Small for gestational age (SGA) refers to neonates who did not meet their expected weight according to gestational age, most commonly defined as a birthweight below the 10th percentile.1–6 The etiologies for the delivery of SGA neonates are diverse and can be divided into maternal and feto-placental.3–6 Among the maternal etiologies are systemic diseases affecting blood vessels such as diabetes, hypertension, connective tissue disease, thrombophilia. Decreased oxygenation, insufficient weight gain during pregnancy, smoking, drug abuse, and other chronic diseases may furthermore affect fetal growth.7–9 The common fetal etiologies are chromosomal abnormalities, congenital malformations, skeletal dysplasia, intrauterine infections, and multiple pregnancy. Abnormal placental implantation, development, absent of physiologic transformation of the spiral arteries, and placental vascular pathologies such as circumvallate placenta, placental abruption, placenta accrete, placental infarction, and placental hemangioma are also associated with the delivery of an SGA neonate.4,10,11
SGA neonates have an increased frequency of perinatal morbidity-cardiovascular, metabolic, hypoglycemia adjacent to labor, neurological and developmental impairment, cerebral palsy, and increased perinatal mortality.2,12–14 SGA is also associated with maternal co-morbidities such as chronic hypertension, pre-eclampsia, renal disease, thyroid abnormalities, and connective tissue disease.2,12,13,15
Fetal growth restriction tends to reoccur in subsequent pregnancies at risk of 4–11 times higher than adequate for gestational age (AGA) pregnancies. Most of these studied displayed the odds ratio (OR) for SGA occurrence and recurrence on a second delivery when the prior (first) delivery was of either an AGA or an SGA. Within mothers that delivered an SGA neonate on their first delivery, 20%–28% had an SGA recurrence in the subsequent birth.2,11,13,16,17
Different descriptions of risk factors for SGA occurrence and recurrence were made,2,12,13,16,17 but none had focused on characterizing the clinical features associated with recurrent delivery of an SGA neonate. Examining the perinatal features associated with the recurrence of the delivery of an SGA neonate in two consecutive pregnancies may provide some clinical tools to the attending physician in the effort to prevent it. Therefore, this study aimed to determine: (1) whether recurrent deliveries of an SGA neonate are associated with increased obstetrical or neonatal complications; (2) whether the risk factors that can predict SGA recurrence.
Materials and methods
This retrospective cohort study was based on Soroka Medical Center's Obstetrics electronic database. The database consisted of 109 022 women who had 320 932 deliveries between the years 1988–2014, it includes demographics, obstetric, and general information regarding the mother and the fetus for each delivery coded according to International Classification of Diseases (ICD)-9 classification by trained secretaries.
Multiparous women who delivered a singleton SGA neonate on their first live delivery were included in the study. Only the first and second deliveries were examined.
Exclusion criteria included: multiple gestation, chromosomal abnormalities, or congenital anomalies, delivery before the 25th or after the 42nd week of gestation. A dead fetus that weighted below 500 gr (was referred to as a miscarriage).
The population was divided into two groups: (1) women who gave birth to a non-SGA neonate on their second delivery (sporadic SGA) (n = 5 416); (2) women who gave birth to an SGA neonate on their second delivery (recurrent SGA) (n = 1 952). Maternal complications (hypertension, diabetes, bleeding) and neonatal complications (polyhydramnios, meconium-stained amniotic fluid, Perinatal death) were compared between the two groups. The study was approved by the IRB committee of the Soroka University Medical Center(120-15-SOR).
Gestational age was determined by the combination of the date of the first day of the last menstrual period along with an ultrasound scan at the first (crown-rump length) or second (bi-parietal diameter) trimester.18
SGA was determined as a birthweight below the 10th percentile for gestational age according to national birthweight standards19 that are customized to fetal gender. Low birthweight was defined as birthweight below 2 500 gr and very low birthweight as weight below 1 500 gr.
Ethnicity was divided into Bedouin and non-Bedouin (mostly Jews) as the cohort population is comprised of Israel's Southern part population.
Severe hypertension was defined as a combination of either severe gestational hypertension (blood pressure >160/110 mm Hg), severe pre-eclampsia or eclampsia.
