40.0%)
19 (30.2%)
4 (25.0%)
591 (25.9%)
649 (26.5%)
9 (28.1%)
18 (34.0%)
1 (20.0%)
24 (38.1%)
7 (43.8%)
361 (15.8%)
420 (17.2%)
Marital status, n, %e
.0011f
Not married
13 (40.6%)
22 (40.7%)
1 (20.0%)
21 (33.3%)
8 (47.1%)
559 (24.4%)
624 (25.3%)
Married or living with partner
19 (59.4%)
32 (59.3%)
4 (80.0%)
42 (66.7%)
9 (52.9%)
1735 (75.6%)
1841 (74.7%)
Less than high school
4 (12.5%)
8 (14.8%)
8 (12.7%)
1 (5.9%)
262 (11.4%)
283 (11.5%)
High school/equivalent
4 (12.5%)
14 (25.9%)
11 (17.5%)
6 (35.3%)
415 (18.1%)
450 (18.2%)
Some college/associate
11 (34.4%)
20 (37.0%)
3 (60.0%)
17 (27.0%)
6 (35.3%)
680 (29.6%)
737 (29.9%)
Bachelor’s degree
11 (34.4%)
7 (13.0%)
1 (20.0%)
19 (30.2%)
1 (5.9%)
548 (23.9%)
587 (23.8%)
2 (6.3%)
5 (9.3%)
1 (20.0%)
8 (12.7%)
3 (17.6%)
391 (17.0%)
410 (16.6%)
Education, n, %
.2239
Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
(continued)
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Postgraduate degree
.0081b < .0001b
Race/ethnicity, n, %
30.0
P value
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391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446
447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
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TABLE 1
Maternal characteristics among normotensive and pregnancy-associated hypertensive disorders (continued) Severe preeclampsia (n ¼ 32)
Variables Family income, n, %
Mild preeclampsia (n ¼ 54)
Severe gestational hypertensiona (n ¼ 5 )
Mild gestational hypertension (n ¼ 63)
Unspecified hypertension (n ¼ 17)
Normotensive (n ¼ 2296)
All (n ¼ 2467)
e
<$30,000 $30,000e74,999
.0899 6 (21.4%)
19 (39.6%)
15 (53.6%)
16 (33.3%)
3 (60.0%)
6 (12.5%) 7 (25.0%)
7 (14.6%)
Other
11 (34.4%)
27 (50.0%)
Private or managed care
21 (65.6%)
27 (50.0%)
17 (32.1%)
7 (41.2%)
566 (28.3%)
615 (28.6%)
14 (26.4%)
6 (35.3%)
617 (30.9%)
671 (31.2%)
270 (13.5%)
281 (13.1%)
5 (9.4%) 2 (40.0%)
17 (32.1%)
4 (23.5%)
544 (27.2%)
581 (27.0%)
22 (34.9%)
8 (47.1%)
840 (36.6%)
908 (36.8%)
41 (65.1%)
9 (52.9%)
1456 (63.4%)
1559 (63.2%)
Insurance, n, %
.2847 5 (100.0%)
Full-time employment/ student status, n, %e No Yes
.0689 5 (15.6%)
17 (31.5%)
1 (20.0%)
12 (19.0%)
2 (11.8%)
677 (29.5%)
714 (29.0%)
27 (84.4%)
37 (68.5%)
4 (80.0%)
51 (81.0%)
15 (88.2%)
1618 (70.5%)
1752 (71.0%)
e
Infant sex, n, %
.9368
Male
15 (46.9%)
26 (48.1%)
1 (20.0%)
30 (47.6%)
9 (52.9%)
1174 (51.4%)
1255 (51.1%)
Female
17 (53.1%)
28 (51.9%)
4 (80.0%)
33 (52.4%)
8 (47.1%)
1111 (48.6%)
1201 (48.9%)
35.9 (3.2)
38.8 (1.6)
39.3 (1.7)
39.2 (1.7)
Gestational age at delivery, wks, mean SDe
37.9 (2.4)
39.2 (1.4)
39.5 (1.1)
< .0001g
P values reported are for global tests. BMI, body mass index. The distribution of racial/ethnic groups was significantly different in the normotensive group compared with all other groups except severe preeclampsia. a
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Because of its small number, severe gestational hypertension was not included in statistical comparisons among hypertension groups; b Although the overall analysis of variance was significant, no pairwise comparisons indicated significant differences in age between groups at the P ¼ .05 level; c The distribution of parity categories was significantly different in the normotensive group compared with all other groups except unspecified hypertension; d The distribution of BMI categories was significantly different in the normotensive group than all other groups; e Not included in the totals are missing data: BMI (n ¼ 19); martial status (n ¼ 2); income (n ¼ 319, 299 from normotensive, 10 from mild gestational hypertension, 6 from mild preeclampsia, 4 from severe preeclampsia groups); full-time employment/student status (n ¼ 1); infant sex (n ¼ 11); and gestational age at delivery (n ¼ 12); f The proportion of those married or living with a partner was significantly different in the normotensive group than for all other groups except mild gestational hypertension; g Gestational age at delivery was significantly smaller in the severe preeclampsia group than that for all other hypertensive groups. Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
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P value
503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558
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test was significant (P < .05) for differences in the overall curves, week-specific differences were tested using the Wald test at each gestational week. Where the weekly global test was significant (P < .05) for differences among hypertensive groups, pairwise tests between hypertensive groups were performed. These tests were conducted on the estimated curves with and without adjustment for maternal characteristics: age, self-reported race/ethnicity (nonHispanic white, non-Hispanic black, Hispanic, and Asian or Pacific Islander), self-reported pregravid weight and height, parity (0, 1, and 2) , full-time employment/student status (yes/no), marital status (married/living as married vs not), insurance (private/ managed vs Medicaid/other), education, and infant sex. Education was analyzed categorically: less than high school, high school or equivalent, some college or associate degree, bachelor’s degree, and postgraduate degree. An analysis of covariance was used to analyze birthweight data, adjusting for the same variables described in previous text for the fetal growth trajectory models. All analyses were performed using SAS (version 9.4; SAS Institute Inc, Cary, NC) or R (version 3.1.2; http://www.Rproject.org).
Results Patient demographics Of the 2462 women eligible for analysis, 2296 (93.3%) were normotensive, 63 (2.6%) had mild gestational hypertension, 54 (2.2%) mild preeclampsia, 32 (1.3%) severe preeclampsia, and 17 (0.7%) unspecified hypertension. Maternal age varied across hypertension groups (global analysis P ¼.008), but no pairwise comparison was statistically significant (Table 1). The distribution of racial/ethnic groups was significantly different between the normotensive group and all other groups, except severe preeclampsia (P < .02 for pairwise comparisons). Parity was significantly different between the normotensive group and all other groups, except unspecified hypertension (P < .02 for pairwise comparisons).
Other maternal characteristics results are presented in Table 1. Compared with the other groups, normotensive women had the lowest obesity rate (15.8%). Women with severe preeclampsia delivered significantly earlier than women with other hypertensive conditions and those without hypertension (Table 1; global P <.0001). Birthweights of infants born to women without hypertension (mean, 3352.9 g, SD, 494.4 g) were significantly higher than the infant birthweights of women with severe preeclampsia (mean, 2297.2 g, SD, 741.0 g). Birthweight mean difference between these groups was e949.5 g (95% CI, e1117.8 to e781.2 g); P < .0001). In contrast, neonates born to women with mild hypertensive disorders had similar birthweights to those born to women with no hypertension (values of P > .05).
Fetal growth trajectories for EFW Fetal growth trajectories for EFW including the fifth, 50th, and 95th percentiles for the normotensive and hypertension groups were statistically different (global P < .0001) and remained significant after adjustment for confounders (Figure 1). Compared with fetuses of normotensive women, fetuses of women with severe preeclampsia had a median EFW significantly higher at 11 weeks’ gestation and became progressively smaller from 22 to 38 weeks’ gestation (Table 2). The median EFW difference for gestational age was 31 g at 22 weeks, 74 g at 28 weeks, 136 g at 32 weeks, and 474 g at 38 weeks (P < .008 for all weekly pairwise comparisons). Furthermore, the median percentage EFW difference for gestational age between these 2 groups was 6.5% at 22 weeks, 6.4% at 28 weeks, 7.2% at 32 weeks, and 15.0% at 38 weeks. By the third trimester, EFW curves in women with severe preeclampsia were characterized by flattening at the fifth and 50th percentiles and progressively separating from the fetal growth curves of women with no hypertension, mild gestational hypertension, and mild preeclampsia.
Median EFW growth trajectories did not differ significantly between the fetuses of normotensive women and those whose mother had mild preeclampsia (Table 2, P > .05 for all weekly pairwise comparisons). Compared with the normotensive group, fetuses of mothers with mild gestational hypertension exhibited a significantly lower median EFW at 11 weeks and from 22 to 25 weeks’ gestation (P < .04 for all weekly pairwise comparisons), but the difference was not statistically significant at later gestational ages.
Fetal growth trajectories for AC Growth curves for AC (Figure 2) were statistically significantly different between the fetuses of normotensive mothers and those of mothers with severe preeclampsia at 11 weeks, from 23 to 31 weeks, and from 33 to 37 weeks’ gestation (P < .04 for all weekly pairwise comparisons). Compared with fetuses of normotensive mothers, the median AC of fetuses whose mothers had severe preeclampsia was 4.9 mm, 6.3 mm, 11.9 mm, and 17.6 mm smaller at 22, 28, 34, and 37 weeks’ gestation, respectively (Table 3). The median percentage AC difference for gestational age was 2.8% at 22 weeks, 2.6% at 28 weeks, 3.9% at 34 weeks, and 5.3% at 37 weeks. AC growth in fetuses of mothers with mild preeclampsia differed only from 13 to 16 weeks’ gestation compared with normotensive mothers (Figure 2; P <.05 for all weekly pairwise comparisons), but the difference became not significant at later gestational ages (P > .05 for all weekly pairwise comparisons). As observed with EFW growth trajectory, AC was significantly smaller in the fetuses of mothers with mild gestational hypertension group compared with those of normotensive mothers from 13 to 16 weeks and from 23 to 27 weeks’ gestation (P < .04 for all weekly pairwise comparisons).
