Ovine surgical model of uterine space restriction: interactive effects of uterine anomalies and multifetal gestations on fetal and placental growth

Abstract

Intrauterine growth restriction (IUGR) is observed in conditions with limitations in uterine space (e.g., uterine anomalies and multifetal gestations). IUGR is associated with reduced fetal weight, organ growth, and a spectrum of adult-onset diseases. To examine the interaction of uterine anomalies and multifetal gestations, we developed a surgical uterine space restriction model with a unilateral uterine horn ligation before breeding (unilateral surgery). Placentas and fetuses were studied on Gestational Day (GD) 120 and GD 130 (term = 147 days). Unilateral surgery decreased placentome numbers in singleton and twin pregnancies (25% and 50%, respectively) but not unilateral triplets. Unilateral surgery decreased total placentome weight in twin pregnancies (decreased 24%). Fetuses categorized as uterine space restricted (unilateral twin and both groups of triplets) had 51% fewer placentomes per fetus and a 31% reduction in placentomal weight per fetus compared to the nonrestricted group (control singleton, unilateral singleton, and control twin). By GD 130, uterine space-restricted fetuses exhibited decreased weight, smaller crown-rump, abdominal girth, and thoracic girth as well as decreased fetal heart, kidney, liver, spleen, and thymus weights. Lung and brain weights were unaffected, demonstrating asymmetric IUGR. At GD 130, placental efficiency (fetal weight per total placentomal weight) was elevated in uterine space-restricted fetuses. However, fetal arterial creatinine, blood urea nitrogen, and cholesterol were elevated, suggesting insufficient placental clearance. Maternal-to-fetal glucose and triglycerides ratios were elevated in the uterine space-restricted pregnancies, suggesting placental nutrient transport insufficiency. This model allows for examination of interactive effects of uterine space restriction-induced IUGR on placental adaptation and fetal organ growth.

FIG. 1.

Diagram of the ovine surgical model of uterine space restriction. The figure shows an example of a control pregnant twin (left) and a unilateral pregnant surgical uterine anomaly (right) of a uterus containing two IUGR fetuses.

FIG. 2.

Placental measurements per ewe in control and unilateral pregnant sheep. A) total number of placentomes per ewe and (B) total placental weight per ewe in control singletons (C-1), unilateral singletons (U-1), control twins (C-2), unilateral twins (U-2), control triplets (C-3), unilateral triplets (U-3), and control quadruplets (C-4). Bars indicate means ± SEM. Individual data points are shown by circles. Means that do not share a common superscript letter are different (P < 0.05). * Indicates significance between key comparisons. NS = not significant.

FIG. 3.

Placental measurements per fetus in control and unilateral pregnant sheep. A) total number of placentomes per fetus and (B) total placentomal weight per fetus in control singletons (C-1), unilateral singletons (U-1), control twins (C-2), unilateral twins (U-2), control triplets (C-3), unilateral triplets (U-3), and control quadruplets (C-4). Bars indicate means ± SEM. Individual data points are shown by circles. Means that do not share a common superscript letter are different (P < 0.05). Based on these results, pregnancies were categorized as either nonrestricted (C-1, U-1, and C-2) or uterine space restricted (U-2, C-3, U-3, and C-4).

FIG. 4.

Fetal morphometric measurements in nonrestricted and uterine space-restricted pregnancies. A) fetal weight, (B) fetal crown-rump, (C) fetal body mass index (BMI), and (D) ponderal index (PI) at GD 120 and GD 130. Bars indicate means ± SEM. * Indicates a decrease in the restricted group vs. the nonrestricted group within a GD (P < 0.05); Ψ indicates a trend (0.05 < P < 0.1); # indicates an increase by GD (P < 0.05).

FIG. 5.

Fetal morphometric measurements in nonrestricted and uterine space-restricted pregnancies. A) fetal abdominal girth, (B) fetal thoracic girth, (C) fetal head length, and (D) fetal head width at GD 120 and GD 130. Bars indicate means ± SEM. * Indicates a decrease in the restricted group vs. the nonrestricted group within a GD (P < 0.05). # Indicates an increase by GD (P < 0.05).

FIG. 6.

Placental efficiency and blood chemistry changes in nonrestricted and uterine space-restricted pregnancies. A) Placental efficiency measured as fetal body weight per total placentomal weight (g/g). Blood chemistry in umbilical artery for (B) creatinine, (C) blood urea nitrogen (BUN), and (D) cholesterol and the ratios of umbilical vein to maternal artery for (E) glucose and (F) triglycerides at GD 120 and GD 130. Bars indicate means ± SEM. * Indicates a decrease in the restricted group vs. the nonrestricted group within a GD (P < 0.05). # Indicates an increase by GD (P < 0.05).