Advertisement

Worse outcomes of pregnancy in COVID-19 infection during parturition may be due to referral bias: analysis in a prospective cohort of 963 pregnancies

Published:September 03, 2021DOI:https://doi.org/10.1016/j.ajog.2021.08.058

      Objective

      The initial studies of COVID-19 suggested that pregnant women have more severe infection with an increased risk of preterm birth, preterm rupture of membranes, and even maternal deaths.
      • Allotey J.
      • Stallings E.
      • Bonet M.
      • et al.
      Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
      Later studies and systematic reviews showed different results.
      • Wang C.L.
      • Liu Y.Y.
      • Wu C.H.
      • Wang C.Y.
      • Wang C.H.
      • Long C.Y.
      Impact of COVID-19 on pregnancy.
      When pregnant women were universally screened, severe disease rates mirrored those of the normal population.
      • Pettirosso E.
      • Giles M.
      • Cole S.
      • Rees M.
      COVID-19 and pregnancy: a review of clinical characteristics, obstetric outcomes and vertical transmission.
      Most studies on outcomes have not controlled for either preexisting maternal risk factors or those acquired during pregnancy.
      • Wang C.L.
      • Liu Y.Y.
      • Wu C.H.
      • Wang C.Y.
      • Wang C.H.
      • Long C.Y.
      Impact of COVID-19 on pregnancy.
      In addition, there is still a gray area in understanding how COVID-19 infection around the time of delivery affects pregnant women. Thus, we analyzed if the apparent high risk of severe COVID-19 in referral centers was confounded owing to other concomitant risk factors.

      Study Design

      In our cohort from a single tertiary referral hospital in India, all pregnant women coming for delivery or with labor pain were universally screened for SARS-CoV-2 infection using reverse transcriptase polymerase chain reaction performed on oronasopharyngeal samples. The patients who left the hospital before delivery were excluded. Of 963 pregnant women, 127 were COVID-19 positive. They were compared using tests for proportion in terms of maternal complications (cesarean deliveries, antepartum and postpartum hemorrhage, preterm and prelabor rupture of membrane, puerperal sepsis, and mortality) and neonatal outcomes (appearance, pulse, grimace, activity, and respiration scores; low birthweight; intensive care requirement; neonatal COVID-19 infection; neonatal sepsis; and death). The generalized linear models (GLMs) were then built to assess the contribution of various maternal risk factors and COVID-19 positivity on these outcomes.

      Results

      The age, gravida, parity, gestational diabetes, and pregnancy-induced hypertension (PIH) rates were similar between the COVID-19 positive and negative cohorts (Supplemental Table 1). The COVID-19 cohort had an overrepresentation of various other pregnancy risk factors (Table). Furthermore, the COVID-19 cohort had higher cesarean deliveries (87 [68%] vs 445 [53.3%] in the negative cohort; P=.02), higher postpartum hemorrhage (6 [4.7%] vs 1 [0.1%]; P<.001), and higher maternal mortality (2 [1.6%] vs 1 [0.1%]; P=.048) (Supplemental Table 2). Among neonatal outcomes, Apgar score was lower at 1 minute (mean [standard deviation], 7.20 (1.63) in COVID-19 vs 7.54 (1.69) in the controls; P=.035) and at 5 minutes (mean [standard deviation], 8.27 (1.72) in COVID-19 vs 9.14 (1.74) in controls; P<.001) (Supplemental Table 3). In the first GLM model on the mode of delivery, the significant predictors were previous cesarean deliveries, COVID-19 positivity, presence of PIH, and gestational diabetes (Supplemental Table 4). In the second GLM model, bad maternal outcomes were only associated with the presence of PIH (Supplemental Table 5). In the third GLM model, bad neonatal outcomes were associated with the presence of PIH or 1 of the 7 other factors for high-risk pregnancy (Supplemental Table 6). Thus, the associations found on univariate analysis reflect a possible referral bias where the high-risk patients were being referred if they were COVID-19 positive than if they were negative.
      TableComorbidities and pregnancy risk factors
      ConditionCOVID-19 (n=127)Controls (n=836)P value
      Prepregnancy comorbidity26 (20.3)159 (19.0).72
      Hypertensive disease of pregnancy9 (7.0)64 (7.7)>.99
      Gestational diabetes6 (4.7)32 (3.8).62
      Other pregnancy-related risk
       None799 (95.70)117 (91.40)NA
       Twin pregnancy7 (0.80)1 (0.80)<.01
      Significant
       Breech presentation10 (1.20)8 (6.30)<.01
      Significant
       Intrauterine growth restriction3 (0.40)1 (0.80)<.01
      Significant
       In-vitro fertilization2 (0.20)0.017
      Significant
       Rhesus-negative pregnancy8 (1.00)1 (0.80)<.001
      Highly significant.
       Thalassemia2 (0.20)0.017
      Significant
       Obstetrical cholestasis4 (0.5)0<.001
      Highly significant.
      Data are presented as number (percentage).
      Mohini. Outcomes of COVID-19 positive deliveries. Am J Obstet Gynecol 2022.
      a Significant
      b Highly significant.

