Maternal and neonatal outcomes of pregnancies of infertile women during the COVID-19 pandemic: a real world evidence

Objective The COVID-19 pandemic began in Dec. 2019 and its effects on pregnancy outcomes are still unknown. This study aimed to evaluate the pregnancy outcomes of infertile women who conceived during the COVID-19 pandemic. Methods This cross-sectional study included infertile women who conceived during the COVID-19 pandemic. Infertile women referred to the infertility center at the Vali-e-Asr hospital who conceived spontaneously or with the aid of ART (IUI, ICSI) were included and followed until delivery or pregnancy termination. Results A total of 38 pregnant women (34 conceiving after ART and four spontaneously) were included. Seventeen (44.74%) of the 38 pregnant women developed COVID-19 symptoms. No significant difference was detected in maternal and neonatal outcomes, including miscarriage, PROM, low birth weight, or premature birth between pregnancies with and without COVID-19 symptoms. A significant difference was found between the two groups in delivery route. Conclusions No associations were found with maternal and neonatal morbidity in women conceiving during the COVID-19 pandemic and in pregnant women with and without COVID-19 symptoms.


INTRODUCTION
Coronavirus Disease 2019  is an emergent widely disseminated condition (Yang et al., 2020). After reports of increasing numbers of individuals with COVID-19 and deaths within a short period of time in numerous countries, the WHO declared COVID-19 a pandemic on March 11, 2020 (Monteleone et al., 2020). COVID-19 is a fast transmitting infection (The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020) that presents with symptoms ranging from common cold to severe acute respiratory distress syndrome  A critical measure taken to manage any communicable disease is providing care to susceptible persons (Alfaraj et al., 2019;Wong et al., 2004). Cardiorespiratory and immune changes in pregnancy increase susceptibility of this population to severe infection and hypoxia (Guan et al., 2020), in addition to changing the hormonal milieu, especially in early pregnancy as a result of adaptive changes to fetal antigens, and influencing immune response to viral infection, an important element due to fetal organ development (Littauer et al., 2017;Wong et al., 2004).
Recent data showed that pregnant women diagnosed with COVID-19 have similar symptoms and clinical characteristics than their non-pregnant counterparts; no cases of vertical transmission in late pregnancy have been confirmed (Monteleone et al., 2020). There is no data available today on COVID-19 and obstetric complication during the first trimester of pregnancy (Monteleone et al., 2020). Fetal complications from COVID-19 include miscarriage (2%), IUGR (10%), and preterm birth (39%). There is no data on perinatal outcomes when infection strikes during early pregnancy (Chen et al., 2020a).
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 as a cell receptor and expression of RNA; ACE2 levels in the placenta between weeks 6 and 14 of pregnancy are low, therefore transmission of SARS-CoV-2 from the mother to the fetus in the first trimester seem unlikely, although severe maternal respiratory failure and disturbed placenta flow may cause miscarriage (Lamouroux et al., 2020). More definitive evidence is needed to counsel mothers about the risk of congenital anomalies from SARS-CoV-2 infection (Lamouroux et al., 2020).
This study aimed to evaluate pregnancy and neonatal outcomes and morbidity in infertile women who conceived during the COVID-19 pandemic, spontaneously or with the aid of ART, to identify potential impacts of COVID-19 on pregnancy, especially in the first trimester.

MATERIALS AND METHODS
This cross-sectional study included infertile women who conceived during the COVID-19 pandemic. Women with a history of infertility referred to the Vali-e-Asr hospital infertility center for treatment, who conceived spontaneously or by ART (Intrauterine insemination (IUI), Intracytoplasmic sperm injection (ICSI)), were included in this study after confirmation of clinical pregnancy by observation of a gestational sac in ultrasound examination. Patients with chemical pregnancies (positive ß-hcG) without a gestational sac or fetal heart beats in ultrasound examination were excluded from the study.
All patients signed informed consent terms before enrollment and the Ethics Committee at the Vali-e-Asr Reproductive Health Research center approved the study protocol. Pregnancy and neonatal outcomes and morbidity of eligible women were evaluated via questionnaires and telephone interviews. Patients were also asked about the presence of COVID-19 symptoms during pregnancy.