½F2
½T3 ½F1
½T2
Fetal growth trajectories for other individual biometric parameters Growth trajectories of all other biometric measurements, BPD, HC, FL, and HL (Figure 3, AeD), had scattered ½F3 weekly growth differences in the first
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Original Research
FIGURE 1
Distribution of EFW by hypertensive condition and gestation
From the NICHD Fetal Growth StudieseSingletons, the estimated fifth, 50th, and 95th percentiles are for fetal weight by hypertensive condition, as estimated from linear mixed models with log-transformed outcomes and cubic splines. EFW, estimated fetal weight; GA, gestational age. Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
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727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782
Original Research 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838
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TABLE 2
Estimated fetal weighta by hypertension group, n [ 2462 Median estimated fetal weight, g GA, wks
Normotensive (n ¼ 2296)
Severe preeclampsia (n ¼ 32)
Mild preeclampsia (n ¼ 54)
Mild gestational hypertension (n ¼ 63)
Unspecified hypertension (n ¼ 17)
11
44
48b
43
41b
44
12
55
56
55
53
55
13
69
69
71
68
70
14
88
86
90
86
89
15
111
109
113
109
113
16
140
139
142
137
143
17
175
174
177
171
179
18
218
215
219
211
222
19
269
261
268
259
271
20
328
314
326
315
328
21
395
374
392
379
b
392 b
463 543
22
472
441
469
454
23
558
518b
556
538b
24
655
b
605
654
634
b
632b
25
763
705b
765
741b
731b
26
883
818b
889
860
841b
27
1016
946b
1026
993
963b
28
1162
b
1088
1177
1139
1100b
29
1323
1242b
1343
1299
1254b
30
1500
1407b
1523
1473
1426b
31
1691
1580b
1716
1659
1616b
32
1893
1757b
1918
1856
1822b
2105
b
2128
2061
2044
b
2343
2272
2276
b
2560
2486
2510
b
33 34 35
2321 2536
1935 2109 2276
36
2748
2432
2780
2702
2732
37
2958
2571b
3005
2921
2923
3165
b
3237
3145
3062
38
2691
Computed from head circumference, abdominal circumference, and femur length; Value differed significantly from the no hypertension group (global and weekly pairwise P < .05, obtained by the Wald test with adjustment for maternal age, self-reported height and prepregnancy weight, parity, racial ethnic group, full-time job or student status, marital status, insurance, education, and infant sex). Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019. a
b
and second trimesters between the normotensive, severe preeclampsia, and the other hypertensive disorder groups.
Comment Principal findings Our analysis of the NICHD Fetal Growth StudyeSingletons found significant and
consistent reductions in fetal growth during the second and third trimesters among women who developed severe preeclampsia compared with normotensive pregnancies. With severe preeclampsia, EFW growth differences occurred consistently, beginning at 22 weeks’ gestation and continued through 38 weeks, with significantly smaller AC
measurements observed between 23 and 31 weeks and from 33 to 37 weeks’ gestation. The EFW differences were corroborated by birthweight, which was lower for the newborns of women who developed severe preeclampsia compared with women without hypertension. Our study demonstrated normal fetal growth patterns, except for temporal
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Original Research
FIGURE 2
Distribution of fetal AC by hypertensive condition and gestation web 4C=FPO
895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950
OBSTETRICS
From the NICHD Fetal Growth StudieseSingletons, the estimated fifth, 50th, and 95th percentiles are for fetal abdominal circumference by hypertensive condition, as estimated from linear mixed models with log-transformed outcomes and cubic splines. AC, abdominal circumference; GA, gestational age. Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
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951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006
Original Research 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062
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TABLE 3
Median abdominal circumference by hypertension group (n [ 2462) Median abdominal circumference, mm GA, wks
Normotensive (n ¼ 2296)
Severe preeclampsia (n ¼ 32)
Mild preeclampsia (n ¼ 54)
Mild Gestational hypertension (n ¼ 63)
Unspecified hypertension (n ¼ 17)
11
45.4
48.8a
44.1
44.4
45.5
12
55.7
56.6
55.9
54.4
56.1
13
66.8
65.8
68.3a
65.2a
67.4
76.4
a
a
79.2
a
91.2
a
103.2
14 15
78.4 90.3
80.8
a
88.2
93.0
a
76.5 88.2
16
102.3
100.7
104.7
17
114.3
113.1
116.0
111.9
115.0
18
126.2
125.2
127.0
123.6
126.7
19
138.1
136.7
138.0
135.2
138.2
20
149.9
147.6
149.3
146.7
149.4
21
161.5
158.0
160.6
158.1
160.2
22
172.9
168.0
171.9
169.4
170.7
23
184.1
177.9a
183.3
180.5a
24
195.0
187.8
a
194.7
191.4
a
190.6a
25
205.8
198.2a
206.1
202.2a
200.2a
26
216.4
209.0a
217.3
212.9a
209.7a
27
226.9
220.1a
228.6
223.6a
219.4a
28
237.6
231.3
a
239.8
234.5
229.4a
29
248.4
242.5a
251.0
245.5
240.0a
30
259.4
253.5a
262.1
256.7
251.2a
31
270.5
263.9a
273.1
268.0
262.8a
32
281.6
273.6
283.9
279.2
274.8
33
292.4
282.7a
294.4
290.1
287.0
303.0
291.1
a
304.5
300.7
299.4
298.9
a
314.5
310.8
311.2
a
34 35
312.9
100.0
180.8
36
322.4
306.5
324.2
320.4
321.5
37
331.4
313.8a
334.1
329.8
329.2
38
340.1
321.1
344.3
339.0
333.1
Value differed significantly from the no hypertension group (global and weekly pairwise P < .05, obtained by the Wald test with adjustment for maternal age, self-reported height and prepregnancy weight, parity, racial ethnic group, full-time job or student status, marital status, insurance, education, and infant sex). Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019. a
differences on AC growth from 13 to 16 weeks’ gestation, in women who developed mild preeclampsia similar to those women without hypertension, suggesting that uteroplacental function is preserved to a greater extent in this milder form of preeclampsia. Women who developed mild gestational hypertension pregnancies had a transitory
deceleration of EFW and AC growth in the second trimester but subsequently normalized fetal growth at later gestational ages.
Results in context of other studies Our results demonstrate different fetal growth patterns across the hypertensive groups. Although fetal growth patterns
in pregnancy-associated hypertensive disorders have not been previously evaluated in a longitudinal fashion, abnormalities of neonatal size associated with pregnancy-associated hypertensive disorders have been previously reported with conflicting results. For example, Srinivas et al12 showed a higher risk for SGA (birthweight <10th percentile for
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Original Research
FIGURE 3
Distribution of fetal biometric measurements by hypertensive condition and gestation
web 4C=FPO
1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174
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From the NICHD Fetal Growth StudieseSingletons, the estimated fifth, 50th, and 95th percentiles for fetal biparietal diameter, head circumference, femur length, and humerus length by hypertensive condition (AeD) were estimated from linear mixed models with log-transformed outcomes and cubic splines. GA, gestational age. Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
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1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230
Original Research 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286
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OBSTETRICS
gestational age) among women with severe preeclampsia compared with normotensive women (AOR, 1.87; 95% CI, 1.11e2.97). A European study demonstrated that birth size was lower with increasing preeclampsia severity.14 Others have reported an association between small as well as large birthweights with preeclampsia and gestational hypertension.15,16 Our study showed an abnormal asymmetric fetal growth pattern in women with severe preeclampsia. In this respect, Rasmussen et al15 reported at increased risk for asymmetric SGA with early-onset preeclampsia (<37 weeks).
Biological mechanisms Fetal growth depends on the efficient transport of nutrients in the uteroplacental circulation. Reduced uteroplacental blood flow is a result of placental vascular pathologic changes highly associated with FGR and preeclampsia.5e11 Impaired spiral arterial remodeling and deficient extravillous trophoblast invasion are highly characteristic abnormalities of these disorders.5e11 Deficient remodeling might be precipitated by inadequate histotrophic nutrition in the first trimester,11 excessive apoptosis in the placental bed,26 reducing the number of extravillous trophoblast cells,5,6,9,11 or failure of interstitial trophoblasts to penetrate the arterial wall.9 A greater gradient of aberrant remodeling at the junctional zone and myometrial segment are highly associated with preeclampsia with FGR.11 Atherotic changes with accumulation of foam cells and arterial narrowing distal to the junctional zone significantly restricts blood flow to the placenta, leading to oxidative stress, endoplasmic reticulum stress, proinflammatory cytokines production, and apoptosis.5,6,9,11 Reduced volume and surface area of the placenta are characteristic features of pregnancies with FGR.11 Downregulated function of the protein kinase B/mechanistic target of rapamycin signaling pathway reduces placental growth and reduces activity of placental transporters in FGR cases.27,28 Unfolded protein response pathways are activated in
response to hypoxic environment.28,29 A greater degree of activation of unfolded protein response stimulates the release of proinflammatory cytokines and apoptosis implicated in endothelial cell activation, a pathognomonic feature of preeclampsia with FGR, but not of FGR alone.28,29 Emerging findings from genetic studies further elucidated pathogenic mechanisms on preeclampsia and FGR.30e41 For instance, Pleckstrin homology like domain family A member 2 that inhibits growth is upregulated, whereas mesoderm specific transcript that promotes growth is downregulated in FGR placentas.33,34 A recent meta-analysis identified 20 miRs associated with cell death/ apoptosis and cell movement in placentas with preeclampsia.35 Other studies have identified miR-20b, miR151, miR-524-3p, and miR-34c-5p associated with angiogenic pathways in preeclampsia.36 Four genes associated with growth and metabolism (IGFBP-1, PRL, LEP, and CHR) have been found in FGR placentas by messenger RNA transcriptome analysis.37,38 Microarray studies in preeclampsia have identified gene expression of LEP, HTRA1, INHA, INHBA, PAPP2, and FSTL3 involved in cell signaling, lipid response, apoptosis, hypoxia, immune, inflammation, and oxidative stress pathways.30,39e41 The expression of a group of 10 genes (LEP, FTRA4, FSTL3, LHD, TREM1, ENG, PAPP2, FLT-1, IHBA, and INHBA) has been found to be higher in early-onset preeclampsia (<34 weeks) than later-onset preeclampsia and also higher in late-onset preeclampsia with SGA than without it.32
Clinical implications Investigators debate whether preeclampsia with and without FGR are distinct entities.10e12,14e16 Our study provides new insights about the relationship between fetal growth and pregnancyassociated hypertensive disorders. We highlight the following findings of clinical relevance. First abnormal fetal growth is identifiable early in gestation in severe preeclampsia and likely precedes its clinical manifestations. Second,
a pattern of asymmetric fetal growth, primarily driven by diminished AC growth, is characteristic of severe preeclampsia. Delayed AC growth begins sooner than the physiological acceleration of AC growth (27e31 weeks) described in normal pregnancies,42 preventing the fetus from achieving normal growth and development. The observed differences of AC growth between normotensive pregnancies and those with severe preeclampsia are corroborated with neonatal size differences noted among these groups. And third, fetal growth is predominantly normal in mild hypertensive disorders, suggesting preserved placental function in these pregnancies. The presence or absence of fetal growth abnormality distinguished in the studied pregnancy-associated hypertensive disorders might depend on a variety of maternal and placental vascular abnormalities reported since early gestation, from severe deficiency of spiral artery remodeling with excessively impaired extravillous trophoblastic migration and formation of atherotic lesions leading to placental infarcts (preeclampsia with FGR) to minimal or inexistent placental involvement (preeclampsia without FGR).11 Recently described distinctive maternal cardiovascular profiles17 between pregnancies complicated by preeclampsia only (high CO and low PVR), FGR only (unaltered CO, high PVR), and preeclampsia with FGR (low CO and high PVR) might have repercussions on uteroplacental blood flow. Compared with normal pregnancies, placental perfusion calculated by magnetic resonance imaging has been found to be significantly lower in women with early-onset preeclampsia (<34 weeks) but significantly higher in women with late-onset preeclampsia.43 The reduction of placental perfusion was more drastic with the presence of FGR. A recent large European study found that the risk of SGA (birthweight percentile of <2.5% of birthweight zscore stratified by infant sex) was almost 3 times higher in women with preeclampsia with a small placenta (lowest 10% of placenta weight) compared with
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normotensive women with small placenta weight.44 Conversely, the association of the highest 10% of placenta weight and LGA (97.5th percentile) was stronger in the preeclampsia group than in the controls. In a recent prospective case-control study, women with preeclampsia and FGR, as compared with women with preeclampsia without FGR, had more severe clinical manifestations, more placental morphologic abnormalities, and lower placental weight and thickness.45 Conversely, decidual vasculopathy was similar in preeclampsia with and without FGR. This suggests that changes in the vascular bed are characteristic of preeclampsia, whereas placental villus abnormalities are more strongly correlated with FGR, but both are highly prevalent in severe preeclampsia. Altogether, preeclampsia is manifested in 2 well-defined clinical phenotypes marked by the presence or absence of FGR, which is ultimately determined by the degree of maternal/placental hemodynamic abnormalities as well as placental functional and structural changes. Our study support the association of poor fetal growth with severe preeclampsia and the lack of fetal growth abnormality in mild preeclampsia.