Mild hypertension was defined as (blood pressure >140/90 mm Hg), gestational hypertension, or mild pre-eclampsia. The variable “Any hypertension” included all types of hypertension during pregnancy, and chronic hypertension (hypertension before 20th gestational week) as well.
Pre-labor rupture of membranes (PROM) was defined as rupture membranes preceding the onset of labor. Preterm PROM was defined as rupture of membranes before 37th gestational week. Pre-term delivery was defined as delivery before the 37th gestational week.
Perinatal death was defined as antepartum, intrapartum or postpartum death (PPD). Antepartum death (APD) was defined as fetal loss after 22nd gestational week weighing at least 500 gr. Intrapartum death was defined as fetal death during labor. PPD was defined as death within the first 28 days of life.
All statistics were performed by SPSS 16.0 (IBM, Armonk, NY, USA). Independent t-test was used for continuous variables’ descriptive statistics, for continuous variables not normally distributed Mann-Whitney test was performed. Chi-square or Fisher test was used for categorical variables’ descriptive statistics. Statistical significance was defined as P < 0.050. We performed a logistic regression in a backward analysis fashion to test the association between variables that differed significantly between the two groups and SGA recurrence. SGA recurrence as the dependent variable, while maternal age, ethnicity, severe hypertension, birthweight <5th percentile, oligohydramnios, perinatal death, and preterm delivery were inserted into the model as the independent variables.
Our database included 109 022 women who had 320 932 deliveries. The study cohort included 6.8% (7 368/109 022) of these patients who gave birth to a singleton SGA neonate on their first delivery and had more than one delivery. This cohort was further divided by the outcome of the second delivery into two groups: (1) sporadic SGA – that on the second delivery gave birth to a non-SGA neonate (n = 5 416 (73.5%)); (2) recurrent SGA group who gave birth to an SGA neonate on the second delivery as well (n = 1 952 (26.5%)).
Table 1 presents the demographic characteristics of the study groups. A Bedouin ethnicity was more prevalent in the recurrent SGA group (sporadic SGA: 57.7% (3 125/5 416) vs. recurrent SGA: 62.8% (1 225/1 952), P < 0.001). Maternal age and marital status did not differ significantly between the groups. The prevalence of systemic lupus erythematous and thrombophilia revealed no difference between the two groups (not displayed in the Table).
The rate of maternal complication in the first pregnancy was similar between the study groups aside that of preterm delivery that was higher in the recurrent SGA group (P = 0.015) (Table 2). The differences in maternal complications between the study groups became more apparent in the second pregnancy. The prevalence of diabetes was higher for the sporadic SGA group on second delivery for all diabetes variables (diabetes (all) (P < 0.001); gestational diabetes (P = 0.002); pre-gestational diabetes (P = 0.011)). Preterm PROM and preterm delivery complicated more pregnancies of the sporadic SGA than in the recurrent SGA group (P = 0.003 and P < 0.001, respectively). Women from the recurrent SGA group were more likely to suffer from severe hypertension (P = 0.005) in their second delivery (Table 2).
Table 3 describes the differences in neonatal complications between the study groups. The mean birthweight was lower among women with recurrent SGA than among those with sporadic SGA in the first (P < 0.001) and second (P < 0.001) pregnancies. As was the rate of birthweight below the 5th percentile (first delivery- recurrent SGA: 61.1% (1 192/1 952) vs. sporadic SGA: 46.5% (2 521/5 416), P < 0.001; 2nd delivery- recurrent SGA: 52.7% (1 029/1 952) vs. sporadic SGA: 0.0%, P < 0.001)). Gestational age at delivery was higher in the sporadic SGA group during the first delivery (P < 0.001) and in the recurrent SGA group in the second delivery (P < 0.001). The rate of fetal and neonatal complication such as polyhydramnios (P < 0.001), meconium-stained amniotic fluid (P < 0.001), nonreassuring fetal heart rate during labor (P < 0.001), and low Apgar score at 1 minute (P = 0.032) in the second delivery was higher the recurrent SGA than in the sporadic SGA group (Table 3). The rate of total perinatal mortality was higher in the sporadic than the recurrent SGA group in the first delivery (P = 0.017) mainly due to post-partum deaths (P < 0.001). In the second delivery the proportions of total perinatal mortality and especially APD were higher in the recurrent than in the sporadic SGA group (P < 0.001, P = 0.001, respectively), The rate of post-partum death was also higher in the recurrent than in the sporadic SGA group but barley reached statistical significance (P = 0.051) (Table 3).