Primary endpoints included pregnancy morbidities such as preeclampsia, IUGR (intrauterine growth retardation), PTL (preterm labor), miscarriage, and PROM (premature rupture of membranes), as well as fetal anomalies in patients with and without COVID-19 symptoms during pregnancy. Secondary endpoints were gestational diabetes, neonatal morbidity, and postpartum complications, which were compared between women with and without COVID-19 symptoms.
PCR testing for COVID-19 was performed in two neonates due to screening and all were negative. None of the neonates presented COVID-19 symptoms, although four mothers experienced COVID-19 symptoms in the third trimester, five in the second trimester, eight in the first trimester, and two in the first week postpartum.
There was no significant difference in maternal and neonatal outcomes, including miscarriage, PROM, low birth weight, and premature birth, between pregnancies with and without COVID-19 symptoms. A significant difference was found between the two groups in delivery route, in that all pregnant women with COVID-19 symptoms had C-sections (p: 0.03).
Comparison of singleton and twin pregnancies found that women with twin pregnancies had significantly more deliveries at gestational ages of less than 37 weeks (75% in twin vs. 16.7% in singleton pregnancies, p=0.04). PROM was also significantly more frequent in twin than in singleton pregnancies (50% in twin vs. 0% in singleton pregnancies, p=0.02). No significant differences in delivery route or other maternal and neonatal complications including postpartum complications, diabetes, hypertension, as well as neonatal low birth weight, neonatal hospital admission, and anomalies were seen between singleton and twin pregnancies (p>0.05).
The comparison of pregnancy outcomes and maternal and fetal complications between IUI, ICSI, and spontaneous pregnancies showed that although all miscarriages occurred in ICSI pregnancies (5/34, 14.7%), the difference between groups was not significant (p=0.45). C-section was the delivery route in 91.7% of ICSI pregnancies, 14.3% of IUI pregnancies, and 50% of spontaneous pregnancies; the difference was statistically significant (p=0.047). Neonatal anomalies were more common in IUI pregnancies (40%) compared to ICSI (6.9%) and spontaneous pregnancies (0%); the difference was not significant by a thin margin (p=0.064). There was no significant difference in other maternal or neonatal outcomes and complications between the three groups of pregnancies (IUI, ICSI, and spontaneous) (p>0.05).

DISCUSSION
All five miscarriages reported in this study involved women submitted to ICSI without COVID-19 symptoms. Therefore, no significant relationship was identified between COVID-19 and abortion. One study reported a 2.5% spontaneous abortion rate among mothers with positive COVID-19 tests (Patanè et al., 2020). One meta-analysis reported two miscarriages in 324 pregnant women with COVID-19, but the study in question had no control group (Baud et al., 2020). Isolated case reports have suggested that late miscarriage may be a manifestation of COVID-19 (Baud et al., 2020;Hachem et al., 2020). We had a late miscarriage at 20 weeks of gestation, but the patient did not have COVID-19 symptoms. Prevalence of miscarriage in our study was similar or lower than other studies enrolling ICSI populations. Miscarriage rates of 16% and 14% have been reported in ICSI pregnancies (Ashrafi et al., 2014). Bahceci & Ulug (2005) reported a rate of 20% for first-trimester pregnancy losses.
Some case reports found increasing stillbirth rates in pregnant women tested positive for COVID-19 (Moore et al., 2016;Wang et al., 2020b). Maternal critical illness has been associated with fetal demise (Dotters-Katz & Hughes, 2020). An early report demonstrated concerns about stillbirth in patients with COVID-19 confirmed patients -6.9 vs. 1.19 per 1000 births (Khalil et al., 2020). In the present study, no stillbirths or neonatal deaths were observed. This may be due to the lack of critically ill patients in our study. Only one woman was hospitalized for COVID-19. She did not have severe disease and experienced mild liver enzyme increases. Her baby was born on week 37 of gestation. Our results are in line with a study that showed no fetal or neonatal deaths, but found a 50% incidence of preterm labor. However, the study in question did not differentiate between iatrogenic or spontaneous preterm labor (Ciobanu et al., 2020).