Research implications This study is unique because the analyzed cohort is composed of a lowrisk population highly representative of the US contemporaneous pregnant population. With this prospective observational design, we were able to identify the timing in gestation when changes of fetal growth occurred, the progression of these changes throughout pregnancy, and the temporary association of fetal growth with hypertensive disorders. The reduction of fetal growth identified in women with severe preeclampsia is in contrast with the similarity of fetal growth patterns observed between women with mild hypertensive disorders and normotensive women. Further investigation is necessary to elucidate the mechanisms that elicit development of preeclampsia with and without FGR.
Our findings prompt the investigation to determine whether the elaborated fetal growth charts for pregnancies later complicated by severe preeclampsia, perhaps in association with biomarkers and other sonographic parameters, may be used effectively to predict the later onset of clinically evident disease. We also highlight the need to determine fetal growth velocities in normotensive vs pregnancy-associated hypertensive disorders and their association with neonatal size and pregnancy outcomes.
Strengths and limitations Our study is strengthened by the prospective design describing longitudinal patterns of fetal growth as well as individual anthropometric parameters in pregnancies complicated by gestational hypertensive disorders in a demographically and racially/ethnically diverse US obstetrical population. Our data collection used a standardized protocol across the 12 centers. The sonographic examinations were performed by experienced and certified sonographers, and the methodology used to analyze the data has been previously validated.24 Although we included a subgroup of obese women (BMI, 30.0e45.0 kg/m2) with other underlying chronic medical conditions such as chronic hypertension and maternal/fetal risks factors were excluded. In addition, our findings remain significant after controlling for major confounders. We also acknowledge several limitations. Information on the characteristics used to define the hypertensive categories was not collected. However, we believe that our categories are clinically relevant because these were the diagnoses that were used in clinical practice. This study predated the widespread implementation of the new 2013 ACOG criteria for the diagnosis and classification of preeclampsia.46 It is believed unlikely that use of the newer classification system would significantly alter our findings. In 2016, Kallela et al47 reanalyzed the diagnosis of preeclampsia from a nationwide Finnish database using both the ACOG 2002 and 2013 criteria. The number of women diagnosed with preeclampsia increased only
Original Research
0.8% (1457 vs 1447) when the new 2013 criteria were applied. Possible biases can exist in the diagnosis assignment. Classification of our patients was based on the discharge diagnosis summaries from each participating center and lacked standardization across all centers. Any potential misclassification is likely to be nondifferential, resulting in a bias toward the null. The low incidence rates of hypertensive disorders in pregnancy in our cohort likely reflects a healthy pregnant population; however, the small sample size in these groups could still potentially result in type II errors. In addition, we did not observe individual changes in growth at every gestational week, so that differences in measurements per week are extrapolated. The linear mixed models with cubic splines for the fixed effects are flexible enough to allow for a robust calculation of growth at any point in gestation.
Conclusions This is the first prospective longitudinal study of fetal growth trajectories in pregnancy-associated hypertensive disorders compared with normotensive pregnancies in a low risk, demographically diverse US pregnant population. Compared with normotensive pregnancies, diminished EFW and AC growth was identifiable as early as 22 and 23 weeks of gestation, respectively, in women with severe preeclampsia. These midesecond-trimester fetal growth abnormalities likely anticipate clinical manifestations of severe preeclampsia. We also highlight the similar fetal growth curves in mild pregnancy-associated hypertensive disorders compared with normotensive women. n Acknowledgment This study was registered at ClinicalTrials.gov with the identifier number of NCT00912132.
References 1. American College of Obstetricians and Gynecologists. Gestational hypertension and preeclampsia. ACOG Practice bulletin no. 202. Obstet Gynecol 2019;133:e1e25. 2. Hauth JC, Ewell MG, Levine RJ, et al. Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for
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1455 Preeclampsia Prevention Study Group. Obstet 1456 Gynecol 2000;95:24–8. 1457 3. Abalos E, Cuesta C, Grosso AL, Chou D, 1458 Say L. Global and regional estimates of pre1459 eclampsia and eclampsia: a systematic review. 1460 Eur J Obstet Gynecol Reprod Biol 2013;170: 1–7. 1461 4. Saudan P, Brown MA, Buddle ML, Jones M. 1462 Does gestational hypertension become pre1463 eclampsia? Br J Obstet Gynaecol 1998;105: 1464 1177–84. 1465 5. Brosens I, Brosens JJ, Muter J, Puttermans P, Benagliano G. Preeclampsia: the role of 1466 persistent endothelial cells in uteroplacental ar1467 Q4 teries. Am J Obstet Gynecol, in press. 1468 6. Labarrere CA, DiCarlo HL, Bammerlin E, et al. 1469 Failure of physiologic transformation of spiral 1470 arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the 1471 placenta. Am J Obstet Gynecol 2017;216:287. 1472 e1–16. 1473 7. Steegers EA, von Dadelszen P, Duvekot JJ, 1474 Pijnenborg R. Pre-eclampsia. Lancet 2010;376: 1475 631–44. 8. Moll W, Nienartowicz A, Hees H, Wrobel KH, 1476 Lenz A. Blood flow regulation in the uteropla1477 cental arteries. Trophoblast Res 1988;3:83–96. 1478 9. Lyall F, Robson SC, Bulmer JN. Spiral artery 1479 remodeling and trophoblastic invasion in pre1480 eclampsia and fetal growth restriction. Hypertension 2013;62:1046–54. 1481 10. Ness RB, Sibai BM. Shared and disparate 1482 components of the pathophysiologies of fetal 1483 growth restriction and preeclampsia. Am J 1484 Obstet Gynecol 2006;195:40–9. 1485 11. Burton GJ, Jauniaux E. Pathophysiology of placental-derived fetal growth restriction. Am J 1486 Obstet Gynecol 2018;218:S745–61. 1487 12. Tay J, Foo L, Masini G, et al. Early and late 1488 preeclampsia are characterized by high cardiac 1489 output, but in the presence of fetal growth re1490 striction, cardiac output is low: insights from a prospective study. Am J Obstet Gynecol 1491 Q5 2018;218:517.e1–12. 1492 13. Srinivas SK, Edlow AG, Neff PM, 1493 Sammel CM, Elovitz MA. Rethinking IUGR in 1494 preeclampsia: dependent or independent of 1495 maternal hypertension? J Perinatol 2009;29: 680–4. 1496 14. American College of Obstetricians and Gy1497 necologists. Diagnosis and management of 1498 preeclampsia and eclampsia. ACOG Practice 1499 bulletin no. 33. Obstet Gynecol 2002;99: 1500 159–67. rd RA, Vatten LJ, Nilsen ST, 15. Ødega 1501 Salvessen KA, Austgulen R. Preeclampsia and 1502 fetal growth. Obstet Gynecol 2000;96:950–5. 1503 16. Rasmussen S, Irgens LM. Fetal growth and 1504 body proportion in preeclampsia. Obstet 1505 Gynecol 2003;101:575–83. 17. Xiong X, Mayes D, Demianczuk N, et al. 1506 Impact of pregnancy-induced hypertension on 1507 fetal growth. Am J Obstet Gynecol 1999;180: 1508 207–13. 1509 18. Gardosi J, Francis A. A customized standard 1510 to assess fetal growth in a US population. Am J Obstet Gynecol 2009;201:25.e1–7.