The results of the logistic regression for the identification of independent risk factors for the recurrence of SGA in the 2nd delivery are presented in Table 4. The regression was performed in a backward method; therefore, the third step presents only the variables found to be statistically significant as predictors for SGA recurrence. Preterm birth and birthweight below 5th percentile at first delivery were found to predict recurrence of an SGA neonate on the second delivery (relative risks (RR):1.530, confidence interval (CI):1.249–1.875; RR: 1.826, CI: 1.641–2.030, respectively). A Bedouin ethnicity, severe hypertension, and perinatal death were found to have a protective effect against the recurrent delivery of an SGA neonate (RR: 0.812, CI: 0.737–0.915; RR: 0.675, CI: 0.506–0.900; RR: 0.418, CI: 0.270–0.64, respectively). Maternal age and oligohydramnios were not found to be predictors for SGA recurrence by this model.
Principle findings of the study:(1) Bedouin ethnicity was more prevalent in the recurrent SGA group; (2) the prevalence of birthweight <5th percentile was higher among the recurrent SGA group in the first and second deliveries; (3) the rate of preterm delivery higher in the first delivery of the recurrent SGA group and the sporadic SGA group in the second delivery; (4) total perinatal mortality was higher in the sporadic SGA in the 1st delivery and the recurrent SGA in the second delivery; (5) preterm delivery and birthweight <5th percentile at the first delivery were independent risk factor for recurrence of an SGA neonate in the subsequent birth.
SGA, an obstetrical syndrome, is a recurrent disease. Previous reports suggested a recurrence rate of 20%–30%.2,13,17 The recurrence rate of SGA in our population is 26.5%, and it is in accord with these reports. The mechanisms leading to recurrent SGA vary among publications. Epidemiological studies pointed out a higher recurrence rate in women who smoke during pregnancy13,17,20–22 or had their first pregnancy when they were teenage.17,21 On the other hand, recent studies suggest that vascular placental lesions at the first pregnancy affected by SGA are an independent risk factor for its recurrence in subsequent pregnancies.23 Thus, factors associated with the recurrence of an SGA neonate can be environmental, maternal, or fetal.
Chronic or recurrent maternal complication of pregnancy was previously suggested to be associated with the delivery of an SGA neonate but not with its recurrent. Maternal hypertension is a well-known risk factor for SGA occurrence.2,24 Pathologically- hypertension disrupts normal placental blood vessels development, leading to placental insufficiency and subsequently to intrauterine growth restriction.4,25 Indeed, in our study in the first pregnancy the rate of severe hypertension was similar between those with sporadic SGA and those with recurrent SGA studies, however, this has changed in the second delivery where the prevalence of severe hypertension was double in those with recurrent SGA which suggesting that these patients may have a recurrent maternal placental mediated disease that contributes also to the recurrence of SGA in the second pregnancy. One may ask if this is the case why severe hypertension has protective effect on the recurrence of SGA? A possible explanation is that most cases who had severe hypertension and delivered an SGA neonate did not have a recurrent disease17 (neither hypertension nor SGA) suggesting that if a pregnancy that is affected by maternal hypertension there is an increased risk for fetal growth restriction; however, in subsequent pregnancies if the maternal morbidity does not occur the risk for recurrent SGA will not increase.
