In total, 6,192 women delivered at PMH during the study period, and 29% were HIV-infected. There were 251 stillbirths; 105 (42%) were among HIV-infected women, 119 (47%) among HIV-uninfected women, and 27 (11%) among women with unknown HIV status. We enrolled 99 women with a confirmed HIV status (accounting for 40% of all women experiencing stillbirth during the study period). Demographic data for HIV-infected and HIV-uninfected women included in the study did not differ substantially from surveillance data collected among all women who delivered stillbirths in the study period (data not shown). Our cohort was enriched for HIV infection, and included 62 (62%) who were HIV-infected, and 37 (37%) who were HIV-uninfected. Maternal characteristics by HIV status are shown in . Among HIV-infected women, maternal demographics were similar for those on or off HAART, except only 1 non-citizen received HAART in pregnancy (p
Characteristics of Women Delivering Stillbirths, by HIV Status, Botswana.
Among the 62 HIV-infected women, 26 (42%) were receiving HAART at the time of the stillbirth (81% from prior to conception, and 19% started during pregnancy); 14 (23%) were receiving zidovudine (ZDV) alone from a median gestation of 28 weeks, and 22 (35%) had not received antiretrovirals. A nevirapine (NVP)-based regimen was reported for 24 (92%) of 26 who received HAART. The median CD4 cell count at the time of the stillbirth delivery was 377 (range 104, 1953) cells/mm3
for those receiving HAART and 353 (range 44, 937) cells/mm3
for those not receiving HAART (p
0.93). At delivery, median HIV RNA was <400 (range <400 to 22,339) copies/mL for women on HAART, and 8,630 (range <400, 714,000) copies/mL for women not receiving HAART (p<0.001).
Delivery characteristics and stillbirth characteristics are shown in . The median gestational age at the time of stillbirth delivery was 31 weeks for both HIV-infected and HIV-uninfected women. For HIV-infected women, delivery characteristics were similar by HAART status. Median gestational age at delivery was 30 weeks for those on HAART and 32 weeks for those not on HAART (p
0.23). Among the 62 HIV-infected women, 53 stillbirths (85%) had successful cardiac puncture for HIV PCR testing, and only 2 (3.7%) were HIV-infected. The first of these stillbirths occurred at 32 weeks' gestation, in a woman with HIV RNA of 31,400 copies/mL and CD4 cell count of 511 cells/mm3
, receiving ZDV for the previous 5 weeks. The second occurred at 31 weeks' gestation, in a woman with HIV RNA of 144,000 copies/mL and CD4 cell count of 44 cells/mm3
, receiving no antiretrovirals in pregnancy. Both had placental pathology indicative of infection (necrotizing funisitis). Neither woman had a reason identified for the stillbirth at the time of the event.
Characteristics of Deliveries, Stillbirths, and Placentas, by HIV Status, Botswana.
Placental pathology results are shown in , by maternal HIV status and antiretroviral exposure status. Placental insufficiency, with features strongly suggestive of chronic placental hypertensive damage, accounted for more than half of all stillbirths in both HIV infected and HIV-uninfected women. Among women with these pathologic findings, 11 were acute, 43 were chronic, and 4 were both acute and chronic. demonstrates a placenta with the typical features of acute and chronic hypertension. Of women with evidence of placental insufficiency, 71% had evidence of peripheral hypertension prior to delivery, as indicated by a blood pressure measurement ≥140 mm Hg systolic or ≥90 mm Hg diastolic, or by a recorded diagnosis of hypertension during pregnancy. Of these, 73% were noted to have started an antihypertensive agent prior to delivery. Only 2 women with placental insufficiency had no recorded blood pressure or hypertension diagnosis in pregnancy. Preeclampsia (with documented proteinuria and edema) was reported in 18% of women, and eclampsia in 3%, and these did not differ by HIV status. Compared with all other women, those with placental insufficiency were more likely to report headache in pregnancy (45% vs. 17%, p
0.003), to report puffy face in pregnancy (30% vs. 8%, p
0.008), to require an induction of labor for intrauterine fetal demise (57% vs. 21%, p
0.0005), and to report smaller than normal size of the stillborn (80% vs. 60%, p
Table 3 Placental Pathology Results, by HIV Status and ARV Exposure, Botswana.
Among HIV-infected women, placental insufficiency was more common among women who had received HAART than among those who had not received HAART (65% vs. 28%, p
0.003) (). Placental findings suggestive of acute hypertensive changes were not associated with HAART use; only 1 HIV-infected women with such findings received HAART. All but one women receiving HAART had a suppressed HIV RNA <400 copies/mL at delivery, so this variable could not be analyzed separately from HAART use itself. Similarly, only 5 women started HAART during pregnancy, so comparisons between HAART from conception vs. starting in pregnancy were limited. CD4 cell count was not associated with either acute or chronic placental insufficiency; however, median CD4 cell count at delivery was >350 cells/mm3
in both HAART-treated and untreated women.
Percentage of stillbirths caused by chronic placental insufficiency, by HIV status and HAART exposure, Botswana.
Among HIV-uninfected women, the percentage with placental insufficiency with features suggestive of chronic hypertensive damage was similar to the HAART-treated HIV-infected women (54% vs. 65%, p
0.37), and there were few women with acute placental insufficiency (8%). As with the HAART treated women, placental insufficiency was significantly more common than among HIV-infected women who were not
receiving HAART (54% vs. 28%, p
0.02) (). Female stillbirth gender was noted in 70% of HIV-uninfected women with placental insufficiency (p
0.005), although gender was equally balanced in HIV-infected women with placental insufficiency (49% female, p
Pathologic evidence of infection was identified in 21% of placentas from HIV-infected women, and in 22% of placentas from HIV-uninfected women (p
0.94). Among HIV-infected women, CD4 cell count, HIV RNA, or HAART use were not associated with placental infection. Fewer maternal delivery complications were reported among women with infection compared with other women (9% vs. 53%, p
0.0003), and more women with infection had ≥24 hours between membrane rupture and delivery (29% vs. 2%, p
0.0001). shows placental pathology typical for infection and other non-hypertensive causes. There were no placentas with evidence of cytomegalovirus (CMV) infection. Necrotizing funisitis was only seen in the two stillbirths that were HIV-infected by PCR testing.
Pathologic fetal findings and congenital abnormalities were more common among stillbirths of HIV-uninfected women (14% vs. 2%, p
0.02), and abnormalities included hydrops fetalis (1); hydrops fetalis with limb abnormalities (1); hydrops fetalis with hydrocephalus and multiple abnormalities (1); hydrocephalus (1); genito-urinary malformation (1); and rectal prolapse (1). Nuchal cord was described in 13% of deliveries, but placental pathology suggested an alternate underlying cause of the stillbirth for all but 2 of these deliveries.