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19. Buck Louis GM, Grewal J, Albert PS, et al. Racial/ethnic standards for fetal growth: the NICHD Fetal Growth Studies. Am J Obstet Gynecol 2015;213:449.e1–41. 20. Mateus J, Newman R, Kim S, et al. Fetal growth patterns in hypertensive disorders in pregnancy: the NICHD Fetal Growth Studies. Am J Obstet Gynecol 2017;216:S134. 21. Grewal J, Grantz KL, Zhang C, et al. Cohort profile: NICHD Fetal Growth StudieseSingletons and Twins. Int J Epidemiol 2018;47:25e25l. 22. Zhang C, Hediger ML, Albert PS, et al. Association of maternal obesity with longitudinal ultrasonographic measures of fetal growth: findings from the NICHD Fetal Growth Studies. JAMA Pediatr 2018;172:24–31. 23. Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK. Estimation of fetal weight gain with the use of head, body, and femur measurements: a prospective study. Am J Obstet Gynecol 1985;151:333–7. 24. Hediger ML, Fuchs KM, Grantz KL, et al. Ultrasound quality assurance for singletons in the National Institute of Child Health and Human Development Fetal Growth Studies. J Ultrasound Med 2016;35:1725–33. 25. Pincheiro JC, Bates DM. Mixed-effects models in S and S-plus. New York: Springer ScienceeBusiness Media; 2000. 26. Kadyrov M, Schmitz C, Black S, Kaufmann P, Huppertz B. Pre-eclampsia and maternal anemia display reduced apoptosis and opposite invasive phenotypes of extravillous trophoblast. Placenta 2003;24:540–8. 27. Roos S, Jansson N, Palmberg I, Saljo K, Powell TL, Jansson T. Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. J Physiol 2007;582: 449–59. 28. Yung HW, Calabrese S, Hynx D, et al. Evidence of placental translation inhibition of endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol 2008;173:451–62. 29. Yung HW, Cox M, Tissot Van Patot M, Burton GJ. Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non-native women at high altitude. FASEB J 2012;26:1970–81. 30. Nishizawa H, Ota S, Suzuki M, et al. Comparative gene expression profiling of placentas from patients with severe pre-eclampsia and unexplained fetal growth restriction. Reprod Biol Endocrinol 2011;9:107. 31. Whitehead CL, Walker SP, Ye L, et al. Placental specific mRNA in the maternal circulation are globally dysregulated in pregnancies complicated by fetal growth restriction. J Clin Endocrinol Metab 2013;98:E429–36. 32. Cox B, Leavey K, Nosi U, Wong F, Kingddom. Placental trancriptome in development and pathology: expression, function, and methods of analysis. Am J Obstet Gynecol 2015;231(Suppl 4):S138–51. 33. McMinn J, Wei M, Schupf N, et al. Unbalanced placental expression of imprinted genes
in human intrauterine growth restriction. Placenta 2006;27:540–9. 34. Diplas AI, Lambertini L, Lee MJ, et al. Differential expression of imprinted genes in normal and IUGR human placentas. Epigenetics 2009;4:235–40. 35. Betoni JS, Derr K, Pahl MC, et al. MicroRNA analysis in placentas from patients with preeclampsia: comparison of new and published results. Hypertens Pregnancy 2013;32:321–39. 36. Wang W, Feng L, Zhang H, et al. Preeclampsia up-regulates angiogenesisassociated microRNA (ie,miR-17, -20a, and -20b) that target ephrin B2 and EPHB4 in human placenta. J Clin Endocrinol Metab 2012;97: 1051–9. 37. Struwe E, Berzi G, Schild R, et al. Microarray analysis of placental tissue in intrauterine growth restriction. Clin Endocrinol (Oxf) 2010;72:241–7. 38. McCarthy C, Cotter FE, McElwaine S, et al. Altered gene expression patterns in intrauterine growth restriction: potential role of hypoxia. Am J Obstet Gynecol 2007;196:1–6. 39. Tsai S, Hardison NE, James A, et al. Transcriptional profiling of human placentas from pregnancies complicated by preeclampsia reveals dysregulation of sialic acid acetylesterase and immune signaling pathways. Placenta 2011;32:175–82. 40. Meng T, Chen H, Sun M, Wang H, Zhao G, Wang X. Identification of differential gene expression profiles in placentas form preeclamptic pregnancies versus normal pregnancies by DNA microarrays. OMICS 2012;16:301–11. 41. Nishizawa H, Pryor-Koishi K, Kato T, Kowa H, Kurashashi H, Udagawa Y. Microarray analysis of differential expressed fetal genes in placental tissue derived from early and late onset severe pre-eclampsia. Placenta 2007;28: 487–97. 42. Grantz KL, Kim S, Grobman W, et al. Fetal growth velocity: the NICHD Fetal Growth Studies. Am J Obstet Gynecol 2018;219:285. e1–36. 43. Sohberg S, Mulic-Lutvica A, Lindgren P, Ortiz-Nieto F, Wikström AK, Wikström J. Placental perfusion in normal pregnancy and early and late preeclampsia: a magnetic resonance imaging study. Placenta 2014;35:202–6. 44. Eskild A, Romundstad PR, Vatten L. Placental weight and birthweight: does the association differ between pregnancies with and without preeclampsia? Am J Obstet Gynecol 2009;201:595.e1–5. 45. Milosevic-Stevanovic J, Krstic M, Radovic-Janosevic D, Stefanovic M, Antic V, Djordjevic I. Preeclampsia with and without intrauterine growth restriction-Two pathogenetically different entities? Hypertens Pregnancy 2016;35:573–82. 46. American College of Obstetricians and Gynecologists. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013:1122–31.
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47. Kallela J, Jääskeläinen T, Kortelainen E, et al. The diagnosis of pre-eclampsia using the revised classifications in the Finnish Preeclampsia Consortium (FINNPEC) cohort. BMC Pregnancy Childbirth 2016;16:221.
Author and article information From the Division of Maternal-Fetal Medicine, Medical University of South Carolina, Charleston, SC (Drs Mateus and Newman); the Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (Drs Zhang, Pugh, Albert, and Grantz and Mr Grewal, and Mr Kim); the Feinberg School of Medicine, Northwestern University, Chicago, IL (Dr Grobman); the Center for Women’s Reproductive Health, University of Alabama at Birmingham, Birmingham, AL (Dr Owen); the Division of Maternal-Fetal Medicine, Department of Obstetrics and
Gynecology, Christiana Hospital, Newark, DE (Dr Sciscione); the Columbia University Medical Center, New York, NY (Dr Wapner); the New York Presbyterian Queens, Flushing (Dr Skupski), and Weill Cornell School of Medicine, New York, NY (Dr Skupski); the Women and Infants Hospital of Rhode Island, Providence, Rhode Island (Dr Chien); the University of California, Irvine, and Long Beach Memorial Medical Center/Miller Children’s Hospital Irvine, CA (Dr Wing); Saint Peter’s University Hospital, New Brunswick, NJ (Dr Ranzini); MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH (Dr Ranzini); the Miller Children’s and Women’s Hospital, Long Beach, CA (Dr Nageotte ); and the Prospective Group, Inc, contractor for the Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (Dr Gerlanc). Received Dec. 28, 2018; revised May 30, 2019; accepted June 12, 2019.
Original Research
This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Q9 Health, and included American Recovery and Reinvestment Act funding (contract numbers HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275 200800003IC, HHSN275200800014C, HHSN275 200800012C, HHSN275200800028C, and HHSN275201000009C). Dr Grantz, Mr Grewal, Dr Albert, Mr Kim, Dr Zhang, and Dr Buck Louis are US federal government investigators. Dr Wing has been a consultant for Parsagen, for which she received no compensation. The Q2 other authors report no conflict of interest. Presented the 37th annual meeting of the Society for Maternal-Fetal Medicine, Las Vegas, NV, 2017, as poster 210. Corresponding author: Julio Mateus, MD, PhD. [email protected]
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1679 1680 Q8 Supplemental Material 1681 1682 1683 GLOSSARY OF TERMS 1684 1685 Cubic splines: cubic transformation to test the relationship between the predictor(s) and outcome(s). Produces flexible functions with robust 1686 behavior at the tails of predictor distributions, resulting in smooth appearance of the curve. 1687 Global tests: used to analyze groups of interrelated variables. The global test establishes the overall statistical difference among the 1688 analyzed variables. 1689 Likelihood ratio test: used to compare the goodness of fit of 2 statistical models that are members of a hierarchical class (the terms more 1690 complex and less complex are well defined). 1691 Linear mixed models: statistical techniques used to analyze correlated data accounting for fixed and random effects. These models are 1692 optimal to assess longitudinal data, are appropriate for small sample sizes and unbalanced sample size groups, and account for auto1693 correlation of repeated measurements. 1694 Three-knot points: the range of values of the predictor variable is subdivided evenly using 3-knot points. Separate regression lines or 1695 curves are fit between the knots producing a smooth appearance. 1696 Wald test: used to test the null hypothesis of a set of variables in a model. Variables that fail to reject the null hypothesis can be removed 1697 from the model because it will not harm substantially the fit of the model. 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 1.e16 American Journal of Obstetrics & Gynecology MONTH 2019 FLA 5.6.0 DTD YMOB12749_proof 3 July 2019 10:56 pm ce
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Fetal growth patterns in pregnancy-associated hypertensive disorders: NICHD Fetal Growth Studies Q10
Q1
Julio Mateus, MD, PhD; Roger B. Newman, MD; Cuilin Zhang, MD, PhD; Sarah J. Pugh, PhD; Jagteshwar Grewal; Sungduk Kim; William A. Grobman, MD; John Owen, MD; Anthony C. Sciscione, DO; Ronald J. Wapner, MD; Daniel Skupski, MD; Edward Chien, MD; Deborah A. Wing, MD; Angela C. Ranzini, MD; Michael P. Nageotte, MD; Nicole Gerlanc, PhD; Paul S. Albert, PhD; Katherine L. Grantz, MD, MS
BACKGROUND: Fetal growth patterns in pregnancy-associated hypertensive disorders is poorly understood because prospective longitudinal data are lacking. OBJECTIVE: The objective of the study was to compare longitudinal fetal growth trajectories between normotensive women and those with pregnancy-associated hypertensive disorders. STUDY DESIGN: This is a study based on data from a prospective longitudinal cohort study of fetal growth performed at 12 US sites (2009e2013). Project gestational age was confirmed by ultrasound between 8 weeks 0 days and 13 weels 6 days, and up to 6 ultrasounds were performed across gestation. Hypertensive disorders were diagnosed based on 2002 American College of Obstetricians and Gynecologists guidelines and grouped hierarchically as severe preeclampsia (including eclampsia or HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome), mild preeclampsia, severe gestational hypertension, mild gestational hypertension, or unspecified hypertension. Women without any hypertensive disorder constituted the normotensive group. Growth curves for estimated fetal weight and individual biometric parameters including biparietal diameter, head circumference, abdominal circumference, and femur and humerus length were calculated for each group using linear mixed models with cubic splines. Global and weekly pairwise comparisons were performed between women with a hypertensive disorder compared with normotensive women to analyze differences while adjusting for confounding variables. Delivery gestational age and birthweights were compared among groups.