Our study is the first to report that preterm delivery of a SGA neonate is an independent risk factor for a recurrent SGA in the subsequent pregnancy. Preterm deliveries of SGA neonates are mostly medically indicated.26–30 Suggesting that these fetuses had a severe form of fetal growth restriction often accompanied by vascular placental disease and abnormal Dopplers that necessitate medical intervention and preterm delivery.25 Thus, it is not surprising that such patients have an inherent risk for recurrent SGA. Evidence in support of this concept is derived from the study of Levy et al. who reported that placental; vascular lesions consistent with maternal vascular malperfusion are associated with recurrent SGA in subsequent pregnancies.23
The second independent risk factor for recurrent SGA was the delivery of a neonate below the 5th percentile for gestational age (adjusted to fetal gender). This, in turn, further represents that the recurrence of SGA deliveries are associated with a severe fetal growth restriction in the first pregnancy. This may be reflecting either severe underlying maternal, fetal and placental morbidity, or may harbor a fraction of constitutionally small neonates delivered to parents with short stature.31 The recurrence of those resulting from maternal or placental diseases may be prevented by prophylactic administration of treatments such as aspirin, or low molecular heparin.32–34 As presented in Tables 2 and 3 in most of the parameters tested the differences between isolated and recurrent SGA were significant. However, in the current study, we were able to focus on the clinical parameters that confer a risk for the recurrence of SGA, including preterm birth of an SGA and the delivery of a neonate below the 5th percentile. It has been proposed that such patients should be referred to a placental clinic in which a though workup of maternal and fetal risk factors and examination of the placenta will be integrated into a risk assessment model for the recurrence of SGA and a preventive strategy will be premeditated.35
As mentioned earlier, being an SGA neonate possesses a higher risk for perinatal mortality due to diverse pathological conditions. Our study's finding regarding perinatal death showed a complex pattern, in which it was more prevalent in the Sporadic SGA group in the first pregnancy and in the recurrent SGA group in the second pregnancy. The mortality in the sporadic group is mostly attributed to PPD. It may be suggested that these cases represent an unexpected perinatal event that leads to late intervention that ends poorly. In contrast, the mortality in the recurrent group is mostly attributed to fetal demise that may be related to the different pathological conditions known to cause SGA and its recurrence.25 Of interest, the logistic regression demonstrated that perinatal mortality and severe hypertension as protective risk factors against SGA recurrence. We assume that after the severe complications during the first pregnancy, these women had a more comprehensive and intensive high-risk perinatal follow-up during their second pregnancy, underlying medical conditions (such as antiphospholipid syndrome) were identified and treated, the medical team intervene by an indicated delivery earlier during gestation. This may result in a lower rate of SGA neonates then affects the results of the meta-analysis.
Strength and limitation
The database used in the study is very big, consisting of a large number of deliveries over a long period. Derived from that is a substantial large incidence of a first SGA singleton delivery concluded in the study. This gives strength to the results of this study. Moreover, the Soroka University Medical Center is a tertiary Medical Center that all the deliveries in the Southern Region of Israel take place, thus the results of the study can be regarded as a population-based study.
Some important suspected risk factors were not included in this study due to missing or insufficient information inherited from our database. This includes smoking, mothers’ body mass index, weight gain through pregnancy, and kidney disease. Another limitation concerns the definition of APD. Because it is usually not possible to know how long was the fetus dead antepartum, in case of a long interval between the fetal demise and its diagnosis these cases may be a misdiagnosis as SGA neonates.
Among women who deliver an SGA neonate, preterm delivery and birthweight below 5th percentile are independent predictors for its recurrence. This may serve the clinician when encountering a woman with an SGA neonate on her first delivery as a tool for estimating the possibility of recurrence.
This study was conducted as part of the requirements for graduation from the medical school of the faculty of health sciences, Ben-Gurion University of the Negev.
Dr. Mor Svorai: established the dataset, analyzed the data and draft the manuscript; Dr. Barak Aricha: Performed the statistical analysis; Prof. Offer Erez: designed the study participated in the analysis of the data and the writing of the manuscript.
Conflicts of Interest
. Campbell MK, Cartier S, Xie B, et al. Determinants of small for gestational age
birth at term. Paediatr Perinat Epidemiol 2012;26(6):525–533. doi:10.1111/j.1365-3016.2012.01319.x.
. Voskamp BJ, Kazemier BM, Ravelli AC, et al. Recurrence
of small-for-gestational-age pregnancy: analysis of first and subsequent singleton pregnancies in The Netherlands. Am J Obstet Gynecol 2013;208(5):374e1–374e6. doi:10.1016/j.ajog.2013.01.045.