      Conclusion

      This study reiterates that COVID-19 infection does not pose additional risk to pregnancy outcomes by itself. Earlier systematic reviews were hampered by the high heterogeneity of the reported cohorts.
      • Teles Abrao Trad A.
      • Ibirogba E.R.
      • Elrefaei A.
      • et al.
      Complications and outcomes of SARS-CoV-2 in pregnancy: where and what is the evidence?.
      This was compounded by duplicate reporting of the same patients in different cohorts, variable inclusion criteria of systematic reviews, and scarce and missing data.
      • Ang X.L.
      • Chonkar S.P.
      • Chua M.S.Q.
      • Sulaiman S.
      • Lee J.C.S.
      Problems with early systematic reviews: the case of coronavirus disease 2019 (COVID-19) in pregnancy.
      More recent systematic reviews have shown that maternal deaths and neonatal outcomes were similar in deliveries conducted in COVID-19 mothers compared with non–COVID-19 mothers.
      • Huntley B.J.F.
      • Mulder I.A.
      • Di Mascio D.
      • et al.
      Adverse pregnancy outcomes among individuals with and without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a systematic review and meta-analysis.
      The limitations of our study include the fact that we do not have the indications for cesarean deliveries in the cohort and that it was carried out in a tertiary center that would receive more complicated cases. It brings to light that COVID-19–positive mothers being treated at tertiary care centers have higher rates of cesarean delivery and higher morbidity and mortality, possibly owing to the extra underlying risk factors arising from a referral bias.