P
regnancy-associated hypertensive disorders including preeclampsia and gestational hypertension are major contributors to severe maternal and perinatal morbidity and mortality.1 Preeclampsia occurs in 4% to 8% of pregnant women while gestational
Cite this article as: Mateus J, Newman RB, Zhang C, et al. Fetal growth patterns in pregnancy-associated hypertensive disorders: NICHD Fetal Growth Studies. Am J Obstet Gynecol 2014;xxx;xx-xx. 0002-9378/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajog.2019.06.028
RESULTS: Of 2462 women analyzed, 2296 (93.3%) were normoten-
sive, 63 (2.6%) had mild gestational hypertension, 54 (2.2%) mild preeclampsia, 32 (1.3%) severe preeclampsia, and 17 (0.7%) unspecified hypertension. Compared with normotensive women, those with severe preeclampsia had estimated fetal weights that were reduced between 22 and 38 weeks (all weekly pairwise values of P < .008). Women with severe preeclampsia compared with those without hypertension also had significantly smaller fetal abdominal circumference between 23e31 and 33e37 weeks’ gestation (weekly pairwise values of P < .04). Scattered weekly growth differences were noted on other biometric parameters between these 2 groups. The consistent differences in estimated fetal weight and abdominal circumference were not observed between women with other hypertensive disorders and those who were normotensive. Women with severe preeclampsia delivered significantly earlier (mean gestational age 35.9 3.2 weeks) than the other groups (global P < .0001). Birthweights in the severe preeclampsia group were also significantly lower (mean e949.5 g [95% confidence interval, e1117.7 to e781.2 g]; P < .0001) than in the normotensive group. CONCLUSION: Among women with pregnancy-associated hypertensive disorders, only those destined to develop severe preeclampsia demonstrated a significant and consistent difference in fetal growth (ie, smaller estimated fetal weight and abdominal circumference) when compared with normotensive women. Key words: biometric parameters, fetal growth trajectory, gestational
hypertension, preeclampsia, pregnancy-associated hypertensive disorders
hypertension, often viewed as a transitory condition, progresses to preeclampsia in almost half of affected pregnancies.2e4 Failure of deep placentation is a central pathophysiologic feature of new-onset hypertension in pregnancy.5e9 Impaired physiological transformation of spiral arteries seen in deep placentation disorders is characterized by poor trophoblastic invasion, persistent endothelial cells, arterial endothelial activation, and frequently acute atherosis5,6 leading to utero-placental hypoperfusion, oxidative stress, intravascular inflammation, and angiogenic imbalance.5e9 The association of fetal growth restriction (FGR) and pregnancy-associated hypertensive disorders is complex, but
has mainly been attributed to placental vascular dysfunction, a common pathologic feature shared by both disorders.5,6,10,11 Preeclampsia is associated with FGR; however, fetal growth remains normal in most pregnancies complicated by this disorder.10,11,12e16 Severe placental abnormalities in- Q3 cluding excessive villous regression and extensive infarction secondary to atherosis are predominant in pregnancies complicated by FGR.11 On the other hand, placental involvement is minimal and fetal growth has been found to be unaffected in pregnancies with milder manifestations of the disease.11 Tay et al17 demonstrated recently that compared with
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AJOG at a Glance Why was this study conducted? To establish fetal growth trajectories in pregnancy-associated hypertensive disorders. To determine gestational timing for any differences of fetal growth in women with pregnancy-associated hypertensive disorders compared with normotensive women. Key findings Women with severe preeclampsia demonstrated reduced estimated fetal weights and abdominal circumferences from as early as 22e23 weeks’ gestation compared with women without hypertension. Fetal growth was similar between the mild preeclampsia and normotensive groups. Fetuses of women with mild gestational hypertension had transitory fetal growth delays that normalized by the third trimester. What does this add to what is known? Women destined to develop severe preeclampsia experienced persistent reduction in fetal growth, with significant divergence from normotensive pregnancies as early as 22 weeks’ gestation. Our study confirms reductions in fetal growth are related to disease severity.
normotensive pregnancies, maternal cardiac output is high and peripheral vascular resistance (PVR) is low in women with preeclampsia without FGR, but CO is low and PVR is elevated when fetal growth is restricted by preeclampsia. Others have postulated that women with preeclampsia have a greater degree of vascular inflammation, endothelial dysfunction, and metabolic abnormalities than those with FGR only.10 Patterns of fetal growth in pregnancyassociated hypertensive disorders are poorly understood, given the lack of prospective studies that compare longitudinal fetal growth between women with and without hypertension. Current evidence is conflicting and limited by several factors including retrospective design,14e16 use of birthweight as a proxy for fetal growth,12,14e18 and use of small for gestational age (SGA) birthweight as a proxy for FGR,12,14e16 and several studies were conducted in populations different from the current US pregnant population.14e16 Srinivas et al12 found that women diagnosed with preeclampsia were at increased risk of having a fetus with SGA,
defined as birthweight <10th percentile (adjusted odds ratio [AOR], 2.7; 95% confidence interval [CI], 1.94e3.86) or birthweight less than the fifth percentile (AOR, 4.3; 95% CI, 2.58e7.17). A retrospective European populationbased study found a 12% mean birthweight reduction, defined as the ratio between the observed and the expected birthweight, in severe preeclampsia and 23% in early-onset severe preeclampsia (<32 weeks’ gestation).14 Another large European study found a significant association of asymmetric SGA, defined as ponderal index (100 g/cm3) <10th or <2.5th percentile, with early-onset preeclampsia (<37 weeks’ gestation), whereas both small and large birthweights were seen in late-onset preeclampsia.15 Also, a large retrospective Chinese cohort study found associations of both small and large birthweights in women with gestational hypertension and preeclampsia, compared with normotensive women.16 A study conducted in 15 US centers found that birthweight at term was significantly lower by 60.7 g in women who developed preeclampsia
compared with the customized standard group (P <.01).18 It is important to note that birthweight reported in these studies is an index of size, not necessarily growth. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Study was a contemporaneous prospective multisite observational study that established standards of normal fetal growth for singleton gestations in a racially/ethnically diverse pregnant population.19 Importantly, that study excluded women with factors, such as medical comorbidities before entering pregnancy, adverse environmental exposures, and previous abnormal pregnancy outcomes, which potentially were associated with abnormal intrauterine growth. Our objectives were to establish fetal growth trajectories for estimated fetal weight (EFW) and individual fetal anthropometric parameters from the NICHD Fetal Growth Studies cohort in pregnancies complicated by hypertensive disorders of pregnancy compared with normotensive pregnancies and to determine the gestational timing of any potential differences. This research work was presented at the 37th annual meeting of the Society for MaternalFetal Medicine, Las Vegas, NV, 2017 (poster number 210).20
Materials and Methods Study protocol The study was based on data from the NICHD Fetal Growth Studiese Singletons, a prospective study conducted in 12 US health care centers between July 2009 and January 2013.19,21 Nonobese (body mass index [BMI] 19.0 to <30.0 kg/m2) women with spontaneous conceptions without medical comorbidities including chronic hypertension, adverse environmental exposures (smoking, alcohol, and illicit drugs), or recognized obstetrical risk factors for abnormal fetal growth were eligible for enrollment. To improve generalizability, women with a BMI 30.0e45.0 kg/m2 were also recruited, although the inclusion and exclusion criteria were not as strict, given
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that obesity is associated with many comorbidities as well as alterations in fetal growth.22 Recalled pregravid weight and self-reported height were used for the calculation of BMI at enrollment. Human subjects’ approval was obtained from all participating sites, the NICHD, and the data coordinating center. All women provided informed consent prior to any data collection. Of 2802 women enrolled, we excluded 168 who deactivated from the study (33 were lost to follow-up, 93 refused to continue, 29 moved, 9 had voluntary termination of the pregnancy, and 4 for other reasons), 17 ineligible after enrollment, 86 who had structural fetal abnormalities, 5 who had fetal chromosomal abnormalities, 11 with pregnancy loss <20 weeks’ gestation, 19 with fetal demise, and 29 with missing data, leaving 2467 who are included in the descriptive analysis (Table 1). For the analyses, we further excluded 5 women with severe gestational hypertension, given that their small number precluded meaningful analysis, leaving a total of 2462 pregnancies.
Sonographic population Ultrasound screening between 8 weeks 0 days and 13 weeks 6 days was performed to ensure dating consistency with the patient’s reported first day of the last menstrual period. Following a standardized ultrasound between 10 weeks 0 days and 13 weeks 6 days, women were randomized to 1 of 4 sonogram schedules, with 5 additional planned study visits (16e22, 24e29, 30e33, 34e37, and 38e41 gestational weeks). By design, this mixed longitudinal randomization scheme captured weekly fetal growth data without exposing women to weekly ultrasound examinations. Study sonographers underwent training and credentialing prior to enrollment. At each ultrasound, biometric measurements for biparietal diameter (BPD, outer to inner), humerus length (HL), and femur length (FL) using the linear function and for head circumference (HC) and abdominal circumference (AC) using the ellipse function were
performed using standard protocols and identical equipment. Study sonographers were blinded to both the gestational age at the measurements and the patient’s clinical condition. EFW was computed from HC, AC, and FL using a Hadlock formula.23 A detailed study protocol has been published elsewhere.19,21,24
Hypertensive groups Prospectively, the study protocol guidebooks instructed the research nurse abstractors to document the presence and severity of pregnancy-associated hypertensive disorders as recorded in the medical record. Diagnosis of pregnancyassociated hypertensive disorders was made by clinicians at participating centers following the 2002 American College of Obstetricians and Gynecologists (ACOG) criteria.13 Gestational hypertension was defined as elevated blood pressure (systolic blood pressure [SBP] 140 mm Hg or a diastolic blood pressure [DBP] 90 mm Hg) after 20 weeks of gestation without proteinuria in a women with previously normal blood pressure. Severe gestational hypertension was defined as gestational SBP 160 mm Hg or DBP 110 mm Hg without proteinuria. Preeclampsia was defined as newonset hypertension after 20 weeks with proteinuria (0.3 g of protein in a 24 hour urine specimen). The criteria for severe preeclampsia included SBP 160 mm Hg or DBP 110 mm Hg, proteinuria 5 g or >3 or greater on 2 random urine samples, oliguria <400 mL in 24 hours, cerebral or visual disturbances, pulmonary edema or cyanosis, epigastric or right upperquadrant pain, impaired liver function, thrombocytopenia, and fetal growth restriction.13 The postpartum discharge diagnoses were as listed in the medical record and abstracted by research nurses: mild gestational hypertension, severe gestational hypertension, mild preeclampsia, severe preeclampsia (including eclampsia or HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome) and unspecified hypertension (all were recorded as mild but
Original Research
lacked sufficient modifiers to differentiate between mild gestational hypertension and mild preeclampsia). For the present analysis, we grouped the hypertensive disorders in a hierarchical manner as severe preeclampsia, mild preeclampsia, severe gestational hypertension, mild gestational hypertension, and unspecified hypertension. Women without any hypertensive disorder recorded as a discharge diagnosis were categorized as normotensive.