. Brosens I, Puttemans P, Benagiano G. Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes. Am J Obstet Gynecol 2019;221(5):437–456. doi:10.1016/j.ajog.2019.05.044.
. Burton GJ, Jauniaux E. Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol 2018;218(2S):S745–S761. doi:10.1016/j.ajog.2017.11.577.
. Mateus J, Newman RB, Zhang C, et al. Fetal growth patterns in pregnancy-associated hypertensive disorders: NICHD fetal growth studies. Am J Obstet Gynecol 2019;221(6):635.e1–635.e16.
. Mendez-Figueroa H, Truong VT, Pedroza C, et al. Small-for-gestational-age infants among uncomplicated pregnancies at term: a secondary analysis of 9 maternal-fetal medicine units network studies. Am J Obstet Gynecol 2016;215(5):628e1–628e7. doi:10.1016/j.ajog.2016.06.043.
. Ciobanu A, Rouvali A, Syngelaki A, et al. Prediction of small for gestational age
neonates: screening by maternal factors, fetal biometry, and biomarkers at 35-37 weeks’ gestation. Am J Obstet Gynecol 2019;220(5):486e1–486e11. doi:10.1016/j.ajog.2019.01.227.
. Deter RL, Lee W, Yeo L, et al. Individualized growth assessment: conceptual framework and practical implementation for the evaluation of fetal growth and neonatal growth outcome. Am J Obstet Gynecol 2018;218(2S):S656–S678. doi:10.1016/j.ajog.2017.12.210.
. Romero R, Kingdom J, Deter R, et al. Fetal growth: evaluation and management. Am J Obstet Gynecol 2018;218(2S):S608. doi:10.1016/j.ajog.2018.01.010.
. Sultana Z, Maiti K, Dedman L, et al. Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction? Am J Obstet Gynecol 2018;218:S762–S773. doi:10.1016/j.ajog.2017.11.567.
. Gabbe SG, Niebyl JR, Galan HL, et al. Obstetrics: Normal and Problem Pregnancies E-Book. Philadelphia, United States: Elsevier Health Sciences; 2016.
. La Batide-Alanore A, Trégouët DA, Jaquet D, et al. Familial aggregation of fetal growth restriction in a French cohort of 7,822 term births between 1971 and 1985. Am J Epidemiol 2002;156(2):180–187. doi:10.1093/aje/kwf002.
. Okah FA, Cai J, Dew PC, Hoff GL. Risk factors for recurrent small-for-gestational-age birth. Am J Perinatol 2010;27(1):1–7. doi:10.1055/s-0029-1223268.
. Stavsky M, Mor O, Mastrolia SA, et al. Cerebral palsy-trends in epidemiology and recent development in prenatal mechanisms of disease, treatment, and prevention. Front Pediatr 2017;5:21. doi:10.3389/fped.2017.00021.
. Juárez SP, Wagner P, Merlo J. Applying measures of discriminatory accuracy to revisit traditional risk factors for being small for gestational age
in Sweden: a national cross-sectional study. BMJ Open 2014;4(7):e005388. doi:10.1136/bmjopen-2014-005388.
. Ananth CV, Kaminsky L, Getahun D, et al. Recurrence
of fetal growth restriction in singleton and twin gestations. J Matern Fetal Neonatal Med 2009;22(8):654–661. doi:10.1080/14767050902740207.
. Hinkle SN, Albert PS, Mendola P, et al. Differences in risk factors for incident and recurrent small-for-gestational-age birthweight: a hospital-based cohort study. BJOG 2014;121(9):1080–1088. doi:10. 1111/1471-0528. 12628.
. Salomon LJ, Alfirevic Z, Da Silva Costa F, et al. ISUOG practice guidelines: ultrasound assessment of fetal biometry and growth. Ultrasound Obstet Gynecol 2019;53(6):715–723. doi:10.1002/uog.20272.
. Dollberg S, Haklai Z, Mimouni FB, et al. Birth weight standards in the live-born population in Israel. Isr Med Assoc J 2005;7(5):311–314.