Another study found no difference in preeclampsia, gestational diabetes, or PROM between patients with and without COVID-19 (Yang et al., 2020). The authors found that COVID-19 did not increase the risk of preeclampsia or PROM (Yang et al., 2020). The impact of COVID-19 in preterm births has not been specifically described and the occurrence of IUGR in mothers with COVID-19 is unclear (Ciobanu et al., 2020). Evidence for preterm birth is not well documented (Dotters-Katz & Hughes, 2020). Similarly, our study showed no significant difference in maternal and neonatal outcomes between pregnancies with and without COVID-19 symptoms. However, the only significant difference between the two groups was in delivery route, in that all women with COVID-19 symptoms had C-sections.
Only one singleton preterm birth (< 34 weeks), involving a patient submitted to ICSI, was observed in our study, as described in other studies (Cavoretto et al., 2018). Similarly to another study (Zhu et al., 2016), three babies (8.8%) from singleton pregnancies had low birth weight (neonatal weight < 2500 g). A comparison between patients with and without COVID-19 symptoms revealed no significant differences in maternal and neonatal outcomes in the present study.
A case-control study found no significant differences in fetal and neonatal outcomes (fetal asphyxia, preterm birth, and fetal distress) between the two groups (Yang et al., 2020), as also seen in our study. In the present study, neonatal anomalies were detected in 10.5% of the newborns (2/5, 40% in the IUI and 2/29, 6.9% in the ICSI group), while in another study the prevalence of neonatal anomalies in women submitted to IVF, ICSI, and natural conception were 7.1% , 9.9%, and 5.7%, respectively (Davies et al., 2017). Prevalence of neonatal anomalies in mothers with and without COVID-19 symptoms was similar and no significant correlation was found between COVID-19 symptoms and neonatal anomalies. Nevertheless, the prevalence of neonatal anomalies was high in our study, possibly due the presence of COVID symptoms seen in 3 of 4 mothers with newborns with neonatal anomalies, two of which in the first trimester. This may suggest a correlation between COVID-19 and fetal anomaly. However, this assumption requires confirmation of infection through positive COVID-19 test results for all mothers of neonates with anomalies. In our study, only one of the three mothers in this group tested positive for COVID-19.
None of our neonates had COVID-19 symptoms or positive tests for the disease within 48 hours of birth, despite the presence of COVID-19 symptoms in four mothers in the third trimester and early postpartum. This result is in line with other studies that rejected vertical transmission of COVID-19 (Chen et al., 2020a;Karimi-Zarchi et al., 2020;Zhu et al., 2020). Prevalence of postpartum complication is shown in Table 1. The comparison of morbidities found no difference between patients with or without COVID-19 symptoms. In one study, the prevalence of postpartum complications such as postpartum hemorrhage in ICSI patients was 8.3% versus 2.9% in patients conceiving normally; the difference between singleton ART pregnancy and controls was 4.9% vs. 2.9%, and between twin ART pregnancy and controls was 11.5% vs. 4.5% (Zhu et al., 2016). In the present study, with the exception of delivery route, we found no significant differences in maternal and neonatal outcomes of pregnancy between the three study groups -IUI, ICSI, and spontaneous conception.
This study is the first to report the pregnancy outcomes of infertile women conceiving during the COVID-19 pandemic. As such, it might provide preliminary data about the impact of COVID-19 in early pregnancy and in the first trimester of pregnancy. The small sample size and the lack of confirmed COVID-19 test results for most of the women with COVID-19 symptoms were two limitations of the current study.
This study found no correlation between maternal and neonatal morbidity during pregnancy and in postpartum in women conceiving during the COVID-19 pandemic and in pregnant women with and without COVID-19 symptoms. Our results did not support the existence of vertical transmission of COVID-19. A higher rate of neonatal anomalies was observed in our study, thereby indicating a potential correlation between COVID-19 and neonatal anomalies; however, additional evidence is needed to confirm such correlation.