Statistical analysis Baseline and clinical data were compared for participants by type of hypertensive disorder. Overall differences (P < .05) were determined using c2 or analysis of variance for categorical and continuous data, respectively. Where overall tests indicated significant differences across the no-hypertension and hypertension groups, pairwise c2 or Tukey’s studentized range test were used to determine significant differences between these groups. Fetal growth curves for the ultrasound biometric measures BPD, HC, AC, FL, and HL, and calculated EFW were generated for each hypertensive group (severe preeclampsia, mild preeclampsia, mild gestational hypertension, unspecified hypertension, and normotensive). The ultrasound biometric measures and EFW were log transformed to stabilize variance across gestational ages and to optimize approximations for the error structures.24 Linear mixed models with cubic splines for the fixed effects were used for the primary analysis to estimate specific fetal growth curves.25 Three-knot points (25th, 50th, and 75th percentiles) were selected at gestational ages that evenly split the distributions. Percentiles (fifth, 50th, and 95th) were estimated for EFW and each biometric parameter in the studied groups from the 11th to 40th week of gestation based on the assumed normal distribution of the random effects on error structure. The overall differences in the curves of EFW and each biometric measure for each group were calculated using a likelihood-ratio test. When the global
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Maternal characteristics among normotensive and pregnancy-associated hypertensive disorders Q6
Variables
Severe preeclampsia (n ¼ 32)
Mild preeclampsia (n ¼ 54)
Severe gestational hypertensiona (n ¼ 5 )
Mild gestational hypertension (n ¼ 63)
Unspecified hypertension (n ¼ 17)
Maternal age, y, mean SD
26.6 (6.0)
26.2 (5.8)
29.0 (6.8)
28.0 (5.5)
25.6 (5.4)
Normotensive (n ¼ 2296)
All (n ¼ 2467)
28.3 (5.4)
28.2 (5.5)
9 (28.1%)
14 (25.9%)
1 (20.0%)
22 (34.9%)
4 (23.5%)
634 (27.6%)
684 (27.7%)
Black/non-Hispanic
14 (43.8%)
22 (40.7%)
1 (20.0%)
25 (39.7%)
10 (58.8%)
602 (26.2%)
674 (27.3%)
Hispanic
6 (18.8%)
18 (33.3%)
1 (20.0%)
14 (22.2%)
3 (17.6%)
667 (29.1%)
709 (28.7%)
Asian
3 (9.4%)
2 (40.0%)
2 (3.2%)
393 (17.1%)
400 (16.2%)
Gravidity, n, %
.1360
1
15 (46.9%)
24 (44.4%)
2
8 (25.0%)
16 (29.6%)
3
9 (28.1%)
14 (25.9%)
3 (60.0%) 2 (40.0%)
28 (44.4%)
5 (29.4%)
729 (31.7%)
804 (32.6%)
18 (28.6%)
5 (29.4%)
713 (31.0%)
760 (30.8%)
17 (27.0%)
7 (41.2%)
854 (37.2%)
903 (36.6%)
OBSTETRICS
White/non-Hispanic
< .0001c
Parity, n, % 0
24 (75.0%)
39 (72.2%)
1
4 (12.5%)
10 (18.5%)
2
4 (12.5%)
5 (9.3%)
4 (80.0%) 1 (20.0%)
40 (63.5%)
10 (58.8%)
1040 (45.3%)
1157 (46.9%)
15 (23.8%)
4 (23.5%)
807 (35.1%)
840 (34.0%)
8 (12.7%)
3 (17.6%)
449 (19.6%)
470 (19.1%) < .0001d
Prepregnancy BMI, kg/m2, n, % <25.0
10 (31.3%)
15 (28.3%)
2 (40.0%)
20 (31.7%)
5 (31.3%)
1327 (58.2%)
1379 (56.3%)
25.0e30.0
13 (40.6%)
20 (37.7%)
2 (40.0%)
19 (30.2%)
4 (25.0%)
591 (25.9%)
649 (26.5%)
9 (28.1%)
18 (34.0%)
1 (20.0%)
24 (38.1%)
7 (43.8%)
361 (15.8%)
420 (17.2%)
Marital status, n, %e
.0011f
Not married
13 (40.6%)
22 (40.7%)
1 (20.0%)
21 (33.3%)
8 (47.1%)
559 (24.4%)
624 (25.3%)
Married or living with partner
19 (59.4%)
32 (59.3%)
4 (80.0%)
42 (66.7%)
9 (52.9%)
1735 (75.6%)
1841 (74.7%)
Less than high school
4 (12.5%)
8 (14.8%)
8 (12.7%)
1 (5.9%)
262 (11.4%)
283 (11.5%)
High school/equivalent
4 (12.5%)
14 (25.9%)
11 (17.5%)
6 (35.3%)
415 (18.1%)
450 (18.2%)
Some college/associate
11 (34.4%)
20 (37.0%)
3 (60.0%)
17 (27.0%)
6 (35.3%)
680 (29.6%)
737 (29.9%)
Bachelor’s degree
11 (34.4%)
7 (13.0%)
1 (20.0%)
19 (30.2%)
1 (5.9%)
548 (23.9%)
587 (23.8%)
2 (6.3%)
5 (9.3%)
1 (20.0%)
8 (12.7%)
3 (17.6%)
391 (17.0%)
410 (16.6%)
Education, n, %
.2239
Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
(continued)
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Postgraduate degree
.0081b < .0001b
Race/ethnicity, n, %
30.0
P value
Original Research
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TABLE 1
391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446
447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502
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TABLE 1
Maternal characteristics among normotensive and pregnancy-associated hypertensive disorders (continued) Severe preeclampsia (n ¼ 32)
Variables Family income, n, %
Mild preeclampsia (n ¼ 54)
Severe gestational hypertensiona (n ¼ 5 )
Mild gestational hypertension (n ¼ 63)
Unspecified hypertension (n ¼ 17)
Normotensive (n ¼ 2296)
All (n ¼ 2467)
e
<$30,000 $30,000e74,999
.0899 6 (21.4%)
19 (39.6%)
15 (53.6%)
16 (33.3%)
3 (60.0%)
6 (12.5%) 7 (25.0%)
7 (14.6%)
Other
11 (34.4%)
27 (50.0%)
Private or managed care
21 (65.6%)
27 (50.0%)
17 (32.1%)
7 (41.2%)
566 (28.3%)
615 (28.6%)
14 (26.4%)
6 (35.3%)
617 (30.9%)
671 (31.2%)
270 (13.5%)
281 (13.1%)
5 (9.4%) 2 (40.0%)
17 (32.1%)
4 (23.5%)
544 (27.2%)
581 (27.0%)
22 (34.9%)
8 (47.1%)
840 (36.6%)
908 (36.8%)
41 (65.1%)
9 (52.9%)
1456 (63.4%)
1559 (63.2%)
Insurance, n, %
.2847 5 (100.0%)
Full-time employment/ student status, n, %e No Yes
.0689 5 (15.6%)
17 (31.5%)
1 (20.0%)
12 (19.0%)
2 (11.8%)
677 (29.5%)
714 (29.0%)
27 (84.4%)
37 (68.5%)
4 (80.0%)
51 (81.0%)
15 (88.2%)
1618 (70.5%)
1752 (71.0%)
e
Infant sex, n, %
.9368
Male
15 (46.9%)
26 (48.1%)
1 (20.0%)
30 (47.6%)
9 (52.9%)
1174 (51.4%)
1255 (51.1%)
Female
17 (53.1%)
28 (51.9%)
4 (80.0%)
33 (52.4%)
8 (47.1%)
1111 (48.6%)
1201 (48.9%)
35.9 (3.2)
38.8 (1.6)
39.3 (1.7)
39.2 (1.7)
Gestational age at delivery, wks, mean SDe
37.9 (2.4)
39.2 (1.4)
39.5 (1.1)
< .0001g
P values reported are for global tests. BMI, body mass index. The distribution of racial/ethnic groups was significantly different in the normotensive group compared with all other groups except severe preeclampsia. a
1.e5
Original Research
Because of its small number, severe gestational hypertension was not included in statistical comparisons among hypertension groups; b Although the overall analysis of variance was significant, no pairwise comparisons indicated significant differences in age between groups at the P ¼ .05 level; c The distribution of parity categories was significantly different in the normotensive group compared with all other groups except unspecified hypertension; d The distribution of BMI categories was significantly different in the normotensive group than all other groups; e Not included in the totals are missing data: BMI (n ¼ 19); martial status (n ¼ 2); income (n ¼ 319, 299 from normotensive, 10 from mild gestational hypertension, 6 from mild preeclampsia, 4 from severe preeclampsia groups); full-time employment/student status (n ¼ 1); infant sex (n ¼ 11); and gestational age at delivery (n ¼ 12); f The proportion of those married or living with a partner was significantly different in the normotensive group than for all other groups except mild gestational hypertension; g Gestational age at delivery was significantly smaller in the severe preeclampsia group than that for all other hypertensive groups. Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
OBSTETRICS
MONTH 2019 American Journal of Obstetrics & Gynecology
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$75,000e99,999 $100,000 or more
P value
503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558
Original Research 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614
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OBSTETRICS
test was significant (P < .05) for differences in the overall curves, week-specific differences were tested using the Wald test at each gestational week. Where the weekly global test was significant (P < .05) for differences among hypertensive groups, pairwise tests between hypertensive groups were performed. These tests were conducted on the estimated curves with and without adjustment for maternal characteristics: age, self-reported race/ethnicity (nonHispanic white, non-Hispanic black, Hispanic, and Asian or Pacific Islander), self-reported pregravid weight and height, parity (0, 1, and 2) , full-time employment/student status (yes/no), marital status (married/living as married vs not), insurance (private/ managed vs Medicaid/other), education, and infant sex. Education was analyzed categorically: less than high school, high school or equivalent, some college or associate degree, bachelor’s degree, and postgraduate degree. An analysis of covariance was used to analyze birthweight data, adjusting for the same variables described in previous text for the fetal growth trajectory models. All analyses were performed using SAS (version 9.4; SAS Institute Inc, Cary, NC) or R (version 3.1.2; http://www.Rproject.org).
Results Patient demographics Of the 2462 women eligible for analysis, 2296 (93.3%) were normotensive, 63 (2.6%) had mild gestational hypertension, 54 (2.2%) mild preeclampsia, 32 (1.3%) severe preeclampsia, and 17 (0.7%) unspecified hypertension. Maternal age varied across hypertension groups (global analysis P ¼.008), but no pairwise comparison was statistically significant (Table 1). The distribution of racial/ethnic groups was significantly different between the normotensive group and all other groups, except severe preeclampsia (P < .02 for pairwise comparisons). Parity was significantly different between the normotensive group and all other groups, except unspecified hypertension (P < .02 for pairwise comparisons).
Other maternal characteristics results are presented in Table 1. Compared with the other groups, normotensive women had the lowest obesity rate (15.8%). Women with severe preeclampsia delivered significantly earlier than women with other hypertensive conditions and those without hypertension (Table 1; global P <.0001). Birthweights of infants born to women without hypertension (mean, 3352.9 g, SD, 494.4 g) were significantly higher than the infant birthweights of women with severe preeclampsia (mean, 2297.2 g, SD, 741.0 g). Birthweight mean difference between these groups was e949.5 g (95% CI, e1117.8 to e781.2 g); P < .0001). In contrast, neonates born to women with mild hypertensive disorders had similar birthweights to those born to women with no hypertension (values of P > .05).
Fetal growth trajectories for EFW Fetal growth trajectories for EFW including the fifth, 50th, and 95th percentiles for the normotensive and hypertension groups were statistically different (global P < .0001) and remained significant after adjustment for confounders (Figure 1). Compared with fetuses of normotensive women, fetuses of women with severe preeclampsia had a median EFW significantly higher at 11 weeks’ gestation and became progressively smaller from 22 to 38 weeks’ gestation (Table 2). The median EFW difference for gestational age was 31 g at 22 weeks, 74 g at 28 weeks, 136 g at 32 weeks, and 474 g at 38 weeks (P < .008 for all weekly pairwise comparisons). Furthermore, the median percentage EFW difference for gestational age between these 2 groups was 6.5% at 22 weeks, 6.4% at 28 weeks, 7.2% at 32 weeks, and 15.0% at 38 weeks. By the third trimester, EFW curves in women with severe preeclampsia were characterized by flattening at the fifth and 50th percentiles and progressively separating from the fetal growth curves of women with no hypertension, mild gestational hypertension, and mild preeclampsia.
Median EFW growth trajectories did not differ significantly between the fetuses of normotensive women and those whose mother had mild preeclampsia (Table 2, P > .05 for all weekly pairwise comparisons). Compared with the normotensive group, fetuses of mothers with mild gestational hypertension exhibited a significantly lower median EFW at 11 weeks and from 22 to 25 weeks’ gestation (P < .04 for all weekly pairwise comparisons), but the difference was not statistically significant at later gestational ages.