      Supplementary Materials

      Supplemental Table 1Demographics of the cohort
      CharacteristicCOVID-19 positive (n=127)COVID-19 negative (n=836)P value
      MeanStandard deviationMeanStandard deviation
      Age28.184.6427.714.23.29
      Gravida1.690.981.720.87.74
      Parity0.420.580.510.59.11
      Period of gestation at delivery36.943.1437.422.90.10
      Body mass index28.001.3328.121.35.34
      Mohini. Outcomes of COVID-19 positive deliveries. Am J Obstet Gynecol 2022.
      Supplemental Table 2Maternal outcomes (univariate analysis)
      OutcomeCOVID-19 (n=127)Controls (n=836)P value
      Cesarean delivery87 (68)445 (53.3).002
      Significant
      Maternal intensive care unit requirement3 (2.3)6 (0.7).10
      Antepartum hemorrhage015 (1.8).11
      Preterm premature rupture of membranes1 (0.8)35 (4.2).036
      Significant
      Preterm rupture of membranes2 (1.6)38 (4.6).08
      Postpartum hemorrhage6 (4.7)1 (0.1)<.001
      Highly significant.
      Puerperal sepsis00NA
      Maternal mortality2 (1.6)1 (0.1).048
      Significant
      Data are presented as number (percentage).
      Mohini. Outcomes of COVID-19 positive deliveries. Am J Obstet Gynecol 2022.
      a Significant
      b Highly significant.
      Supplemental Table 3Neonatal outcomes (univariate analysis)
      OutcomeCOVID-19 (n=127)Controls (n=836)P value
      Apgar score at 1 min, mean (SD)7.20 (1.63)7.54 (1.69).035
      Significant
      Apgar score at 5 min, mean (SD)8.27 (1.72)9.14 (1.74)<.001
      Highly significant.
      Low birthweight <2 kg16 (17.4)127 (24.1).19
      Neonatal intensive care unit requirement28 (21.9)206 (24.7).58
      Neonatal COVID-19 positivity5 (3.9)0<.001
      Highly significant.
      Neonatal sepsis02 (0.2).75
      Neonatal death2 (1.6)14 (1.7).64
      Data are presented as number (percentage) unless stated otherwise.
      SD, standard deviation.
      Mohini. Outcomes of COVID-19 positive deliveries. Am J Obstet Gynecol 2022.
      a Significant
      b Highly significant.
      Supplemental Table 4Generalized linear model for mode of delivery
      ParameterBStandard errorWald chi-squareP value
      (Intercept)−2.6252.01601.696.193
      Previous lower segment cesarean delivery−2.590.281984.436<.001
      Significant.
      (COVID-19 status=negative) vs (COVID-19 status=positive).655.21968.909.003
      Significant.
      (Hypertensive disease of pregnancy=no) vs (hypertensive disease of pregnancy=yes)1.330.330716.173<.001
      Significant.
      (Gestational diabetes=no) vs (gestational diabetes=yes)1.184.42487.771.005
      Significant.
      (Other risk factor=no) vs (other risk factor=yes).607.34123.167.075
      Body mass index−.002.0535.002.965
      Hemoglobin.050.0812.377.539
      Gravida−.068.1277.284.594
      Parity.120.2087.332.564
      Period of gestation at delivery−.032.02321.883.170
      Mohini. Outcomes of COVID-19 positive deliveries. Am J Obstet Gynecol 2022.
      a Significant.
      Supplemental Table 5Generalized linear model for maternal complications
      ParameterBStandard errorWald chi-squareP value
      (Intercept).2372.8844.007.935
      Previous lower segment cesarean delivery.472.30102.456.117
      (COVID-19 status=negative) vs (COVID-19 status=positive)−.204.3296.381.537
      (Hypertensive disease of pregnancy=no) vs (hypertensive disease of pregnancy=yes).971.31579.464.002
      Highly significant.
      (Gestational diabetes=no) vs (gestational diabetes=yes).502.47111.135.287
      (Other risk factor=no) vs (other risk factor=yes).586.39292.228.136
      Body mass index−.011.0797.020.888
      Hemoglobin.171.11332.275.131
      Gravida−.055.1804.093.760
      Parity−.229.2953.602.438
      Period of gestation at delivery−.033.0355.864.353
      Mohini. Outcomes of COVID-19 positive deliveries. Am J Obstet Gynecol 2022.
      a Highly significant.
      Supplemental Table 6Generalized linear model for poor neonatal outcomes
      ParameterBStandard errorWald chi-squareP value
      (Intercept)−2.8362.02161.967.161
      Previous lower segment cesarean delivery.335.19402.984.084
      (COVID-19 status=negative) vs (COVID-19 status=positive)−.298.22861.695.193
      (Hypertensive disease of pregnancy=no) vs (hypertensive disease of pregnancy=yes)1.129.253319.850<.001
      Significant.
      (Gestational diabetes=no) vs (gestational diabetes=yes).290.3614.642.423
      (Other risk factor=no) vs (other risk factor=yes).730.32195.145.023
      Significant.
      Body mass index.115.05484.383.036
      Hemoglobin−.054.0836.416.519
      Gravida−.124.12211.034.309
      Parity.070.2070.114.735
      Period of gestation at delivery−.013.0239.308.579
      Mohini. Outcomes of COVID-19 positive deliveries. Am J Obstet Gynecol 2022.
      a Significant.

      References

        • Allotey J.
        • Stallings E.
        • Bonet M.
        • et al.
        Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
        BMJ. 2020; 370: m3320
        • Wang C.L.
        • Liu Y.Y.
        • Wu C.H.
        • Wang C.Y.
        • Wang C.H.
        • Long C.Y.
        Impact of COVID-19 on pregnancy.
        Int J Med Sci. 2021; 18: 763-767
        • Pettirosso E.
        • Giles M.
        • Cole S.
        • Rees M.
        COVID-19 and pregnancy: a review of clinical characteristics, obstetric outcomes and vertical transmission.
        Aust N Z J Obstet Gynaecol. 2020; 60: 640-659
        • Teles Abrao Trad A.
        • Ibirogba E.R.
        • Elrefaei A.
        • et al.
        Complications and outcomes of SARS-CoV-2 in pregnancy: where and what is the evidence?.
        Hypertens Pregnancy. 2020; 39: 361-369
        • Ang X.L.
        • Chonkar S.P.
        • Chua M.S.Q.
        • Sulaiman S.
        • Lee J.C.S.
        Problems with early systematic reviews: the case of coronavirus disease 2019 (COVID-19) in pregnancy.
        Matern Child Health J. 2021; 25: 38-41
        • Huntley B.J.F.
        • Mulder I.A.
        • Di Mascio D.
        • et al.
        Adverse pregnancy outcomes among individuals with and without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a systematic review and meta-analysis.
        Obstet Gynecol. 2021; 137: 585-596