. Read AW, Stanley FJ. A comparison of recurrent and isolated small-for-gestational-age term births. Paediatr Perinat Epidemiol 1991;5(2):138–156. doi:10.1111/j.1365-3016.1991.tb00695.x.
. Read AW, Stanley FJ. Small-for-gestational-age term birth: the contribution of socio-economic, behavioural and biological factors to recurrence
. Paediatr Perinat Epidemiol 1993;7(2):177–194. doi:10.1111/j.1365-3016.1993.tb00392.x.
. Spinillo A, Capuzzo E, Piazzi G, et al. Maternal high-risk factors and severity of growth deficit in small for gestational age
infants. Early Hum Dev 1994;38(1):35–43. doi:10.1016/0378-3782(94)90048-5.
. Levy M, Mizrachi Y, Leytes S, et al. Can placental histopathology lesions predict recurrence
of small for gestational age
neonates? Reprod Sci 2018;25(10):1485–1491. doi: 10.1177/1933719117749757.
. Catov JM, Nohr EA, Olsen J, et al. Chronic hypertension related to risk for preterm and term small for gestational age
births. Obstet Gynecol 2008;112(2 Pt 1):290–296. doi:10.1097/AOG.0b013e31817f589b.
. Caradeux J, Martinez-Portilla RJ, Basuki TR, et al. Risk of fetal death in growth-restricted fetuses with umbilical and/or ductus venosus absent or reversed end-diastolic velocities before 34 weeks of gestation: a systematic review and meta-analysis. Am J Obstet Gynecol 2018;218(2S):S774–S782. doi:10.1016/j.ajog.2017.11.566.
. Ananth CV, Vintzileos AM. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med 2006;19(12):773–782. doi:10.1080/14767050600965882.
. Gyamfi-Bannerman C, Ananth CV. Trends in spontaneous and indicated preterm delivery among singleton gestations in the United States, 2005-2012. Obstet Gynecol 2014;124(6):1069–1074. doi:10.1097/AOG.0000000000000546.
. Besser L, Sabag-Shaviv L, Yitshak-Sade M, et al. Medically indicated late preterm delivery and its impact on perinatal morbidity and mortality: a retrospective population-based cohort study. J Matern Fetal Neonatal Med 2019;32(19):3278–3287. doi:10.1080/14767058.2018.1462325.
. Hershkovitz R, Erez O, Sheiner E, et al. Comparison study between induced and spontaneous term and preterm births of small-for-gestational-age neonates. Eur J Obstet Gynecol Reprod Biol 2001;97(2):141–146. doi:10.1016/s0301-2115(00)00517-0.
. Mazaki-Tovi S, Romero R, Kusanovic JP, et al. Recurrent preterm birth. Semin Perinatol 2007;31(3):142–158. doi:10.1053/j.semperi.2007.04.001.
. Safiri S. The effect of customization and use of a fetal growth standard on the association between birthweight percentile and adverse perinatal outcome: methodologic issues. Am J Obstet Gynecol 2018;218(6):629. doi:10.1016/j.ajog.2018.03.002.
. Groom KM, David AL. The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction. Am J Obstet Gynecol 2018;218(2S):S829–S840. doi:10.1016/j.ajog.2017.11.565.
. Mastrolia SA, Mazor M, Holcberg G, et al. The physiologic anticoagulant and anti-inflammatory role of heparins and their utility in the prevention of pregnancy complications. Thromb Haemost 2015;113(6):1236–1246. doi:10.1160/TH14-10-0848.
. Mastrolia SA, Novack L, Thachil J, et al. LMWH in the prevention of preeclampsia and fetal growth restriction in women without thrombophilia. A systematic review and meta-analysis. Thromb Haemost 2016;116(5):868–878. doi:10.1160/TH16-02-0169.
. Kingdom JC, Audette MC, Hobson SR, et al. A placenta clinic approach to the diagnosis and management of fetal growth restriction. Am J Obstet Gynecol 2018;218(2S):S803–S817. doi:10.1016/j.ajog.2017.11.575.