Fetal growth trajectories for AC Growth curves for AC (Figure 2) were statistically significantly different between the fetuses of normotensive mothers and those of mothers with severe preeclampsia at 11 weeks, from 23 to 31 weeks, and from 33 to 37 weeks’ gestation (P < .04 for all weekly pairwise comparisons). Compared with fetuses of normotensive mothers, the median AC of fetuses whose mothers had severe preeclampsia was 4.9 mm, 6.3 mm, 11.9 mm, and 17.6 mm smaller at 22, 28, 34, and 37 weeks’ gestation, respectively (Table 3). The median percentage AC difference for gestational age was 2.8% at 22 weeks, 2.6% at 28 weeks, 3.9% at 34 weeks, and 5.3% at 37 weeks. AC growth in fetuses of mothers with mild preeclampsia differed only from 13 to 16 weeks’ gestation compared with normotensive mothers (Figure 2; P <.05 for all weekly pairwise comparisons), but the difference became not significant at later gestational ages (P > .05 for all weekly pairwise comparisons). As observed with EFW growth trajectory, AC was significantly smaller in the fetuses of mothers with mild gestational hypertension group compared with those of normotensive mothers from 13 to 16 weeks and from 23 to 27 weeks’ gestation (P < .04 for all weekly pairwise comparisons).
½F2
½T3 ½F1
½T2
Fetal growth trajectories for other individual biometric parameters Growth trajectories of all other biometric measurements, BPD, HC, FL, and HL (Figure 3, AeD), had scattered ½F3 weekly growth differences in the first
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615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670
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print & web 4C=FPO
671 672 673Q7 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726
OBSTETRICS
Original Research
FIGURE 1
Distribution of EFW by hypertensive condition and gestation
From the NICHD Fetal Growth StudieseSingletons, the estimated fifth, 50th, and 95th percentiles are for fetal weight by hypertensive condition, as estimated from linear mixed models with log-transformed outcomes and cubic splines. EFW, estimated fetal weight; GA, gestational age. Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
MONTH 2019 American Journal of Obstetrics & Gynecology FLA 5.6.0 DTD YMOB12749_proof 3 July 2019 10:56 pm ce
1.e7
727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782
Original Research 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838
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OBSTETRICS
TABLE 2
Estimated fetal weighta by hypertension group, n [ 2462 Median estimated fetal weight, g GA, wks
Normotensive (n ¼ 2296)
Severe preeclampsia (n ¼ 32)
Mild preeclampsia (n ¼ 54)
Mild gestational hypertension (n ¼ 63)
Unspecified hypertension (n ¼ 17)
11
44
48b
43
41b
44
12
55
56
55
53
55
13
69
69
71
68
70
14
88
86
90
86
89
15
111
109
113
109
113
16
140
139
142
137
143
17
175
174
177
171
179
18
218
215
219
211
222
19
269
261
268
259
271
20
328
314
326
315
328
21
395
374
392
379
b
392 b
463 543
22
472
441
469
454
23
558
518b
556
538b
24
655
b
605
654
634
b
632b
25
763
705b
765
741b
731b
26
883
818b
889
860
841b
27
1016
946b
1026
993
963b
28
1162
b
1088
1177
1139
1100b
29
1323
1242b
1343
1299
1254b
30
1500
1407b
1523
1473
1426b
31
1691
1580b
1716
1659
1616b
32
1893
1757b
1918
1856
1822b
2105
b
2128
2061
2044
b
2343
2272
2276
b
2560
2486
2510
b
33 34 35
2321 2536
1935 2109 2276
36
2748
2432
2780
2702
2732
37
2958
2571b
3005
2921
2923
3165
b
3237
3145
3062
38
2691
Computed from head circumference, abdominal circumference, and femur length; Value differed significantly from the no hypertension group (global and weekly pairwise P < .05, obtained by the Wald test with adjustment for maternal age, self-reported height and prepregnancy weight, parity, racial ethnic group, full-time job or student status, marital status, insurance, education, and infant sex). Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019. a
b
and second trimesters between the normotensive, severe preeclampsia, and the other hypertensive disorder groups.
Comment Principal findings Our analysis of the NICHD Fetal Growth StudyeSingletons found significant and
consistent reductions in fetal growth during the second and third trimesters among women who developed severe preeclampsia compared with normotensive pregnancies. With severe preeclampsia, EFW growth differences occurred consistently, beginning at 22 weeks’ gestation and continued through 38 weeks, with significantly smaller AC
measurements observed between 23 and 31 weeks and from 33 to 37 weeks’ gestation. The EFW differences were corroborated by birthweight, which was lower for the newborns of women who developed severe preeclampsia compared with women without hypertension. Our study demonstrated normal fetal growth patterns, except for temporal
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Original Research
FIGURE 2
Distribution of fetal AC by hypertensive condition and gestation web 4C=FPO
895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950
OBSTETRICS
From the NICHD Fetal Growth StudieseSingletons, the estimated fifth, 50th, and 95th percentiles are for fetal abdominal circumference by hypertensive condition, as estimated from linear mixed models with log-transformed outcomes and cubic splines. AC, abdominal circumference; GA, gestational age. Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
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1.e9
951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006
Original Research 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062
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OBSTETRICS
TABLE 3
Median abdominal circumference by hypertension group (n [ 2462) Median abdominal circumference, mm GA, wks
Normotensive (n ¼ 2296)
Severe preeclampsia (n ¼ 32)
Mild preeclampsia (n ¼ 54)
Mild Gestational hypertension (n ¼ 63)
Unspecified hypertension (n ¼ 17)
11
45.4
48.8a
44.1
44.4
45.5
12
55.7
56.6
55.9
54.4
56.1
13
66.8
65.8
68.3a
65.2a
67.4
76.4
a
a
79.2
a
91.2
a
103.2
14 15
78.4 90.3
80.8
a
88.2
93.0
a
76.5 88.2
16
102.3
100.7
104.7
17
114.3
113.1
116.0
111.9
115.0
18
126.2
125.2
127.0
123.6
126.7
19
138.1
136.7
138.0
135.2
138.2
20
149.9
147.6
149.3
146.7
149.4
21
161.5
158.0
160.6
158.1
160.2
22
172.9
168.0
171.9
169.4
170.7
23
184.1
177.9a
183.3
180.5a
24
195.0
187.8
a
194.7
191.4
a
190.6a
25
205.8
198.2a
206.1
202.2a
200.2a
26
216.4
209.0a
217.3
212.9a
209.7a
27
226.9
220.1a
228.6
223.6a
219.4a
28
237.6
231.3
a
239.8
234.5
229.4a
29
248.4
242.5a
251.0
245.5
240.0a
30
259.4
253.5a
262.1
256.7
251.2a
31
270.5
263.9a
273.1
268.0
262.8a
32
281.6
273.6
283.9
279.2
274.8
33
292.4
282.7a
294.4
290.1
287.0
303.0
291.1
a
304.5
300.7
299.4
298.9
a
314.5
310.8
311.2
a
34 35
312.9
100.0
180.8
36
322.4
306.5
324.2
320.4
321.5
37
331.4
313.8a
334.1
329.8
329.2
38
340.1
321.1
344.3
339.0
333.1
Value differed significantly from the no hypertension group (global and weekly pairwise P < .05, obtained by the Wald test with adjustment for maternal age, self-reported height and prepregnancy weight, parity, racial ethnic group, full-time job or student status, marital status, insurance, education, and infant sex). Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019. a
differences on AC growth from 13 to 16 weeks’ gestation, in women who developed mild preeclampsia similar to those women without hypertension, suggesting that uteroplacental function is preserved to a greater extent in this milder form of preeclampsia. Women who developed mild gestational hypertension pregnancies had a transitory
deceleration of EFW and AC growth in the second trimester but subsequently normalized fetal growth at later gestational ages.
Results in context of other studies Our results demonstrate different fetal growth patterns across the hypertensive groups. Although fetal growth patterns
in pregnancy-associated hypertensive disorders have not been previously evaluated in a longitudinal fashion, abnormalities of neonatal size associated with pregnancy-associated hypertensive disorders have been previously reported with conflicting results. For example, Srinivas et al12 showed a higher risk for SGA (birthweight <10th percentile for
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Original Research
FIGURE 3
Distribution of fetal biometric measurements by hypertensive condition and gestation
web 4C=FPO
1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174
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From the NICHD Fetal Growth StudieseSingletons, the estimated fifth, 50th, and 95th percentiles for fetal biparietal diameter, head circumference, femur length, and humerus length by hypertensive condition (AeD) were estimated from linear mixed models with log-transformed outcomes and cubic splines. GA, gestational age. Mateus et al. Pregnancy-associated hypertensive disorders and fetal growth. Am J Obstet Gynecol 2019.
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gestational age) among women with severe preeclampsia compared with normotensive women (AOR, 1.87; 95% CI, 1.11e2.97). A European study demonstrated that birth size was lower with increasing preeclampsia severity.14 Others have reported an association between small as well as large birthweights with preeclampsia and gestational hypertension.15,16 Our study showed an abnormal asymmetric fetal growth pattern in women with severe preeclampsia. In this respect, Rasmussen et al15 reported at increased risk for asymmetric SGA with early-onset preeclampsia (<37 weeks).
Biological mechanisms Fetal growth depends on the efficient transport of nutrients in the uteroplacental circulation. Reduced uteroplacental blood flow is a result of placental vascular pathologic changes highly associated with FGR and preeclampsia.5e11 Impaired spiral arterial remodeling and deficient extravillous trophoblast invasion are highly characteristic abnormalities of these disorders.5e11 Deficient remodeling might be precipitated by inadequate histotrophic nutrition in the first trimester,11 excessive apoptosis in the placental bed,26 reducing the number of extravillous trophoblast cells,5,6,9,11 or failure of interstitial trophoblasts to penetrate the arterial wall.9 A greater gradient of aberrant remodeling at the junctional zone and myometrial segment are highly associated with preeclampsia with FGR.11 Atherotic changes with accumulation of foam cells and arterial narrowing distal to the junctional zone significantly restricts blood flow to the placenta, leading to oxidative stress, endoplasmic reticulum stress, proinflammatory cytokines production, and apoptosis.5,6,9,11 Reduced volume and surface area of the placenta are characteristic features of pregnancies with FGR.11 Downregulated function of the protein kinase B/mechanistic target of rapamycin signaling pathway reduces placental growth and reduces activity of placental transporters in FGR cases.27,28 Unfolded protein response pathways are activated in
response to hypoxic environment.28,29 A greater degree of activation of unfolded protein response stimulates the release of proinflammatory cytokines and apoptosis implicated in endothelial cell activation, a pathognomonic feature of preeclampsia with FGR, but not of FGR alone.28,29 Emerging findings from genetic studies further elucidated pathogenic mechanisms on preeclampsia and FGR.30e41 For instance, Pleckstrin homology like domain family A member 2 that inhibits growth is upregulated, whereas mesoderm specific transcript that promotes growth is downregulated in FGR placentas.33,34 A recent meta-analysis identified 20 miRs associated with cell death/ apoptosis and cell movement in placentas with preeclampsia.35 Other studies have identified miR-20b, miR151, miR-524-3p, and miR-34c-5p associated with angiogenic pathways in preeclampsia.36 Four genes associated with growth and metabolism (IGFBP-1, PRL, LEP, and CHR) have been found in FGR placentas by messenger RNA transcriptome analysis.37,38 Microarray studies in preeclampsia have identified gene expression of LEP, HTRA1, INHA, INHBA, PAPP2, and FSTL3 involved in cell signaling, lipid response, apoptosis, hypoxia, immune, inflammation, and oxidative stress pathways.30,39e41 The expression of a group of 10 genes (LEP, FTRA4, FSTL3, LHD, TREM1, ENG, PAPP2, FLT-1, IHBA, and INHBA) has been found to be higher in early-onset preeclampsia (<34 weeks) than later-onset preeclampsia and also higher in late-onset preeclampsia with SGA than without it.32
Clinical implications Investigators debate whether preeclampsia with and without FGR are distinct entities.10e12,14e16 Our study provides new insights about the relationship between fetal growth and pregnancyassociated hypertensive disorders. We highlight the following findings of clinical relevance. First abnormal fetal growth is identifiable early in gestation in severe preeclampsia and likely precedes its clinical manifestations. Second,
a pattern of asymmetric fetal growth, primarily driven by diminished AC growth, is characteristic of severe preeclampsia. Delayed AC growth begins sooner than the physiological acceleration of AC growth (27e31 weeks) described in normal pregnancies,42 preventing the fetus from achieving normal growth and development. The observed differences of AC growth between normotensive pregnancies and those with severe preeclampsia are corroborated with neonatal size differences noted among these groups. And third, fetal growth is predominantly normal in mild hypertensive disorders, suggesting preserved placental function in these pregnancies. The presence or absence of fetal growth abnormality distinguished in the studied pregnancy-associated hypertensive disorders might depend on a variety of maternal and placental vascular abnormalities reported since early gestation, from severe deficiency of spiral artery remodeling with excessively impaired extravillous trophoblastic migration and formation of atherotic lesions leading to placental infarcts (preeclampsia with FGR) to minimal or inexistent placental involvement (preeclampsia without FGR).11 Recently described distinctive maternal cardiovascular profiles17 between pregnancies complicated by preeclampsia only (high CO and low PVR), FGR only (unaltered CO, high PVR), and preeclampsia with FGR (low CO and high PVR) might have repercussions on uteroplacental blood flow. Compared with normal pregnancies, placental perfusion calculated by magnetic resonance imaging has been found to be significantly lower in women with early-onset preeclampsia (<34 weeks) but significantly higher in women with late-onset preeclampsia.43 The reduction of placental perfusion was more drastic with the presence of FGR. A recent large European study found that the risk of SGA (birthweight percentile of <2.5% of birthweight zscore stratified by infant sex) was almost 3 times higher in women with preeclampsia with a small placenta (lowest 10% of placenta weight) compared with
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normotensive women with small placenta weight.44 Conversely, the association of the highest 10% of placenta weight and LGA (97.5th percentile) was stronger in the preeclampsia group than in the controls. In a recent prospective case-control study, women with preeclampsia and FGR, as compared with women with preeclampsia without FGR, had more severe clinical manifestations, more placental morphologic abnormalities, and lower placental weight and thickness.45 Conversely, decidual vasculopathy was similar in preeclampsia with and without FGR. This suggests that changes in the vascular bed are characteristic of preeclampsia, whereas placental villus abnormalities are more strongly correlated with FGR, but both are highly prevalent in severe preeclampsia. Altogether, preeclampsia is manifested in 2 well-defined clinical phenotypes marked by the presence or absence of FGR, which is ultimately determined by the degree of maternal/placental hemodynamic abnormalities as well as placental functional and structural changes. Our study support the association of poor fetal growth with severe preeclampsia and the lack of fetal growth abnormality in mild preeclampsia.
Research implications This study is unique because the analyzed cohort is composed of a lowrisk population highly representative of the US contemporaneous pregnant population. With this prospective observational design, we were able to identify the timing in gestation when changes of fetal growth occurred, the progression of these changes throughout pregnancy, and the temporary association of fetal growth with hypertensive disorders. The reduction of fetal growth identified in women with severe preeclampsia is in contrast with the similarity of fetal growth patterns observed between women with mild hypertensive disorders and normotensive women. Further investigation is necessary to elucidate the mechanisms that elicit development of preeclampsia with and without FGR.
Our findings prompt the investigation to determine whether the elaborated fetal growth charts for pregnancies later complicated by severe preeclampsia, perhaps in association with biomarkers and other sonographic parameters, may be used effectively to predict the later onset of clinically evident disease. We also highlight the need to determine fetal growth velocities in normotensive vs pregnancy-associated hypertensive disorders and their association with neonatal size and pregnancy outcomes.
Strengths and limitations Our study is strengthened by the prospective design describing longitudinal patterns of fetal growth as well as individual anthropometric parameters in pregnancies complicated by gestational hypertensive disorders in a demographically and racially/ethnically diverse US obstetrical population. Our data collection used a standardized protocol across the 12 centers. The sonographic examinations were performed by experienced and certified sonographers, and the methodology used to analyze the data has been previously validated.24 Although we included a subgroup of obese women (BMI, 30.0e45.0 kg/m2) with other underlying chronic medical conditions such as chronic hypertension and maternal/fetal risks factors were excluded. In addition, our findings remain significant after controlling for major confounders. We also acknowledge several limitations. Information on the characteristics used to define the hypertensive categories was not collected. However, we believe that our categories are clinically relevant because these were the diagnoses that were used in clinical practice. This study predated the widespread implementation of the new 2013 ACOG criteria for the diagnosis and classification of preeclampsia.46 It is believed unlikely that use of the newer classification system would significantly alter our findings. In 2016, Kallela et al47 reanalyzed the diagnosis of preeclampsia from a nationwide Finnish database using both the ACOG 2002 and 2013 criteria. The number of women diagnosed with preeclampsia increased only
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0.8% (1457 vs 1447) when the new 2013 criteria were applied. Possible biases can exist in the diagnosis assignment. Classification of our patients was based on the discharge diagnosis summaries from each participating center and lacked standardization across all centers. Any potential misclassification is likely to be nondifferential, resulting in a bias toward the null. The low incidence rates of hypertensive disorders in pregnancy in our cohort likely reflects a healthy pregnant population; however, the small sample size in these groups could still potentially result in type II errors. In addition, we did not observe individual changes in growth at every gestational week, so that differences in measurements per week are extrapolated. The linear mixed models with cubic splines for the fixed effects are flexible enough to allow for a robust calculation of growth at any point in gestation.
Conclusions This is the first prospective longitudinal study of fetal growth trajectories in pregnancy-associated hypertensive disorders compared with normotensive pregnancies in a low risk, demographically diverse US pregnant population. Compared with normotensive pregnancies, diminished EFW and AC growth was identifiable as early as 22 and 23 weeks of gestation, respectively, in women with severe preeclampsia. These midesecond-trimester fetal growth abnormalities likely anticipate clinical manifestations of severe preeclampsia. We also highlight the similar fetal growth curves in mild pregnancy-associated hypertensive disorders compared with normotensive women. n Acknowledgment This study was registered at ClinicalTrials.gov with the identifier number of NCT00912132.
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Author and article information From the Division of Maternal-Fetal Medicine, Medical University of South Carolina, Charleston, SC (Drs Mateus and Newman); the Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (Drs Zhang, Pugh, Albert, and Grantz and Mr Grewal, and Mr Kim); the Feinberg School of Medicine, Northwestern University, Chicago, IL (Dr Grobman); the Center for Women’s Reproductive Health, University of Alabama at Birmingham, Birmingham, AL (Dr Owen); the Division of Maternal-Fetal Medicine, Department of Obstetrics and
Gynecology, Christiana Hospital, Newark, DE (Dr Sciscione); the Columbia University Medical Center, New York, NY (Dr Wapner); the New York Presbyterian Queens, Flushing (Dr Skupski), and Weill Cornell School of Medicine, New York, NY (Dr Skupski); the Women and Infants Hospital of Rhode Island, Providence, Rhode Island (Dr Chien); the University of California, Irvine, and Long Beach Memorial Medical Center/Miller Children’s Hospital Irvine, CA (Dr Wing); Saint Peter’s University Hospital, New Brunswick, NJ (Dr Ranzini); MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH (Dr Ranzini); the Miller Children’s and Women’s Hospital, Long Beach, CA (Dr Nageotte ); and the Prospective Group, Inc, contractor for the Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (Dr Gerlanc). Received Dec. 28, 2018; revised May 30, 2019; accepted June 12, 2019.
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This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Q9 Health, and included American Recovery and Reinvestment Act funding (contract numbers HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275 200800003IC, HHSN275200800014C, HHSN275 200800012C, HHSN275200800028C, and HHSN275201000009C). Dr Grantz, Mr Grewal, Dr Albert, Mr Kim, Dr Zhang, and Dr Buck Louis are US federal government investigators. Dr Wing has been a consultant for Parsagen, for which she received no compensation. The Q2 other authors report no conflict of interest. Presented the 37th annual meeting of the Society for Maternal-Fetal Medicine, Las Vegas, NV, 2017, as poster 210. Corresponding author: Julio Mateus, MD, PhD. [email protected]
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1679 1680 Q8 Supplemental Material 1681 1682 1683 GLOSSARY OF TERMS 1684 1685 Cubic splines: cubic transformation to test the relationship between the predictor(s) and outcome(s). Produces flexible functions with robust 1686 behavior at the tails of predictor distributions, resulting in smooth appearance of the curve. 1687 Global tests: used to analyze groups of interrelated variables. The global test establishes the overall statistical difference among the 1688 analyzed variables. 1689 Likelihood ratio test: used to compare the goodness of fit of 2 statistical models that are members of a hierarchical class (the terms more 1690 complex and less complex are well defined). 1691 Linear mixed models: statistical techniques used to analyze correlated data accounting for fixed and random effects. These models are 1692 optimal to assess longitudinal data, are appropriate for small sample sizes and unbalanced sample size groups, and account for auto1693 correlation of repeated measurements. 1694 Three-knot points: the range of values of the predictor variable is subdivided evenly using 3-knot points. Separate regression lines or 1695 curves are fit between the knots producing a smooth appearance. 1696 Wald test: used to test the null hypothesis of a set of variables in a model. Variables that fail to reject the null hypothesis can be removed 1697 from the model because it will not harm substantially the fit of the model. 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 1.e16 American Journal of Obstetrics & Gynecology MONTH 2019 FLA 5.6.0 DTD YMOB12749_proof 3 July 2019 10:56 pm ce
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